Fluid biomarker

Abstract

Disclosed herein are methods of diagnosing, selecting, monitoring, and treating subjects having, suspected of having, or at risk for developing Alzheimer's disease (AD).

Description

[0001] FLUID BIOMARKER

[0002] RELATED APPLICATIONS

[0003] [1] This Application claims the benefit of and priority to US Provisional Patent Application Nos. 63 / 670,673, filed July 12, 2024, and 63 / 763,784, filed February 26, 2025.

[0004] SEQUENCE LISTING

[0005] [2] The instant application contains a Sequence Listing which has been submitted electronically in ST.26 XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on July 9, 2025, is named "08061_0070-00304_SL.xml" and is 34,440 bytes in size.

[0006] FIELD

[0007] [3] Described herein are methods for diagnosing, selecting patients for treatment, monitoring, and treating Alzheimer’s disease (AD) in a subject, relating to measurements of various peptides from the microtubule-binding region of tau containing the residue 243 (MTBR-tau243), based on determining levels of the peptides in biofluid samples from a subject. MTBR-tau243 levels may be used for different aspects of treating AD, such as selecting a subject for treatment, treating AD and symptoms associated with AD, monitoring and / or adjusting the treatment, and determining maintenance dosing regimens for subjects.

[0008] BACKGROUND

[0009] [4] Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder of uncertain etiology and the most common form of dementia among older people. In 2006, there were 26.6 million cases of AD in the world (range: 11.4-59.4 million) (Brookmeyer, R., et al.. Forecasting the global burden of Alzheimer’s Disease. Alzheimer Dement. 2007; 3: 186-91), while there were more than 5 million people in the United States reportedly living with AD (Alzheimer’s Association, Alzheimer’s Association report, 2010 Alzheimer’s disease facts and figures. Alzheimer Dement. 2010;6: 158-94). By the year 2050, the worldwide prevalence of AD is predicted to grow to 106.8 million (range: 47.2-221.2 million), while in the United States alone the prevalence is estimated to be 11 to 16 million. (Brookmeyer, supra, and 2010 Alzheimer’s disease facts and figures, supra).

[0010] [5] The disease generally involves a global decline of cognitive function that progresses slowly and leaves end-stage subjects bedridden. AD subjects typically survive for only 3 to 10 years after symptom onset, although extremes of 2 and 20 years are known. (Hebert, L.E., et aL, Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol. 2003; 60: 1119-1122.) AD is the seventh leading cause of all deaths in the United States and the fifth leading cause of death in Americans older than the age of 65 years, despite the fact that mortality due to AD is greatly underestimated because death certificates rarely attribute the cause of death to AD. (Alzheimer’s Association.

[0011] Alzheimer’s Association report. 2010 Alzheimer’s disease facts and figures. Alzheimer Dement. 2010; 6: 158-94.)

[0012] [6] AD represents a significant economic burden across industrialized countries with a substantial impact on healthcare systems and the public purse as well as on subjects and their families. In the United States alone, total payments for 2010 were estimated at $172 billion, including $123 billion for Medicare and Medicaid.

[0013] [7] Histologically, the disease is characterized by the presence of extracellular neuritic plaques, which primarily consist of amyloid beta (AP), as well as the presence of intracellular tangles, which primarily consist of aggregated, insoluble tau species. Both Ap and tau exists in various conformational states - Ap in monomers, oligomers, protofibrils, and insoluble fibrils and tau in neurofibrillary tangles (NFTs) in neuronal somata, neuropil threads (NTs) in neuronal dendrites, and also neuritic plaques (NPs). These pathological forms of Ap and tau accumulate in the brain of AD patients and are believed to interact, for example, with Ap acting as a molecular trigger for events leading to tau aggregation, or possibly in a synergistic manner in which pathological forms of Ap and tau enhance the function of one another (Busche and Hyman, Nature Neuroscience, 2020: 23, 1183-1193). Ap plaques may be present decades before any cognitive symptoms are detected, while tau accumulation, starting in the medial temporal lobe after around 60 years of age, spreads to limbic and association areas in concert with the emergence of clinical symptoms.

[0014] [8] Details of the exact mechanistic relationship between onset of Alzheimer’s disease, Ap, and tau are poorly understood. However, as key components of AD pathology, both Ap and tau have been targeted as treatments are developed for AD. Currently, anti-Ap antibodies and anti-tau antibodies are undergoing clinical studies as potential therapeutic agents for Alzheimer’s disease.

[0015] [9] Despite the recent development of treatments for AD, including those targeting Ap and tau, there remains a need for better monitoring of treatments, including non-invasive assays to evaluate treatment efficacy and to calibrate treatment regimens in subjects. Currently, disease monitoring is largely dependent upon assays such as positron emission tomography (PET), in which amyloid plaques or tau tangles are bound to radiotracers and imaged. However, PET is an expensive procedure that requires complex equipment and expert analysis, and the process can increase the risk of complications to the subject.

[0016]

[0010] There remains a need in the art for minimally invasive methods of diagnosing AD in subjects, determining the stage of AD and prognosis, selecting subjects for treatment, and monitoring efficacy of treatments for AD. Methods based on biomarkers found in biofluids such as cerebrospinal fluid (CSF) and blood offer promise, particularly where biomarkers track with progression of AD, as well as changes in amyloid and / or tau pathology which are mediated by treatments. However, a need remains to identify improved markers, including those that can correlate with effects on amyloid and tau in the brain.

[0017] SUMMARY

[0018]

[0011] An aspect of the present disclosure relates to a method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the MTBR- tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and / or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti- Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0019]

[0012] In some embodiments, the method further comprises in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; and in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a p-tau217 concentration in a control sample, or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

[0020]

[0013] In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is elevated as compared to the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration is comparable to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject.

[0021]

[0014] In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject, wherein the further therapeutically effective dose of the anti-Ap protofibril antibody is administered according to a maintenance dosing regimen.

[0022]

[0015] An aspect of the present disclosure relates to a method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0023]

[0016] In some embodiments, the method further comprises in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), selecting the subject for treatment if the p-tau217 concentration is elevated compared to a p- tau217 concentration in the control sample or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

[0024]

[0017] An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and / or if the first MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD; and c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, wherein a decrease in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration, and / or a rate of increase from the first MTBR-tau243 concentration to the first MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0025]

[0018] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample from the subject; in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the first p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample; and in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample, wherein a decrease in the second p-tau217 concentration as compared to the first p- tau217 concentration or a decrease in the rate of increase from the first p-tau217 concentration to the second p-tau217 concentration as compared to the rate of increase in the positive control indicates a reduction in tau tangles.

[0019] An aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the MTBR-tau243 concentration to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and / or comparing the MTBR- tau243 concentration to a positive control, e.g., a MTBR-tau243 concentration in an individual who has AD; and c) adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody if the MTBR-tau243 concentration differs from the control sample or if the MTBR-tau243 concentration differs from the positive control sample, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0026]

[0020] In some embodiments, the method further comprises in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the control sample and / or comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample; and in step c), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody, if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the control sample or if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample.

[0027]

[0021] In some embodiments, the control is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[0022] In some embodiments, wherein the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[0028]

[0023] An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second MTBR-tau243 concentration as compared to first MTBR- tau243 concentration is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0029]

[0024] In some embodiments, a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates an effective treatment.

[0030]

[0025] In some embodiments, a lack of a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control, indicates a non-effective treatment.

[0031]

[0026] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration is an indicator of treatment efficacy.

[0032]

[0027] In some embodiments, a decrease from the first p-tau217 concentration to the second p-tau217 concentration, or reduction in a rate of increase from the first p-tau217 concentration to the second p-tau217 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first p-tau217 to a second tau217 concentration in an individual who has AD and is not treated, indicates an effective treatment.

[0033]

[0028] In some embodiments, a lack of a decrease from the first p-tau217 concentration to the second p-tau217 concentration and from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in a rate of increase between the first and second p-tau217 concentrations and MTBR-tau243 concentrations, as compared to rates in a placebo control, indicates a non-effective treatment.

[0034]

[0029] An aspect of the present disclosure relates to a method of detecting a decrease in a brain Ap level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0035]

[0030] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration indicates a decrease of the brain Ap level in the subject.

[0036]

[0031] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease in the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, or a reduction in a rate of increase between the first and second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0037]

[0032] In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change from the first p-tau217 concentration to the second p-tau217 concentration indicates a decrease of the brain tau level in the subject.

[0038]

[0033] In some embodiments, a decrease in a brain tau level is a reduction in tau tangles.

[0039]

[0034] In some embodiments, the treatment with the anti-Ap protofibril antibody comprises administration of a therapeutically effective dose of the anti-Ap protofibril antibody according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen.

[0040]

[0035] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

[0041]

[0036] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of p-tau217 and a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject are at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

[0042]

[0037] In some embodiments, the subject is switched to a maintenance dosing regimen when at least one of: a decrease in amyloid or tau positron emission tomography (PET); an increase in cerebrospinal fluid level of Ap42 and / or AP42 / 40 ratio; a decrease in cerebrospinal fluid level of total tau, cerebrospinal fluid level of neurogranin, and / or cerebrospinal fluid level of neurofilament light peptide (NfL); and a change in blood biomarkers as measured in the serum or plasma (e.g. increased levels of Ap42 and / or AP42 / 40 ratio; decreased plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np- tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light (NfL)) is detected in a sample from the subject as compared to a control disease sample, e.g., a sample from an individual who has AD.

[0043]

[0038] In some embodiments, the subject is switched to a maintenance dosing regimen when a decrease in tau PET SUVr is measured in the subject as compared to control sample, e.g., a sample from an individual who has AD.

[0044]

[0039] In some embodiments, the subject is switched to a maintenance dosing regimen when a low tau PET level as measured by PET SUVr is detected in the subject, e.g., a tau PET SUVr of about 1.1, preferably about 1.06, as measured with a MK6240 PET scan, e.g., of whole cortical gray matter.

[0045]

[0040] In some embodiments, the maintenance dosing regimen comprises administering a maintenance dose that maintains a tau PET SUVr level at or below 1.06.

[0046]

[0041] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

[0047]

[0042] In some embodiments, the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody.

[0043] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject.

[0048]

[0044] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

[0049]

[0045] In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg / kg relative to the weight of the subject.

[0050]

[0046] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

[0051]

[0047] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[0052]

[0048] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[0053]

[0049] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[0054]

[0050] In some embodiments, at least one of the initiation dosing regimen and the maintenance dosing regimen further comprises administration of a therapeutically effective dose of an anti-tau antibody, e.g., E2814, sequentially or simultaneously with administration of the anti-Ap protofibril antibody.

[0055]

[0051] In some embodiments, the anti-tau antibody is E2814.

[0056]

[0052] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

[0057]

[0053] In some embodiments, the method comprises intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., (e.g., 1500, 3000, 4500 mg).

[0058]

[0054] In some embodiments, the anti-tau antibody is administered prior to the first administration of the anti-Ap protofibril antibody, optionally wherein the subject has pre- AD (e.g., is asymptomatic for AD).

[0055] In some embodiments, the anti-Ap antibody is administered prior to the first administration of the anti-tau antibody, optionally wherein the subject has AD (e.g., early AD).

[0059]

[0056] In some embodiments, the MTBR-tau243 concentration is quantified by LC / MS.

[0060]

[0057] In some embodiments, the biofluid sample is CSF.

[0061]

[0058] In some embodiments, the biofluid sample is blood.

[0062]

[0059] In some embodiments, the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment.

[0063]

[0060] In some embodiments, the change and / or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0064]

[0061] In some embodiments, the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology during and / or after treatment.

[0065]

[0062] In some embodiments, the change and / or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0066]

[0063] In some embodiments, the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

[0067]

[0064] In some embodiments, the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR- SB; or e) delays clinical decline as measured by an ADAS-Cog.

[0068]

[0065] In some embodiments, the method further comprises monitoring for ARIA, e.g., ARIA-E and / or ARIA-H, e g., as observed by MRI.

[0069]

[0066] In some embodiments, the subject has a genetic mutation for a dominantly inherited

[0070] Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

[0071]

[0067] In some embodiments, the subject has a mutation in APP.

[0072]

[0068] In some embodiments, the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

[0073]

[0069] In some embodiments, the subject is ApoE4-positive.

[0074]

[0070] In some embodiments, the subject is 65 to 80 years old.

[0075]

[0071] In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

[0076]

[0072] In some embodiments, the subject is amyloid positive.

[0077]

[0073] In some embodiments, the subject is amyloid positive based on a PET assessment, a CSF assessment of AP(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), a CSF assessment of the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and / or a blood biomarker assessment (e.g. a plasma Api-42 / 1- 40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), and / or the plasma ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231)).

[0078]

[0074] In some embodiments, the subject has Alzheimer’s disease.

[0079]

[0075] In some embodiments, the subject has early Alzheimer’s disease.

[0076] In some embodiments, the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and / or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

[0080]

[0077] In some embodiments, the subject is suspected of having AD.

[0081]

[0078] In some embodiments, the subject is a subject at risk for developing AD.

[0082]

[0079] In some embodiments, the subject is at risk for developing AD has pre-Alzheimer’ s disease (pre- AD).

[0083]

[0080] In some embodiments, the subject does not have cognitive impairment.

[0084]

[0081] In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0085]

[0082] In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0086]

[0083] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[0087]

[0084] In some embodiments, the anti-tau antibody is E2814.

[0088]

[0085] In some embodiments, the MTBR-tau243 is MTBR-tau243-254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

[0089]

[0086] In some embodiments, the MTBR-tau243 is MTBR-tau243-254.

[0090]

[0087] In some embodiments, the MTBR-tau243 is MTBR-tau243-256.

[0091]

[0088] In some embodiments, the MTBR-tau243 MTBR-tau243-256 (deamidation on 255N).

[0092]

[0089] An aspect of the present disclosure relates to a method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration and / or the first MTBR-tau243 concentration are elevated compared to a first control sample, e.g., a sample from an individual who does not have AD;c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p- tau217 concentration and the second MTBR-tau243 concentration are elevated compared to the first p-tau217 concentration and the second MTBR-tau243 concentration, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0093]

[0090] An aspect of the present disclosure relates to a method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having AD, or at risk for developing AD, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., a p-tau217 concentration in an individual who does not have AD; c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have AD; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0094]

[0091] In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0095]

[0092] In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0096]

[0093] An aspect of the present disclosure relates to a method of selecting a subject having, suspected of having, or at risk for developing AD for treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the first p-tau217 concentration and / or the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0097]

[0094] An aspect of the present disclosure relates to a method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0098]

[0095] In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample; and in step b), selecting the subject for the first treatment with the anti-Ap protofibril antibody if the p- tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0099]

[0096] In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step d), selecting the subject for a second treatment with the anti-tau antibody if the second p- tau217 concentration and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0100]

[0097] An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first p-tau217 concentration and a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the first p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD; e) optionally obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the third p-tau217 concentration as compared to the second p-tau217 concentration and in the third MTBR-tau243 concentration as compared to the second MTBR-tau243 concentration, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0101]

[0098] An aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p- tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); e) obtaining a measurement of a second MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the second MTBR-tau243 concentration after the second treatment as compared to the MTBR-tau243 concentration after the first treatment, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0102]

[0099] In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0103]

[0100] In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0104]

[0101] In some embodiments, the first control sample and / or the second control sample are obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[0105]

[0102] In some embodiments, the second control sample is obtained from the subject after the first treatment and prior to the second treatment.

[0106]

[0103] An aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the first p-tau217 concentration and the first MTBR-tau243 to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) adjusting the treatment regimen to further administer a therapeutically effective amount of an anti-tau antibody if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample, ptionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

[0107]

[0104] In some embodiments, the method further comprises: d) obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject; e) comparing the third p-tau217 concentration and the third MTBR-tau243 concentration to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); and f), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody and / or the anti-tau antibody, if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

[0108]

[0105] In some embodiments, the control sample is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[0109]

[0106] In some embodiments, the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[0110]

[0107] An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second p- tau217 concentration and a change in the second MTBR-tau243 concentration, as compared to the first p-tau217 concentration and the first MTBR-tau243 concentration, is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0111]

[0108] In some embodiments, a decrease or reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and / or in the second MTBR- tau243 concentration as compared to the first MTBR-tau243 concentration indicates an effective treatment.

[0112]

[0109] In some embodiments, a lack of a decrease or lack of a reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and / or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a non-effective treatment.

[0113] [HO] An aspect of the present disclosure relates to a method of detecting a decrease in a brain Ap level in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p- tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p-tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0114] [Hl] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p-tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0115]

[0112] In some embodiments, a decrease in a brain tau level is a reduction in tau tangles.

[0116]

[0113] In some embodiments, the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen if the subject receives treatment with an anti -tau antibody.

[0117]

[0114] In some embodiments, the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen of the anti-Ap protofibril antibody.

[0118]

[0115] In some embodiments, the maintenance dosing regimen of the anti-Ap protofibril antibody is administered if a subject receives a treatment with an anti -tau antibody.

[0119]

[0116] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen of the anti-Ap protofibril antibody at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

[0117] In some embodiments, wherein the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody.

[0120]

[0118] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject.

[0121]

[0119] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

[0122]

[0120] In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg / kg relative to the weight of the subject.

[0123]

[0121] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

[0124]

[0122] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[0125]

[0123] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[0126]

[0124] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[0127]

[0125] In some embodiments, the second treatment comprises administration of a therapeutically effective dose of the anti-tau antibody E2814.

[0128]

[0126] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

[0129]

[0127] In some embodiments, the method comprises intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., (e.g., 500, 1000, 1500, 3000, or 4500 mg).

[0130]

[0128] In some embodiments, the MTBR-tau243 concentration is quantified by LC / MS.

[0131]

[0129] In some embodiments, the biofluid sample is CSF.

[0130] In some embodiments, the biofluid sample is blood.

[0132]

[0131] In some embodiments, the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment with the anti-Ap protofibril antibody.

[0133]

[0132] In some embodiments, the change and / or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0134]

[0133] In some embodiments, the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology during and / or after treatment with the anti -tau antibody.

[0135]

[0134] In some embodiments, the change and / or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0135] In some embodiments, the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

[0136]

[0136] In some embodiments, the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR- SB; or e) delays clinical decline as measured by an ADAS-Cog.

[0137]

[0137] In some embodiments, the method further comprises monitoring for ARIA, e.g., ARIA-E and / or ARIA-H, e g., as observed by MRI.

[0138]

[0138] In some embodiments, the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

[0139]

[0139] In some embodiments, the subject has a mutation in APP.

[0140]

[0140] In some embodiments, the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

[0141]

[0141] In some embodiments, the subject is ApoE4-positive.

[0142]

[0142] In some embodiments, the subject is 65 to 80 years old.

[0143]

[0143] In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

[0144]

[0144] In some embodiments, the subject is amyloid positive.

[0145]

[0145] In some embodiments, the subject is amyloid positive based on a PET assessment, a CSF assessment of AP(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), a CSF assessment of the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and / or a blood biomarker assessment (e.g. a plasma Api-42 / 1- 40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), and / or the plasma ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231)).

[0146]

[0146] In some embodiments, the subject has Alzheimer’s disease.

[0147]

[0147] In some embodiments, the subject has early Alzheimer’s disease.

[0148]

[0148] In some embodiments, the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and / or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

[0149]

[0149] In some embodiments, the subject is suspected of having AD.

[0150]

[0150] In some embodiments, the subject is a subject at risk for developing AD.

[0151]

[0151] In some embodiments, the subject at risk for developing AD has pre- Alzheimer’ s disease (pre- AD).

[0152]

[0152] In some embodiments, the subject does not have cognitive impairment.

[0153]

[0153] In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0154]

[0154] In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0155]

[0155] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[0156]

[0156] In some embodiments, the anti-tau antibody is E2814.

[0157]

[0157] In some embodiments, the MTBR-tau243 is MTBR-tau243-254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

[0158]

[0158] In some embodiments, the MTBR-tau243 is MTBR-tau243-254.

[0159]

[0159] In some embodiments, the MTBR-tau243 is MTBR-tau243-256.

[0160]

[0160] In some embodiments, the MTBR-tau243 is MTBR-tau243-256 (deamidation on 255N).

[0161] BRIEF DESCRIPTION OF DRAWINGS

[0162]

[0161] Figure 1 shows effects of lecanemab on the rate of increase in CSF MTBR-tau243.

[0163]

[0162] Figure 2 shows effects of lecanemab on tau PET SUVr in 3 brain regions of interest.

[0163] Figure 3 shows an adjusted mean change from baseline (CFB) in CSF MTBR- tau243 over time, as determined in subjects who were categorized as having low tau PET levels or medium-high tau PET levels.

[0164]

[0164] Figure 4 show the result of a baseline correlation analysis of CSF MTBR-tau243, tau PET SUVr across brain regions of interest, and other fluid biomarkers assessed (CSF markers: ptaul81, total tau, neurogranin, NfL, Ap40 and Ap42; plasma markers: pTau217, pTaul81, AP42 / 40, NfL and GFAP).

[0165]

[0165] Figure 5 shows a correlation of CSF MTBR-tau243 with amyloid PET and tau PET SUVr.

[0166]

[0166] Figure 6 shows the association of brain amyloid and tau status with various biomarkers, indicated by the AUROC.

[0167]

[0167] Figure 7 shows the association of amyloid status (20 CL) with various biomarkers.

[0168]

[0168] Figure 8 shows the association of various biomarkers with tau progression.

[0169] DETAILED DESCRIPTION

[0170]

[0169] The presence of Ap and tau pathology in Alzheimer’s disease (AD) has led to the emergence of two hypotheses to explain the cause and progression of the disease. According to each hypothesis, one of the two pathologies emerges first and acts as a trigger for the other. For example, Ap aggregation may be observed before tau aggregation, and studies have identified molecular mechanisms by which Ap leads to aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). Conversely, tau tangles may be observed in the brains of patients with no Ap pathology, and tau pathology correlates more closely with AD severity and progression than Ap plaque load (Knox, StressMarq Biosciences Inc., 2022. stressmarq.com / amyloid-hvpothesis-vs-tau-hypothesis / ). Depending on the hypothesis, either Ap or tau may be targeted to treat AD.

[0171]

[0170] The “amyloid hypothesis” of AD proposes that amyloid P (AP) peptides play a central role in the pathogenesis of AD. Specifically, it is hypothesized that neurodegeneration in AD may be caused by deposition of Ap plaques in brain tissue due to an imbalance between Ap production and Ap clearance, leading to formation of neurofibrillary tangles containing tau protein. Ap peptides generally exist in a dynamic continuum of conformational states such that species tend to progress from monomeric Ap, to soluble Ap assemblies that include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally to insoluble fibrils (plaques) which accumulate in extracellular spaces. Targeting these soluble and insoluble Ap tangles and plaques may provide therapeutic benefit.

[0172]

[0171] A number of immunotherapies have been developed with the intent to reduce the amount of insoluble Ap fibrils deposited in the brain, and / or, to reduce formation of tau tangles. However, a simple correlation between the quantity and progressive accumulation of insoluble amyloid plaques and the clinical course of AD has not been determined. While therapeutic strategies continue to focus on removal of insoluble amyloid plaques, an additional approach to therapy may include reducing the toxic Ap aggregates, such as protofibrils, that may contribute to the neuronal degeneration characteristic of AD. (See, e.g., Dodort, J.-C. and May, P., “Overview on rodent models of Alzheimer’s disease.” Curr. Protocols Neurosci. 2005; 9.22-1-9.22-6; Englund, H. et al., “Sensitive ELISA detection of amyloid-P protofibrils in biological samples.” J. Neurochem. 2007; 103:334-45; and Gotz, J. et al., “Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy.” Mol. Psychiat. 2004; 9:664-83.)

[0173]

[0172] In addition to Ap toxicity, tau protein pathology is a major hallmark of AD. Tau proteins belong to the family of microtubule-associated proteins (MAPs) that normally function to promote assembly and stability of microtubules. Changes in tau, such as hyperphosphorylation, affect its ability to bind microtubules and perform physiological functions, eventually leading to pathologies associated with AD. The “tau hypothesis” of AD proposes that accumulation of pathogenic misfolded tau proteins leads to the formation of neurofibrillary tangles (NFTs) inside neurons. NFTs correlate strongly with mitochrondial dysfunction, inflammation, synaptic loss, and neurodegeneration in affected neurons. In addition, pathological tau “seeds” of misfolded tau proteins, as well as fibrillar tau species, are believed to spread between neurons, possibly through direct anatomical connections, and across brain regions (Zhang et al., Front. Cell Dev. Biol., 2021, Sec. Molecular and Cellular Pathology, Volume 9). Evidence of tau spreading has been reported in animal studies, and circumstantial evidence has been found in post-mortem human brains from AD patients, analyses of tau PET signals in human brains at disease stages across the AD continuum, and simulations (Schoonhaven et al., Brain. 2023; 146(10): 4040-4054; Vogel et al., Nat Commun., 2020; 11, 2612). Brain regions where tau NFTs appear are affected by atrophy and hypometabolism, and the spatial distribution of tau NFTs over time tracks closely with clinical symptoms of AD (Koychev et al., Journal of Nuclear Medicine October 2020, 61 (10) 1413-1418).

[0173] Immunotherapies for targeting different forms of tau and reducing tau pathology have been developed. In clinical trials, various anti-tau antibodies have been used to target epitopes in each of the regions of tau (N-terminus, proline-rich domain, microtubule binding region, and C-terminus). Some antibodies are reported to facilitate tau clearance intracellularly, which may help to prevent tau toxicity mediated by oligomeric and soluble tau aggregates, while other antibodies are predicted to act on tau seeds extracellularly (Ji and Sigurdsson, Drugs. 2021; 81(10) 1135-1152). An exemplary anti-tau antibody, E2814, has been designed to target epitopes in the MTBR with the aim to prevent tau species from becoming seed competent (Roberts et al., Acta Neuropathol Commun. 2020; 8: 13) and WO2023079485A1, the contents of which are incorporated by reference herein.

[0174]

[0174] While immunotherapies for Ap and tau are an active area of research in both pre- clinical and clinical studies, the precise mechanisms by which any of these antibodies mediate their effects is not known. The relationship between Ap pathology, tau pathology, and clinical symptoms of AD is not clear. In one model, Ap pathology is upstream to tau in AD progression, and triggers or facilitates mechanisms leading to tau pathology, such as tau hyperphosphorylation and oligomerization (Hampel et al., Mol Psychiatry. 2021; 26, 5481— 5503; Zhang et al., Int J Biol Sci. 2021; 17(9): 2181-2192). According to this model, it may be possible to use certain anti-Ap antibodies to inhibit amyloid-induced tau phosphorylation in the neuron where the Ap aggregates, e.g., particularly by inhibiting soluble forms of amyloid that may interact with tau. This amyloid removal could slow existing tau intracellular aggregation and secretion in the neuron and / or reduce or prevent formation of new tau seeds. However, existing tau seeds may still spread to neighboring neurons, facilitating tau spreading. Thus, the overall effect of an Ap antibody on tau NFT formation and AD symptoms is challenging to predict.

[0175]

[0175] Biomarkers for Ap pathology and tau pathology can help to track progress of AD and determine effects of therapeutic antibodies on the disease. Biomarkers may be any measurement obtained in an individual or from a sample obtained from an individual whose levels indicate the disease. In AD, exemplary biomarkers include PET biomarkers obtained from positron emission tomography (PET) imaging of radiotracers that bind to Ap plaques or tau aggregates and indicate the presence, localization, and density of the pathological structures. Data from PET biomarker imaging indicates that Ap may accumulate, sometimes for decades, without evidence of cognitive impairment, however, tracking of increased Ap accumulation and density in brain regions over time (e.g., by amyloid-PET) may be used to predict progression of cognitive impairment (Hampel et al., Mol Psychiatry. 2021; 26, 5481- 5503; Koychev et al., Journal of Nuclear Medicine October 2020, 61 (10) 1413-1418). In contrast, tau NFTs appear to correlate more closely with brain regions affected by atrophy and hypometabolism, and the spatial distribution of tau NFTs over time tracks closely with clinical symptoms of AD (Koychev et al., 2020, supra).

[0176]

[0176] Biomarkers may also be obtained from biofluids such as cerebrospinal fluid (CSF) or blood. Exemplary biomarkers which have been shown to reflect amyloid, tau pathology, and / or clinical symptoms of AD include but are not limited to Ap (Ap42, Ap40, ratio AP42 / 40), tau (total tau, phosphorylated tau, e.g., at sites 181, 205, 217, and 231, and the ratio of a phosphorylated tau species to its non-phosphorylated tau species), neurogranin, neurofilament light chain (NfL), and GFAP, which can be measured in CSF and / or blood (e.g., plasma) (Wang et al., Front Cell Neurosci. 2023; 17: 1279046). Notably, biomarkers such as tauPET, AP42 / 40, and p-taul81 have been shown to reflect not only changes which occur during AD, but also therapeutic effects mediated by the anti-Ap-protofibril antibody lecanemab (WO2023283650, WO2023149970, and WO2024118665, the contents of which are incorporated herein in their entirety).

[0177]

[0177] A further biomarker for tau is MTBR-tau243, which may be measured in CSF or blood, and which correlates closely with tau PET and clinical tests for dementia (Horie et al., Brain, 2021, 144(2): 515-527; Horie et al., Nature Medicine, 2023, 29: 1954-1963; Horie et al., The Journal of Prevention of Alzheimer’s Disease 2023,10: S36; Horie et al., Nature Medicine 2025, https: / / doi.org / 10.1038 / s41591-025-03617-7). One species of MTBR-tau243 is a peptide fragment of tau, spanning residues 243-254 in the microtubule-binding region of tau and is enriched in tau aggregates (also called “tryptic MTBR-tau243”). Another species of MTBR-tau243 is a peptide fragment of tau spanning residues 243-256 (also called “E- MTBR-tau243”). As used herein, “MTBR-tau243” encompasses both tryptic MTBR-tau243 and E-MTBR-tau243 unless context indicates otherwise. CSF MTBR-tau243 is more closely correlated with tau PET SUVR and MMSE scores than were other tau biomarkers, suggesting that MTBR-tau243 tracks more closely with tau pathology than with amyloid pathology, and may be a suitable biomarker for changes in aggregated tau pathology (Horie et al., 2023, supra).

[0178]

[0178] Surprisingly, however, certain forms of MTBR-tau243 have been demonstrated herein to track with changes mediated by an anti-Ap protofibril antibody. MTBR-tau243 levels in CSF showed a reduced rate of increase after treatment with lecanemab; the tryptic MTBR-tau243 species was measured in CSF after about 12 months and about 18 months of lecanemab treatment. These results were unexpected from prior studies. For example, subjects treated with the anti-Ap antibody gantenerumab, which binds to Ap fibrils, did not show a change in MTBR-tau243 even after 4 years of treatment ( Bateman et al., J Prev Alzheimers Dis. 2023;10(Suppl 1): S7; Barkhof et al., presentation at AD / PD 2023, available at https: / / medically.roche.com / global / en.html / home), although gantenerumab has been shown to reduce amyloid plaques and affect other measures of amyloid pathology (Bateman et al., N Engl J Med, 2023; 389(20): 1862-1876). Despite this, MTBR-tau243 has been shown herein to surprisingly be a proxy for the selection and monitoring of effectiveness of an anti-Ap protofibril antibody such as lecanemab.

[0179]

[0179] Without being bound by theory, binding of lecanemab to protofibrils may reduce the formation of new amyloid plaques and / or disrupt existing amyloid plaques, thereby reducing tau hyperphosphorylation and formation of new tau tangles. The reduction in tau tangles may be reflected in decreased MTBR-tau243 levels. In addition, MTBR-tau243 may be a pathological species that acts as a tau seed for extracellular tau propagation (Horie et al., 2021, supra), and decreased MTBR-tau243 levels after lecanemab treatment may reflect a reduction in formation of any or all tau seeds after lecanemab treatment. Accordingly, ongoing treatment with lecanemab, e.g., by maintenance dosing, may not only reduce formation and maintenance of amyloid plaques, but also downstream events related to tau seeding and / or formation of tau tangles.

[0180]

[0180] Described herein are methods and uses that link the biomarker MTBR-tau243 and immunotherapy for AD. In various embodiments, an anti-Ap protofibril antibody, such as lecanemab (also called BAN2401, see Tables 1-4), may be used to treat AD, e.g., by selecting a patient for treatment, treating, monitoring treatment, and making decisions regarding maintenance dosing, based on MTBR-tau243 levels in biofluid samples, e.g., CSF or blood.

[0181] Biomarkers for anti-Ap protofibril antibodies and anti-tan antibodies

[0182]

[0181] One aspect of the present disclosure relates to a biomarker which may be used at any step of treating a subject who has, is suspected of having, or is at risk of developing AD. In some embodiments, the biomarker may be used for selecting a subject for treatment with an anti-Ap protofibril antibody such as lecanemab, treating the subject with the anti-Ap protofibril antibody, reducing a brain Ap level by administering the anti-Ap protofibril antibody, reducing a brain tau level or slowing an increase in brain tau level by administering the anti-Ap protofibril antibody, monitoring efficacy of treatment with the anti-Ap protofibril antibody, and / or altering a treatment regimen that comprises administration of the anti-Ap protofibril antibody. Altering the treatment regimen may comprise adding an additional therapy, such as an anti-tau antibody (e.g., E2814). In some embodiments, the biomarker is a tau species. In some embodiments, the biomarker is an MTBR-tau243 species. In some embodiments, the biomarker is CSF MTBR-tau243 or blood (e.g., plasma) MTBR-tau243. In some embodiments, the MTBR-tau243 species is used in conjunction with one or more additional markers, such as p-tau217 or a ratio of p-tau217 to total tau217. In some embodiments, the additional marker is at least one of Ap42 and / or AP42 / 40 ratio; plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light (NfL)..

[0183] MTBR-tau243 Peptides

[0184]

[0182] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the biomarker is tryptic MTBR-tau243, e.g., in CSF or plasma. In some embodiments, the biomarker is E-MTBR-tau243, e.g., in CSF or plasma.

[0185]

[0183] In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma. As used herein, the terms “MTBR-tau243 species”, “MTBR-tau243” and “MTBR-tau243 peptide” are interchangeably used to refer to peptide fragments of the microtubule-binding region containing residue 243, unless context indicates otherwise, e.g. as in Example 4.

[0186]

[0184] In some embodiments, the tau isoform 2N4R comprises an N-terminus (amino acids 1-103), mid-domain (amino acids 104-243), MTBR (amino acids 244-268), and C- terminus (amino acids 369-441). Other tau isoforms vary in a predictable way the corresponding amino acids may be determined in other tau isoforms. In some embodiments, MTBR-tau refers to a tau peptide comprising at least two amino acids from the microtubule binding region (MTBR) of tau (e.g., amino acids 244-368 of the human tau isoform 2N4R, 441 amino acids in length). In some embodiments, a long form of MTBR (also called “long MTBR tau”) comprises at least two, e.g., all of the amino acids 259-441 of 2N4R. In some embodiments, a short form of MTBR (also called “short MTBR-tau”) comprises at least two, e.g., all of the amino acids 235-254 of 2N4R.

[0187]

[0185] In some embodiments, MTBR-tau243 fragments are purified from a biological samples (e.g., CSF and / or blood) and quantified using methods disclosed in WO2024044637, the contents of which are incorporated herein by reference in their entirety. For example, MTBR-tau243 may be purified from endogenously cleaved fragments of tau, which have been produced by an in vivo proteolytic cleavage event to identify E-MTBR-tau243. In some embodiments, purification of MTBR-tau243 comprises contacting a sample (e.g., CSF or blood) with one or more anti-tau antibodies in an immunodepletion step, followed by contacting the immunodepleted sample with an antibody that binds to a short MTBR-tau fragment, then washing the sample, digesting with a protease (e.g., trypsin) to mediate proteolytic cleavage, desalting, and analysis by liquid chromatography / mass spectrometry (LC-MS) to identify tryptic MTBR-tau243.

[0188]

[0186] In some embodiments, purification of MTBR-tau243 comprises a two-step process, in which a sample (e.g, CSF or blood) is contacted with one or more anti-tau antibodies (e.g., 3 or 4 anti-tau antibodies) in an immunodepletion step, followed by washing, digestion with a protease (e.g., trypsin), desalting, and analysis by LC-MS. In some embodiments, the remaining immunodepleted precipitate is immunoprecipitated with an antibody that binds to the short form of tau-MTBR, washed, and subjected to trypsin digestion, desalted, and analyzed by LC-MS.

[0189]

[0187] In some embodiments, purification of MTBR-tau243 comprises using a capture step for MTBR-tau species. In some embodiments, purification comprises a first and / or second immunodepletion step, or, optionally, no immunodepletion step. In some embodiments, the method comprises immunoprecipitation of the sample with an antibody to the short form of MTBR-tau, washing, digesting with a protease, desalting, and analyzing by LC-MS. In some embodiments, digestion with a protease comprises digestion with an endopeptidase such as a cysteine protease (Arg-C) that selectively cleaves at the C-terminal side of arginine residues. In some embodiments, the Arg-C is a highly selective Arg-C that primarily cleaves at the C-terminal side of Arg sites and does not substantially cleave Lys residues. An exemplary Arg-C is gingipain (Arg-C Ultra, a mass spec grade endoprotease, Promega, USA). Cleavage with such an Arg-C produces the MTBR-tau243-256 (E-MTBR- tau243) peptide, because of cleavage at the endogenous arginine at position 256. In some embodiments, digestion with a protease comprises digestion with trypsin, which cleaves at both lysine and arginine residues. Cleavage with trypsin produces the MTBR-tau243-254 peptides, because of cleavage of a lysine residues at position 254.

[0190]

[0188] In some embodiments, different MTBR-tau243 peptides are purified using the methods disclosed in WO2024044637. In some embodiments, trypsinized fragments of MTBR-tau243 comprise MTBR-tau243-254 (“tryptic MTBR-tau243). In some embodiments, non-trypsinized, endogenous fragments of MTBR-tau243 comprise MTBR-tau243-256 (also called “E-MTBR-tau243”). MTBR-tau243 fragments may be deamidated, for example, at position 255 in MTBR-tau243-256.

[0191]

[0189] In some embodiments, a level of a biomarker such as an MTBR-tau243 species (e.g., tryptic MTBR-tau243 and / or E-MTBR-tau243) in a biofluid sample obtained from a subject (“from a subject”) is compared to a level of the biomarker (e.g., MTBR-tau243 species) in a biofluid sample obtained from a control (“from a control” or from a “control sample”, e.g., a sample obtained from a control). In some embodiments, the control is a healthy individual. In some embodiments, the control is an individual who does not have AD. In some embodiments, the control is an individual who has signs or symptoms of AD, preclinical AD, prodromal AD, and / or early AD, but is at an earlier stage of disease progression than the subject. In some embodiments, the control is a sample from a subject with more advanced AD.

[0192]

[0190] In some embodiments, a level of a biomarker (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 and / or E-MTBR-tau243) in a biofluid sample obtained from a subject (“from a subject”) may be compared to a reference or threshold level of the biomarker (e.g., MTBR-tau243 species), reflecting a value obtained by using measurements of the biomarker (e.g., the MTBR-tau243 species) from a population of individuals who are at a known stage of disease or lack of disease, e.g., from an individual(s) who is healthy, does not have AD, and / or at an earlier stage of the disease than the subject. In some embodiments, the control is an individual who has amyloid-negative status, e.g., as indicated by biomarkers and / or amyloid PET. In some embodiments, the positive control is an individual who has tau- negative status, as indicated by biomarkers and / or tau PET. In some embodiments, the control is a reference / threshold level of a biomarker (e.g., MTBR-tau243 species) that has been determined by modeling. In some embodiments, the control sample is a previous measurement of a biomarker (e.g., a MTBR-tau243 species) in a biofluid sample from the subject who is receiving a treatment for AD. For example, the control sample may have been obtained from the subject prior to the treatment, or at an earlier time during the course of treatment, prior to performing the steps of the method. As used herein, the identity of the control will be apparent from the context of the embodiment.

[0193]

[0191] In some embodiments, a level of a biomarker (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 and / or E-MTBR-tau243) may be compared to a level of the biomarker in a biofluid sample from a positive control (also, “from a positive control sample”). As disclosed herein, a “positive control” (also “disease positive control”) refers to an individual who has AD, who is at a later stage of disease progression than the subject, and / or whose disease progresses without treatment while the subject receives treatment. In some embodiments, a positive control is an untreated AD subject or untreated control subject who is not being treated for AD. In some embodiments, a positive control has AD and is not treated with an anti-protofibril antibody. In some embodiments, a positive control has AD and is not treated with an anti-tau antibody. In some embodiments, the positive control is an individual with amyloid and / or tau pathology, e.g., as measured by biomarkers (e.g., AP42 / 40 ratio, p-tau species) and / or by amyloid PET and / or tau PET. In some embodiments, the positive control is an individual who has a known stage of AD and / or amyloid-positive status, e.g., as indicated by biomarkers, cognitive scores, and / or amyloid PET. In some embodiments, the positive control is an individual who has tau-positive status, as indicated by biomarkers and / or tau PET (e.g., low, intermediate, or high levels of tau PET). In some embodiments, a level of a biomarker (e.g., a MTBR-tau243 species such as tryptic MTBR- tau243 and / or E-MTBR-tau243) in a biofluid sample obtained from a subject may be compared to a reference or threshold level of the biomarker (e.g., MTBR-tau243 species), reflecting a value obtained by using measurements of the biomarker (e.g., the MTBR-tau243 species) from a population of individuals who have AD, who are at a later stage of the disease than the subject, and / or whose disease progresses without treatment while the subject receives treatment. In some embodiments, the control is a reference / threshold level of the biomarker (e.g., MTBR-tau243 species) that has been determined by modeling. In some embodiments, a measurement in a biofluid sample (e.g., CSF or blood) obtained from a subject may be comparable to a positive control, e.g., measurement from an individual who has AD. In some embodiments, a measurement obtained from subject sample is comparable to the positive control if it is equal, about equal, equivalent, about equivalent, similar, or has features in common such as quantity or rate of change after treatment, to the positive control. As used herein, the identity of the positive control will be apparent from the context of the embodiment.

[0194]

[0192] Without being bound by theory, the peptides MTBR-tau243-254 and MTBR- tau243-256 may show different dynamics during the course of AD and / or may show different responses to treatment with the anti-Ap protofibril antibody (e.g, lecanemab). For example, plasma MTBR-tau243, e.g., plasma E-MTBR-tau243, may show robust correlation with tau- PET in late Braak regions and may maintain diagnostic accuracy of tau-PET positivity in subjects who are AP-positive. Plasma E-MTBR-tau243 performance in predicting MMSE is similar to tau-PET, and may be better than p-tau217 in predicting subjects who are AP- positive, and thus may be used in selecting and monitoring patients for treatment with lecanemab, including decisions about when to add other therapies (e.g., E2814) to address build up of MTBR-tau243 and associated advancement in AD stage.

[0195]

[0193] In some embodiments, the MTBR-tau243 species is MTBR-tau243-254 (also called “tryptic MTBR-tau243”) or MTBR-tau243-256 (also called “E-MTBR-tau243”). In some embodiments, the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR- tau243) is measured in CSF. In some embodiments, the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) is measured in blood, e.g., plasma.

[0196]

[0194] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau-243 or E-MTBR-tau243) in CSF and / or plasma of a subject is used to select a subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, a method of selecting a subject for a treatment with an anti-Ap protofibril antibody, comprises a) obtaining a measurement of a level of a MTBR-tau243 species in a biofluid sample (e.g., concentration of a MTBR-tau243 species in a biofluid sample), e.g., in a CSF or blood sample, from the subject; b) selecting the subject for treatment if the level of the MTBR- tau243 species is elevated compared to a control sample, e.g., compared to a level of the MTBR-tau243 species in a biofluid sample from an individual who does not have Alzheimer’s disease (AD). p-tau217 at early stages of AD progression

[0197]

[0195] In some embodiments, the biomarker p-tau217 (and / or the ratio of p-tau217 to non- p-tau217, also called the “p-tau217 ratio” or “ptau217R”) may also be assayed in addition to MTBR-tau243. CSF p-tau217 has been shown to correlate closely with amyloid PET in cohorts of subjects across certain stages of Alzheimer’s disease (AD) neuropathology (Barthelemy et al., Journal of Alzheimer’s Disease 85 (2022) 415-429, DOI 10.3233 / JAD- 210677). Plasma p-tau217 has also been shown to accelerate in subjects with preclinical AD (amyloid-P-positive, cognitively unimpaired) or prodromal AD (amyloid-P-positive, with mild cognitive impairment) as compared to amyloid-P-negative counterparts (either cognitively unimpaired or with mild cognitive impairment), and to accelerate in subjects with mild cognitive impairment who later converted to AD dementia (Mattsson-Carlgren et al., Brain 2020: 143; 3234-3241, doi: 10.1093 / brain / awaa286). Levels of p-tau217 (and / or the ratio of p-tau217) may be elevated in a subject sooner in the time course of disease for AD subjects than levels of MTBR-tau243. In addition, plasma p-tau217R measurements have been shown to improve plasma biomarker algorithms for identifying preclinical amyloid PET positivity (Rissman et al., Alzheimers Dement. 2023 Nov 6;20(2): 1214-1224. doi: 10.1002 / alz.l3542). Thus, in some embodiments, p-tau217 and / or p-tau217R, measured in CSF and / or plasma, is used to stage subjects as being at early (e.g., preclinical or prodromal) stages of AD, as well as subjects who progress to AD. In some embodiments, staging is performed using a combination of p-tau217 and / or p-tau217R with an MTBR-243 species, e.g., as measured in CSF and / or plasma.

[0198]

[0196] In some embodiments, a level of the MTBR-tau243 species (e.g., tryptic MTBR- tau-243 or E-MTBR-tau243) in CSF and / or plasma of a subject is used in conjunction with a level of p-tau217 (or the level of a ratio of p-tau217 / tau217) to select a subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, a method of selecting a subject for a treatment with an anti-Ap protofibril antibody, comprises a) obtaining a measurement of a level (e.g., concentration) of a MTBR-tau243 species and a level (e.g., concentration) of p-tau217 (or the level of a ratio of p-tau217 / tau217) in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the level of the MTBR-tau243 species and p-tau217 (or the level of a ratio of p- tau217 / tau217) is elevated compared to a control sample, e.g., compared to levels in a biofluid sample from an individual who does not have Alzheimer’s disease (AD).

[0199]

[0197] In some embodiments, the level of p-tau217 and / or p-tau217R in the CSF and / or plasma of a subject is used to select the subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, a high level of p-tau217 and / or p-tau217R (e.g., including an increasing level of p-tau217 and / or p-tau271R measured over a period of time) and a low level of a MTBR-tau243 species (e.g., including little or no increase in the level of a MTBR-tau243 species measured over the same period of time) in the sample from the subject as compared to a control sample (e.g., a sample from the level of p-tau217 and / or p-tau217R and / or the MTBR-tau243 species in a biofluid sample from a subject who does not have AD) indicates an early Braak stage, e.g., stage I or stage II, of AD and / or tau progression. In some embodiments, a method of selecting a subject for a treatment with an anti-Ap protofibril antibody, comprises a) obtaining a measurement of a level of p-tau217 and / or p-tau217R in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the level of p-tau217 and / or p-tau217R is elevated compared to a control sample, e.g., compared to a level of p-tau217 and / or p-tau217R in a biofluid sample from an individual who does not have Alzheimer’s disease (AD).

[0200]

[0198] In some embodiments, the subject with a high level of p-tau217 and / or p-tau217 (e.g., including an increasing level of p-tau217 and / or p-tau271R measured over a period of time in biofluid samples from the subject) and a low level of a MTBR-tau243 species (e.g., levels comparable to a healthy control, levels lower than a subject with more advanced AD, levels that show little or no increase measured over a period of time prior to commencing therapy) is administered the anti-Ap protofibril antibody. In some embodiments, the levels of p-tau217 and / or p-tau217R as well as the levels of MTBR-tau243 (tryptic MTBR-tau243 and / or E-MTBR-tau243 species) are monitored in biofluid samples from the subject over the course of treatment with lecanemab. In some embodiments, an increase in the level of either or both MTBR-tau243 species in CSF and / or plasma during treatment with lecanemab indicates tau progression, e.g., an increase in levels of pathogenic tau species such as tau tangles and / or spreading of pathogenic tau species across brain regions. In some embodiments, an increase in the level of either or both MTBR-tau243 species in CSF and / or plasma during treatment with lecanemab indicates tau progression, as confirmed by tau PET.

[0201]

[0199] In some embodiments, an increase in the level of either or both MTBR-tau243 species (tryptic MTBR-tau243 and / or E-MTBR-tau243 species) in CSF and / or plasma during treatment with lecanemab indicates AD progression, e.g., indicates that AD is advancing in severity. In some embodiments, when either or both MTBR-tau243 species increases in biofluid samples (e.g., CSF and / or plasma) obtained from the subject during lecanemab treatment as compared to levels of either or both MTBR-tau243 species in a biofluid sample from a control subject (e.g., a subject who does not have AD, a subject who has early AD, and / or the subject at baseline prior to treatment with the anti-Ap protofibril antibody), the subject is administered a further treatment, e.g., an anti-tau antibody such as E2814. In some embodiments, a subject is monitored for reduction in the MTBR-tau243 species in a biofluid sample (e.g., CSF and / or plasma) following treatment with an anti-tau antibody such as E2814. In some embodiments, a reduction in the level of the MTBR-tau243 species indicates effective treatment with the anti-tau antibody such as E2814. In some embodiments, a further dose of the anti-tau antibody such as E2814 is administered if an effective treatment is observed.

[0202] MTBR-tau243 and treatment with an anti-Ap protofibril antibody

[0203]

[0200] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau243 and / or E-MTBR-tau243) measured in biofluid samples from the subject is elevated relative to a healthy control prior to treatment with an anti-Ap protofibril antibody such as lecanemab. In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 and / or E-MTBR-tau243) measured in biofluid samples from the subject is comparable to a positive control, e.g., a MTBR-tau243 level from an individual who has AD, e.g., early AD. In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 and / or E-MTBR-tau243) measured in biofluid samples from the subject continues to change over time as AD progresses. In some embodiments, the tryptic MTBR- tau243 level changes (e.g., increases) as AD progresses, and the change occurs in at least one of CSF and plasma. In some embodiments, the level of tryptic MTBR-tau243 increases in at least one of, or both of, CSF and plasma as AD progresses. In some embodiments, the E- MTBR-tau243 level changes (e.g., increases) as AD progresses, and the change occurs in one or both of CSF and plasma. In some embodiments, the level of E-MTBR-tau243 increases in at least one of, or both of, CSF and plasma as AD progresses.

[0204]

[0201] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau243 or E-MTBR-tau243) in the biofluid samples obtained from the subject changes in response to treatment with an anti-Ap protofibril antibody (e.g., lecanemab). For example, the level of the MTBR-tau243 species, e.g., tryptic MTBR-243, may increase in CSF and / or plasma as AD progresses, but treatment with lecanemab may lead to a decrease in the level of the MTBR-tau243 species or a reduced rate of increase in the level of the MTBR-tau243 species. In some embodiments, the level of tryptic MTBR-tau243 shows a decrease (or a reduced rate of increase) in response to lecanemab treatment.

[0205]

[0202] In some embodiments, the level of the E-MTBR-tau243 species in biofluid samples obtained from the subject does not change in response to lecanemab treatment as compared to biofluid samples from an untreated and / or positive control patient, or, changes less with treatment than is observed in that patient from measurements of the tryptic MTBR- 243 species. In some embodiments, the level of MTBR-tau243 species, e.g., E-MTBR- tau243, continues to increase during treatment with lecanemab.

[0206]

[0203] In some embodiments, when the level of an MTBR-tau243 species has increased to a threshold suitable for treatment with an anti-tau antibody such as E2814, e.g., to the level in a positive control subject known to have accumulated tau in the brain (e.g., as measured by tau PET, e.g., a tau PET SUVR level of about 1.0, or tauPET SUVR imaging indicating that the subject is at least at Braak Stage I or II, where tau pathology is visible in the transentorhinal and entorhinal cortices), then an additional therapy is administered in addition or instead of lecanemab (e.g., a treatment with a combination of lecanemab and E2814). In some embodiments, an elevated level of MTBR-tau243 after treatment with lecanemab indicates that the subject has likely accumulated tau and / or tau pathology (e.g., when the MTBR-tau243 has increased, this indicates a progression of tauPET and / or tau pathology), indicating a patient may benefit from adding treatment with an anti-tau antibody such as E2814.

[0207]

[0204] In some embodiments, lecanemab treatment has the same effect on the levels of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) whether measured in CSF or plasma from the subject. In some embodiments, the levels of the MTBR-tau243 species (e.g., tryptic MTBR-tau243) in both CSF and plasma show a decrease (or a reduced rate of increase) in response to lecanemab treatment. In some embodiments, treatment with an anti-tau antibody such as E2814 reduces levels of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243).

[0208]

[0205] In some embodiments, the level of the MTBR-tau243 species (e.g., tryptic MTBR- tau243 or E-MTBR-tau243) may be monitored in CSF and / or plasma from the subject during treatment with the anti-Ap protofibril antibody (e.g., lecanemab) to determine how the subject is responding to the anti-Ap protofibril antibody, e.g., if the treatment with the anti- Ap protofibril antibody is an effective treatment or not.

[0209]

[0206] In some embodiments, the level of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment is compared to the level of the MTBR-tau243 species in a biofluid sample from a positive control, e.g, an individual who has AD, e.g., wherein a lower level in the subject indicates early stages of AD, whereas the same or a higher level relative to the positive control indicates a more advanced stage.

[0210]

[0207] In some embodiments, a decrease (or a reduced rate of increase) in the level of the MTBR-tau243 species in the biofluid sample from the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. In some embodiments, a decrease (or a reduced rate of increase) in the level of tryptic MTBR-tau243 in the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. In some embodiments, a decrease (or a reduced rate of increase) in the level of CSF tryptic MTBR-tau243 in the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. In some embodiments, a decrease (or a reduced rate of increase) in the level of plasma tryptic MTBR-tau243 in the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control, indicates an effective treatment. Where treatment is effective, a further dose of lecanemab may be administered, e.g., as a part of an ongoing treatment dosing regimen or as part of a maintenance dosing regimen. MTBR-tau243 and anti-tau antibody treatment

[0211]

[0208] Without being bound by theory, increases in the level of MTBR-tau243 species, e.g., tryptic MTBR-tau243 or E-MTBR-tau243, in biofluid samples (e.g., CSF and / or plasma) from a subject, may be observed at a later timepoint in disease progression than when increases in the level of p-tau217 and / or p-tau217R are observed in the biofluid samples from the same subject. At the same time, again without being bound by theory, MTBR-tau243 levels may be elevated relative to a control (e.g., as measured in a sample from a healthy subject) at any stage of the disease. Thus, in some embodiments, the two markers may be used to refine disease staging and to select treatment with anti-amyloid therapies such as lecanemab (e.g., if increased levels of p-tau217 and / or p-tau217R, either alone or in combination with increased levels of MTBR-tau243) are observed in samples from a subject) and to select add-on or replacement anti-tau therapy such as E2814 (e.g., if increased levels of MTBR-tau243 species are observed).

[0212]

[0209] In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with the levels of the MTBR-tau243 species in a biofluid sample from a control, e.g., an individual who does not have AD. In some embodiments, the control is an individual who has no or low tau accumulation. In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with a control that is a reference or threshold level of the MTBR-tau243 species, as determined based on measurements from a population of individuals who do not have AD and / or has no or low tau accumulation; or determined by modeling. In some embodiments, a change in the level of the MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) in biofluid samples (e.g., CSF and / or plasma) from a subject during treatment with the anti-Ap protofibril antibody (e.g., lecanemab), e.g., an increased level of MTBR-tau243 compared to threshold or control indicates that the treated patient has progressed to a more advanced stage of disease (e.g., intermediate or high tau accumulation, intermediate or high amyloid, worsening of clinical symptoms of AD, etc.). In some embodiments, such a patient is administered an additional therapy (e.g., an anti-tau antibody such as E2814). For example, if a subject treated with lecanemab shows an increase in the level of the MTBR-tau243 species relative to the control (e.g., where the level in the treated subject does not decrease or does not show a reduction in the rate of increase), the subject may be administered an additional therapy such as E2814 (in addition or in lieu of lecanemab treatment).

[0210] In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with the levels of the MTBR-tau243 species in a biofluid sample from a positive control, e.g., an individual who has AD and / or whose AD is progressing or has progressed. In some embodiments, the positive control is an individual who shows amyloid positivity, tau progression, and / or clinical symptoms of AD, and / or who is not receiving treatment for AD. In some embodiments, the levels of the MTBR-tau243 species in a biofluid sample from a subject undergoing treatment are compared with a positive control that is a threshold level of the MTBR-tau243 species, as determined based on measurements from a population of individuals who have AD, amyloid positivity, tau progression, and / or clinical symptoms of AD, and / or who is not receiving treatment for AD; or a threshold determined by modeling.

[0213]

[0211] In some embodiments, when the level of the MTBR-tau243 species increases in a biofluid sample (e.g., in CSF and / or plasma) from a subject receiving lecanemab, the subject is administered an anti-tau antibody such as E2814. In some embodiments, when the level of the MTBR-tau243 species increases in a biofluid sample (e.g., in CSF and / or plasma) from a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered an anti-tau antibody such as E2814. In some embodiments, when the subject is administered an anti-tau antibody such as E2814, a reduction in MTBR-tau243 species is observed.

[0214]

[0212] In some embodiments, when the level of CSF tryptic MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control (e.g., a control subject identified as having tau accumulation, e.g., as determined by tau PET, meriting treatment with an anti-tau antibody such as E2814), the subject is administered E2814. In some embodiments, when the level of plasma tryptic MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered E2814. In some embodiments, when the level of CSF E-MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered E2814. In some embodiments, when the level of plasma E-MTBR-tau243 increases in a subject receiving lecanemab, and the increase is comparable to a positive control, the subject is administered E2814. p-tau217, MTBR-tau243, and treatment for AD

[0215]

[0213] In some embodiments, a subject is administered a therapy (e.g., an anti-tau antibody such as E2814) in addition to the anti-Ap protofibril antibody (such as lecanemab) when the level of an MTBR-tau243 species is higher than a set threshold, e.g., a threshold indicating the subject has intermediate or high tau accumulation in the brain. In some embodiments, the subject is selected for treatment with E2814 when the level of MTBR- tau243 (e.g., CSF tryptic MTBR-tau243 or CSF E-MTBR-tau243 ) is about 300 - 700 pg / mL, e.g., about 300 - 400 pg / mL, 400 - 500 pg / mL, 500 - 600 pg / mL, or 600 - 700 pg / mL. In some embodiments, the level of MTBR-tau243 is about 300 - 350 pg / mL, 450 - 500 pg / mL, 500 - 550 pg / mL, 550 - 600 pg / mL, or 650 - 700 pg / mL.

[0216]

[0214] In some embodiments, the level of p-tau217 and / or p-tau217R changes as AD progresses. In some embodiments, level of p-tau217 and / or p-tau217R in a biofluid sample from the subject changes (e.g., increases) as AD progresses, and the change occurs in at least one of CSF and plasma. In some embodiments, the level of p-tau217 and / or p-tau217R increases in at least one of CSF and plasma as AD progresses. In some embodiments, the level of p-tau217 and / or p-tau217R is a biomarker for early stages of AD, e.g., pre- AD, early AD, and / or stages where clinical symptoms of AD may be absent or minimal, and / or stages where amyloid centiloid levels are around 20, and / or tau PET SUVR levels are below about 1.12. In some embodiments, the level of p-tau217 and / or p-tau217R increases in early stages of AD progression.

[0217]

[0215] In some embodiments, the level of p-tau217 and / or p-tau217R in the biofluid sample from the subject changes in response to treatment with an anti-Ap protofibril antibody (e.g., lecanemab). For example, where the level of p-tau217 and / or p-tau217R increases in CSF and / or plasma as AD progresses, treatment with lecanemab may lead to a decrease in the level of p-tau217 and / or p-tau217R or a reduced rate of increase in the level of p-tau217 and / or p-tau217R.

[0218]

[0216] In some embodiments, the level of p-tau217 and / or p-tau217R may be monitored in CSF and / or plasma during treatment with the anti-Ap protofibril antibody (e.g., lecanemab) to determine how the subject is responding to the anti-Ap protofibril antibody, e.g., if the treatment with the anti-Ap protofibril antibody is an effective treatment or not.

[0219]

[0217] In some embodiments, a decrease (or a reduced rate of increase) in the level of the p-tau217 and / or p-tau217R in a biofluid sample from the subject undergoing treatment with the anti-Ap protofibril antibody (e.g., lecanemab), as compared to a positive control (e.g., an individual with AD amyloid positivity, tau pathology, and / or clinical symptoms of AD; or a threshold level reflective thereof), indicates an effective treatment. Where treatment is effective, a further dose of lecanemab may be administered.

[0218] In some embodiments, an increase in the level of p-tau217 and / or p-tau217R in CSF and / or plasma indicates a subject has early AD and is ready for treatment with an anti- Ap protofibril antibody (e.g., lecanemab). In some embodiments, a subsequent increase in the level of an MTBR-tau243 species after commencing treatment with lecanemab indicates that the subject has progressed to or beyond to a stage where the subject should be administered an additional therapy (e.g., an anti-tau antibody such as E2814). In some embodiments, the stage is a stage of early AD, intermediate AD, and / or a stage where the subject has intermediate or high levels of tau accumulation as measured by tauPET SUVR. In some embodiments, lecanemab and the anti-tau antibody are administered in conjunction. In some embodiments, lecanemab is no longer administered and the anti-tau antibody is administered alone. In some embodiments, the level of p-tau217 and / or p-tau217R in the biofluid sample (e.g., CSF and / or plasma) may be measured in a subject after commencement of the anti-tau therapy (e.g., E2814 therapy). In some embodiments, a reduction in the level of p-tau217 and / or p-tau217R in CSF and / or plasma from the subject indicates the anti-tau therapy is effective. In some embodiments, where therapy is effective, a further dose of the anti-tau therapy is administered.

[0220]

[0219] Aspects of the present disclosure relate to methods in which a level of a MTBR- tau243 species (e.g., tryptic MTBR-tau-243 or E-MTBR-tau243) in CSF and / or plasma of a subject is measured in conjunction with a level of p-tau217 (or the level of a ratio of p- tau217 / tau217) and used to diagnose and / or treat subjects having, suspected of having AD, or at risk for developing AD. The methods relate to selecting a subject for treatment, treating a subject with a treatment, monitoring treatment efficacy, adjusting a treatment regimen, or detecting a decrease in a brain Ap level or detecting a decrease in a brain tau level, e.g., after administering a treatment. In some embodiments, the treatment is an anti-Ap protofibril antibody (e.g., lecanemab) and, optionally, an anti-tau antibody (e.g., E2814).

[0221]

[0220] An aspect of the present disclosure relates to a method of selecting a subject for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, wherein the method comprises: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR- tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the first p-tau217 concentration and / or the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD).

[0222]

[0221] In some embodiments, a method of selecting a subject for a treatment with an anti- Ap protofibril antibody and an anti-tau antibody comprises obtaining measurements of a p- tau217 concentration and a MTBR-tau243 concentration at different times. In some embodiments, a method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprises: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD). In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample; and in step b), selecting the subject for the first treatment with the anti-Ap protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step d), selecting the subject for a second treatment with the anti-tau antibody if the second p-tau217 concentration and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0222] An aspect of the present disclosure relates to a method of treating or preventing AD in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration and / or the first MTBR-tau243 concentration are elevated compared to a first control sample, e.g., a sample from an individual who does not have AD; c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to the first p-tau217 concentration and the second MTBR-tau243 concentration.

[0223]

[0223] p-tau217 and MTBR-tau243 concentrations may be measured at different time points during a method of treating AD. An aspect of the present disclosure relates to a method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having AD, or at risk for developing AD, comprising: a) obtaining a measurement of a p- tau217 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., a p-tau217 concentration in an individual who does not have AD; c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., a MTBR- tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0224]

[0224] p-tau217 and p-tau243 concentrations may be used in methods for reducing tau tangles. One aspect of the present disclosure relates to a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), may comprise: a) obtaining a measurement of a first p-tau217 concentration and a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the first p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD; e) optionally obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the third p-tau217 concentration as compared to the second p-tau217 concentration and in the third MTBR-tau243 concentration as compared to the second MTBR-tau243 concentration, indicates a reduction in tau tangles.

[0225]

[0225] p-tau217 and MTBR-tau243 concentrations may be measured at different time points during a method of reducing tau tangles. An aspect of the present disclosure relates to a method of reducing tau tangles comprises: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); e) obtaining a measurement of a second MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the second MTBR-tau243 concentration after the second treatment as compared to the MTBR-tau243 concentration after the first treatment, indicates a reduction in tau tangles. In some embodiments, the method further comprises: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR- tau243 concentration in an individual who does not have AD. In some embodiments, the method further comprises: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

[0226]

[0226] p-tau217 and p-tau243 concentrations may be used in methods of preventing or treating Alzheimer’s disease (AD), e.g., by indicating how a treatment regimen may be adjusted. An aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the first p-tau217 concentration and the first MTBR-tau243 to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) adjusting the treatment regimen to further administer a therapeutically effective amount of an anti-tau antibody if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

[0227]

[0227] In some embodiments, the method further comprises: d) obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject; e) comparing the third p-tau217 concentration and the third MTBR-tau243 concentration to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); and f), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody and / or the anti-tau antibody, if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

[0228]

[0228] In some embodiments, the control sample is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status. In some embodiments, the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[0229]

[0229] p-tau217 and p-tau243 concentrations may be used in methods of monitoring treatment efficacy in a subject, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody. An aspect of the present disclosure relates to a method relates to a method of monitoring treatment efficacy in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second p-tau217 concentration and / or a change in the second MTBR-tau243 concentration, as compared to the first p-tau217 concentration and the first MTBR-tau243 concentration, is an indicator of treatment efficacy.

[0230] In some embodiments, a decrease or reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and / or in the second MTBR- tau243 concentration as compared to the first MTBR-tau243 concentration indicates an effective treatment. In some embodiments, a lack of a decrease or lack of a reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and / or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a non-effective treatment, or that additional treatments need to be added to an initial course of therapy.

[0230]

[0231] p-tau217 and p-tau243 concentrations may be used in methods of detecting a decrease in a measure of AD pathology, e.g., a brain Ap level and / or a brain tau level, in a subject who is receiving a treatment for AD. One aspect of the present disclosure relates to a method of detecting a decrease in a measure of AD pathology, e.g., a brain Ap level and / or a brain tau level, in a subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, in comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR- tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p-tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration indicates a decrease of a measure of AD pathology (e.g., a brain Ap level and / or a brain tau level). In some embodiments, the measure of AD pathology is a brain Ap level. In some embodiments, the measure of AD pathology is a brain tau level.

[0231] Biomarker use with anti-tau antibodies

[0232]

[0232] In some embodiments, when an anti-tau antibody is administered, it is E2814. In some embodiments, E2814 may be administered according to one of the following regimens, alone or in combination with lecanemab:

[0233]

[0233] In some embodiments, treatment with an anti-tau antibody such as E2814 leads to a reduction in levels of MTBR-tau243 (e.g., tryptic MTBR-tau243 and / or E-MTBR-tau243) in the CSF and / or in the plasma. In some embodiments, treatment with an anti-tau antibody such as E2814 lowers tryptic MTBR-tau243 levels by at least 40%, e.g., by 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or over 95%. In some embodiments, treatment with an anti-tau antibody such as E2814 lowers E-MTBR-tau243 levels by at least 40%, e.g., by 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or over 95%.

[0234]

[0234] In some embodiments, E2814 is administered in conjunction with lecanemab. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks (biweekly). In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks.

[0235]

[0235] In some embodiments, the subject is switched to a maintenance dosing regimen of lecanemab, e.g., after 18 or 24 months and / or after levels of biomarkers such as Abeta 42:40 ratio and / or pTau217 / pRtau217R indicate the subject is amyloid negative. In some embodiments, the maintenance dosing regimen is 360 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 250 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 10 mg / kg of lecanemab administered intravenously once every 4 weeks.

[0236]

[0236] Exemplary maintenance dosing regimens may comprise both E2814 and lecanmab. For example, in some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks.

[0237]

[0237] In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the anti-Ap protofibril antibody lecanemab comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Ap protofibril antibody lecanemab comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0238]

[0238] In some embodiments, the anti-Ap protofibril antibody comprises the CDRs of lecanemab. In some embodiments, the anti-Ap protofibril antibody comprises the variable regions of lecanemab.

[0239]

[0239] In some embodiments, the anti-tau antibody E2814 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). In some embodiments, the anti-tau antibody E2814 comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[0240] Selecting a subject for treatment

[0241]

[0240] One aspect of the present disclosure relates to a method of selecting a subject for a treatment comprising an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and / or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., a MTBR- tau243 concentration in an individual who has AD. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0242]

[0241] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a p- tau217 concentration in the biofluid sample from the subject; in step b), selecting the subject for treatment if the p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

[0243]

[0242] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42 / 40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and / or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has severe AD. In some embodiments, the subject has moderate AD. In some embodiments, the subject has mild AD. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre- AD.

[0244]

[0243] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). Other exemplary MTBR-tau243 peptides are listed in Table 9. In some embodiments, MTBR- tau243-256 may be deamidated, for example, on residue N255. In some embodiments, a patient selected for treatment with lecanemab does not have elevated E-MTBR-tau243 (e.g., the patient has preclinical AD or early AD). In some embodiments, elevated levels of MTBR- tau243-256 in a sample (e.g., a CSF sample or preferably a blood sample) from a subject as compared to a sample from a control (e.g., an individual who does not have AD) indicate that the subject has a more advanced disease, e.g., AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI. In some embodiments, such a patient is administered lecanemab and a second agent, e.g., an anti-tau antibody, e.g., E2814.

[0245]

[0244] In some embodiments, the MTBR-tau243 species is CSF tryptic MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma tryptic MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0246]

[0245] In some embodiments, a subject is selected for treatment with an anti-Ap protofibril antibody (e.g., lecanemab) when the level of MTBR-tau243 (e.g., CSF tryptic MTBR-tau243 or E-MTBR-tau243) is about 300 - 700 pg / mL, e.g., about 300 - 400 pg / mL, 400 - 500 pg / mL, 500 - 600 pg / mL, or 600 - 700 pg / mL. In some embodiments, the level of MTBR-tau243 is about 300 - 350 pg / mL, 450 - 500 pg / mL, 500 - 550 pg / mL, 550 - 600 pg / mL, or 650 - 700 pg / mL.

[0247]

[0246] In some embodiments, a subject is selected for treatment with an anti-Ap protofibril antibody (e.g., lecanemab) when a level of ptau217 and / or ptau-217R is elevated in a biofluid sample from the subject as compared to a control sample (e.g., a sample from a subject who does not have AD), but the level of an MTBR-tau243 species (e.g., tryptic MTBR-tau243 or E-MTBR-tau243) is not elevated in the biofluid sample. In some embodiments, high levels of p-tau217 and / or p-tau217R but little or no increase in level of a MTBR-tau243 species in a subject as compared to a control indicates an early Braak stage, e.g., stage I or stage II. In some embodiments, high levels of p-tau217 / np-tau217 and MTBR- tau243 species from a subject as compared to a control may indicate a later stage of AD, e.g., Ap+, CDR >1, or Braak stage III or higher. In some embodiments, when an elevated level of p-tau217 and / or p-tau217R and a low level of a MTBR-tau243 species indicates early AD, the patient is administered lecanemab. In some embodiments, when a high level of p-tau217 and / or p-tau217R indicate more advanced AD (e.g., Braak stage, e.g., stages V or VI), the patient is administered lecanemab and a second agent, e.g., an anti-tau agent (e.g., E2814).

[0248]

[0247] In some embodiments, levels of MTBR-tau243 (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 and / or E-MTBR-tau243) are used to determine or predict the stage of AD in a subject. Without being bound by theory, MTBR-tau243 may correlate with amyloid CL and / or tau PET SUVR, either alone or in conjunction with measurements of one or more CSF biomarkers (e.g., AP42 / 40 ratio, p-taul81, or total tau), and / or plasma biomarkers (e.g., AP42 / 40 ratio, p-taul81, p-tau217, or p-tau217R). In some embodiments, MTBR-tau243 may correlate with amyloid CL, wherein a MTBR-tau243 level (e.g., CSF tryptic MTBR-tau243 and / or CSF E-MTBR-tau243) is used to determine that a subject has a baseline level of amyloid that is <20 CL, <50 CL, 20 CL, or 50 CL. In some embodiments, the CSF MTBR-tau243 may correlate with amyloid CL levels in either tau negative or tau positive subjects, as determined by tau PET SUVR levels. In some embodiments, the tau positive subjects have a tau PET SUVR that is about <1, 1-1.126, 2.126-1.5, 1.5-2, or >2. In some embodiments, CSF MTBR-tau243 is a proxy for global tau PET SUVR, wherein a CSF MTBR-tau243 level (e.g., CSF tryptic MTBR-tau243 and / or CSF E-MTBR-tau243) is used to determine that a subject has a baseline level of tau PET SUVR that is about <1, 1-1.126, 2.126-1.5, 1.5-2, or >2. In some embodiments, the subjects with these tau PET SUVR levels have amyloid CL levels of about <50, 50-75, 75-100, or >100.

[0249] Monitoring treatment efficacy

[0250]

[0248] An aspect of the present disclosure relates to a method of monitoring treatment efficacy in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab), wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second MTBR-tau243 concentration ratio as compared to first MTBR-tau243 concentration is an indicator of treatment efficacy. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0251]

[0249] In some embodiments, a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates an effective treatment.

[0252]

[0250] In some embodiments, a lack of a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control, indicates a non-effective treatment.

[0253]

[0251] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p-tau217 concentration is an indicator of treatment efficacy. In some embodiments, a decrease from the first p-tau217 concentration to the second p-tau217 concentration, or reduction in a rate of increase from the first p-tau217 concentration to the second p-tau217 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first p-tau217 to a second tau217 concentration in an individual who has AD and is not treated, indicates an effective treatment. In some embodiments, a lack of a decrease from the first p-tau217 concentration to the second p-tau217 concentration and from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in a rate of increase between the first and second p-tau217 concentrations and MTBR-tau243 concentrations, as compared to rates in a placebo control, indicates a non-effective treatment.

[0254]

[0252] In some embodiments, the measurement of the first MTBR-tau243 concentration may be obtained from the subject prior to treatment. In some embodiments, the measurement of the first MTBR-tau243 concentration is a measurement of the MTBR-tau243 concentration in a subject who had already begun treatment without having a prior measurement of the MTBR-tau243 concentration.

[0255]

[0253] In some embodiments, a decrease in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration ratio indicates an effective treatment.

[0256]

[0254] In some embodiments, a lack of a decrease in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration indicates a less effective treatment. In some embodiments, a lack of a decrease in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration indicates no or less reduction in tau tangles. In some embodiments, the lack of a decrease is no change in the MTBR-243 concentration. In some embodiments, the lack of a decrease is an increase.

[0257]

[0255] In some embodiments, steps b) and c) of the method of monitoring treating efficacy may be repeated at least once in order to continue monitoring the treatment efficacy over time. In an exemplary example, the method further comprises, after step c), obtaining a measurement of a third MTBR-tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject at a time point after obtaining the second biofluid sample and comparing the third MTBR-tau243 concentration to an earlier measurement of the MTBR- tau243 concentration (e.g., the first and / or the second MTBR-tau243 concentration), wherein a change in the third MTBR-tau243 concentration as compared to the earlier MTBR-tau243 concentration is an indicator of treatment efficacy. In some embodiments, steps b) and c) may be repeated for as long as the subject receives treatment. In some embodiments, steps b) and c) may be repeated at regular intervals, e.g., once weekly, biweekly, monthly, quarterly, semiannually, or yearly.

[0258]

[0256] In some embodiments, the method of monitoring treatment efficacy may further comprise, after step c), a further step of d) modifying the treatment by administering a modified treatment comprising a further therapeutically effective dose of the anti-Ap protofibril antibody. For example, if the treatment is not effective, the dose may be modified by increasing the size of the dose, increasing the frequency of administration, and / or changing the route of administration. In some embodiments, an additional therapeutic may be added, e.g., an anti-tau antibody such as E2814. Conversely, if the treatment is effective, the dose may be modified by decreasing the size of the dose, increasing the frequency of administration, and / or changing the route of administration. In some embodiments, the subject may be switched from a treatment administered according to a treatment dosing regimen to a treatment administered according to a maintenance dosing regimen. In some embodiments, the treatment may be discontinued. In some embodiments, steps b) and c) may be repeated for as long as the subject receives treatment, e.g., after the subject receives a modified treatment. In some embodiments, steps b) and c) may be repeated if the subject no longer receives treatment, e.g., to continue monitoring treatment efficacy after the treatment has been discontinued.

[0259]

[0257] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42 / 40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and / or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre-AD.

[0260]

[0258] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0259] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0261]

[0260] In some embodiments, maintained or reduced levels of E-MTBR-tau243 indicate treatment efficacy. In some embodiments, elevated levels of MTBR-tau243-256 in a sample over time (e.g., a CSF sample or preferably a blood sample) indicate that the subject has progressed to a later form of AD while on treatment, e.g., Braak stages III, IV, V, or VI, e.g., stage V or stage VI. In some embodiments, when the E-MTBR-tau243 indicates progression to a later stage of disease, at least one additional therapy is provided, e.g., an anti-tau antibody, e.g., E2814. The additional therapy may be provided in conjunction with or in lieu of lecanemab treatment.

[0262]

[0261] In some embodiments, the subject receiving lecanemab at a late Braak stage, may respond more slowly to lecanemab treatment than a subject at an earlier stage, such that levels of MTBR-tau243 (e.g., MTBR-tau243-256) in a sample from a subject being treated with lecanemab may remain elevated as compared to sample from a control for longer period of time before an effect of lecanemab is observed.

[0263] Adjusting a treatment regimen

[0264]

[0262] A further aspect of the present disclosure relates to a method of preventing or treating Alzheimer’s disease (AD) (e.g., by adjusting a treatment regimen) in a subject having, suspected of having, or at risk for developing AD adjusting a treatment regimen, wherein the method comprises a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, b) comparing the MTBR-tau243 concentration to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and / or comparing the MTBR-tau243 concentration to a positive control, e.g., a MTBR-tau243 concentration in an individual who has AD; and c) adjusting the treatment regimen, e.g., by adjusting the size of the dose, the frequency of administration, and / or the route of administration, if the MTBR-tau243 concentration differs from the control sample or if the MTBR-tau243 concentration differs from the positive control sample.

[0265]

[0263] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a p- tau217 concentration in the biofluid sample from the subject; in step b), comparing the p- tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the control sample and / or comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample; and in step c), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody, if the p- tau217 concentration and the MTBR-tau243 concentration in the sample differ from the control sample or if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample.

[0266]

[0264] In some embodiments, the control is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

[0267]

[0265] In some embodiments, the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

[0268]

[0266] In some embodiments, the control sample is a measurement of a MTBR-tau243 concentration obtained from a biofluid sample, e.g., a CSF or blood sample, from a control subject. The control subject may be an individual who does not have AD. In some embodiments, the control sample is a measurement of a previous MTBR-tau243 concentration obtained from a biofluid sample, e.g., a CSF or blood sample from the subject receiving the treatment. For example, the control sample may have been obtained from the subject prior to the treatment, or at an earlier time during the course of treatment, prior to performing the steps of the method.

[0269]

[0267] In some embodiments, the measurement of the MTBR-tau243 concentration may be obtained prior to treatment. In some embodiments, the measurement of the MTBR-tau243 concentration is a first measurement of the MTBR-tau243 concentration in a subject who had already begun treatment without having a prior measurement of the MTBR-tau243 concentration.

[0270]

[0268] In some embodiments, the treatment regimen (also called a “dosing regimen” or “treatment dosing regimen”), comprises a schedule specifying doses of the anti-Ap protofibril antibody administered per unit of time, including the number of doses over a given time period and the elapsed time between doses. In some embodiments, the treatment regimen comprises administering the anti-Ap protofibril antibody at a specified dose, according to a schedule (e.g., on a repetitive basis).

[0271]

[0269] In some embodiments, adjusting the treatment regimen comprises increasing the size of the dose, increasing the frequency of administration, and / or changing the route of administration of the anti-Ap protofibril antibody if the MTBR-tau243 concentration is higher than the MTBR-tau243 concentration in the control sample (e.g., a sample from an individual who does not have AD). In some embodiments, an additional therapeutic may be added, e.g., an anti-tau antibody such as E2814. In some embodiments, the anti-tau antibody may be administered at a dose of 500 mg - 4500 mg (e.g., 500 mg, 750 mg, 1000 mg, 1500 mg, 3000 mg, 4500 mg), as described herein (Section C, Anti-Tau Antibodies).

[0272]

[0270] In some embodiments, adjusting the treatment regimen comprises decreasing the size of the dose, decreasing the frequency of administration, and / or changing the route of administration if the MTBR-tau243 concentration is lower than the control sample. In some embodiments, a treatment regimen comprising intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered biweekly, may be adjusted to comprise intravenous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered monthly. In some embodiments, a treatment regimen comprising subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 720 mg, administered weekly, may be adjusted to comprise subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, a treatment regimen comprising subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, may be adjusted to comprise subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, a treatment regimen comprising intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered biweekly, may be adjusted to comprise subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly. In some embodiments, a treatment regimen comprising subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, or administered biweekly, may be adjusted to comprise intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject.

[0271] In some embodiments, the subject may be switched from a treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody (e.g., an initiation dose) administered according to an initiation dosing regimen to a treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody (e.g., a maintenance dose) administered according to a maintenance dosing regimen. In some embodiments, the initiation dosing regimen comprises intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered biweekly and the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered monthly. In some embodiments, the initiation dosing regimen comprises subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 720 mg, administered weekly, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, the initiation dosing regimen comprises subcutaneous administration the anti- Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 360 mg, or 250 mg, e.g., administered weekly. In some embodiments, the initiation dosing regimen comprises intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered biweekly, and the maintenance dosing regimen comprises subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly. In some embodiments, the initiation dosing regimen comprises subcutaneous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, administered weekly and the maintenance dosing regimen comprises intravenous administration the anti-Ap protofibril antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered monthly.

[0273]

[0272] In some embodiments, the treatment may be discontinued.

[0274]

[0273] In some embodiments, without being bound by theory, the maintenance dose may maintain therapeutically effective concentrations of the anti-Ap protofibril antibody in the subject and / or to maintain or continue to reduced levels of Ap protofibril in the brain of the treated subject. In some embodiments, the maintenance dose also maintains reduced levels of tau, e.g., as indicated by reduced levels of MTBR-tau243, e.g., due to the prevention of tangle formation downstream of amyloid. In some embodiments, reduction in tau (e.g., MTBR- tau243) is an effect of reduction of Ap protofibrils mediated by the anti-Ap protofibril antibody. Exemplary maintenance doses are disclosed herein in Sections A6 (Switch to a maintenance dose) and D (Dosage Regimens and Routes).

[0275]

[0274] In some embodiments, the steps a) and b) of the method of adjusting a treatment regimen may be repeated at least once in order to monitor the efficacy of the adjusted treatment regimen and optionally, to further adjust the treatment regimen. In an exemplary example, the method further comprises, after step c), obtaining a measurement of a further MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject at a time point after adjusting the treatment regimen, and comparing the further MTBR-tau243 concentration to the MTBR-tau243 concentration from prior to adjusting the treatment regimen or to a control sample (e.g., a MTBR-tau243 concentration in an individual who does not have AD, a MTBR-tau243 concentration obtained from the subject prior to the treatment, or a MTBR-tau243 concentration obtained from the subject at an earlier time during the course of treatment, prior to performing the steps of the method). In some embodiments, if the further MTBR-tau243 concentration still differs from the control sample, the treatment may be adjusted further. The steps a) and b) may be repeated for as long as the subject receives the treatment or the adjusted treatment. In some embodiments, steps b) and c) may be repeated if the subject no longer receives treatment, e.g., to continue monitoring treatment efficacy after the treatment has been discontinued. In some embodiments, steps b) and c) may be repeated at regular intervals, e.g., once weekly, biweekly, monthly, quarterly, semiannually, or yearly.

[0276]

[0275] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42 / 40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and / or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre-AD.

[0277]

[0276] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0278]

[0277] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0279] Detecting a decrease in a brain A|J level or a brain tan level

[0280]

[0278] An aspect of the present disclosure relates to a method of detecting a decrease in a brain Ap level in a subject in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain Ap level in the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0281]

[0279] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p-tau217 concentration indicates a decrease of the brain Ap level in the subject.

[0282]

[0280] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease in the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, or a reduction in a rate of increase between the first and second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain tau level in the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0283]

[0281] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change from the first p-tau217 concentration to the second p-tau217 concentration indicates a decrease of the brain tau level in the subject.

[0284]

[0282] In some embodiments, a decrease in a brain tau level is a decrease in tau tangles. Tau tangles may be reduced, for example, by preventing, reducing, and / or slowing formation of new tau tangles; and / or by promoting, increasing, and / or speeding up breakdown of existing tau tangles. In some embodiments, tau tangles are detected by tauPET.

[0285]

[0283] An aspect of the present disclosure relates to a method of detecting a decrease in a brain tau PET level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, wherein the method comprises a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decreased concentration in the second sample relative to the first sample indicates a decrease of a brain tau PET level in the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the subject showing a decrease in MTBR-tau243 concentration and an associated decrease in brain tau PET level is receiving an anti-tau antibody (e.g., E2814) in addition to lecanemab.

[0286]

[0284] In some embodiments, the subject has, is suspected of having, or is at risk for developing Alzheimer’s disease (AD). For example, the subject may have symptoms of AD, such, cognitive impairment or high levels of amyloid PET or tau PET, or levels of one or more biomarkers in addition to MTBR-tau243 (e.g., Ap42, Ap40, AP42 / 40 ratio, total tau, or phosphorylated tau (p-tau 181, p-tau217, and / or p-tau231) indicate that the subject may have AD. In some embodiments, the individual may have additional risk factors for developing AD, such as family history, genetic background, gender, age over 60 years, head injury, comorbidities (e.g., vascular disease and / or diabetes), or certain lifestyle factors such as smoking, consuming alcohol, or limiting physical activity. In some embodiments, the subject has early-AD. In some embodiments, the subject has pre-AD.

[0287]

[0285] In some embodiments, the MTBR-tau243 species is a peptide fragment of MTBR- tau243, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR- tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0288]

[0286] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0289] A method of reducing tau tangles

[0290]

[0287] In various embodiments, a method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprises: a) obtaining a measurement of a first MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and / or if the first MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD; and c) obtaining a measurement of a second MTBR-tau243 concentration, wherein a decrease in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a reduction in tau tangles, and / or a rate of increase from the first MTBR-tau243 concentration to the first MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0291]

[0288] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample from the subject; in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the first p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample; and in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample, wherein a decrease in the second p-tau217 concentration as compared to the first p- tau217 concentration or a decrease in the rate of increase from the first p-tau217 concentration to the second p-tau217 concentration as compared to the rate of increase in the positive control indicates a reduction in tau tangles.

[0292]

[0289] In some embodiments, tangles are reduced by preventing, reducing, and / or slowing formation of new tau tangles; and / or by promoting, increasing, and / or speeding up breakdown of existing tau tangles, as evidenced by a reduction in MTBR-tau243 in a sample taken after treatment.

[0293]

[0290] In various embodiments, a method for identifying tau tangles in a subject comprises a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) identifying tau tangles in the subject if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD).

[0294]

[0291] In some embodiments, a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab) may be administered to the subject in whom tau tangles have been identified. In some embodiments, measurements of further MTBR- tau243 concentration may be obtained from further biofluid samples (e.g., a further CSF or blood sample) in order to determine if the treatment has changed the MTBR-tau243 concentration. In some embodiments, a reduction in MTBR-tau243 concentration over time indicates that the treatment is reducing tau tangles.

[0292] In some embodiments, the MTBR-tau243 species is a peptide fragment, such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0295]

[0293] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0296] A method of treating a subject

[0297]

[0294] An aspect of the present disclosure relates to method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), wherein the method comprises: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody (e.g., lecanemab) if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and / or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to a MTBR-tau243 concentration in an individual who has AD. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0298]

[0295] In some embodiments, a measurement of p-tau217 is included in the method. In some embodiments, the method further comprises in step a), obtaining a measurement of a p- tau217 concentration in the biofluid sample from the subject; and in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a p-tau217 concentration in a control sample, or if the p-tau217 concentration is comparable to a p- tau217 concentration in the positive control sample. In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is elevated as compared to the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration is comparable to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject. In some embodiments, the method further comprises c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject, wherein the further therapeutically effective dose of the anti-Ap protofibril antibody is administered according to a maintenance dosing regimen.

[0299]

[0296] In some embodiments, a method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD) is provided, wherein the method comprises: a) obtaining a measurement of a ptau-217 concentration or a ratio of p-tau217 to total tau217 in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody (e.g., lecanemab) if the ptau217 concentration or a ratio of p-tau217 to total tau217 is elevated compared to a control sample, e.g., compared to a an individual who does not have Alzheimer’s disease (AD), and / or if the ptau217 concentration or a ratio of p-tau217 to total tau217 is comparable to a positive control sample, e.g., comparable to an individual who has AD; c) ) obtaining a measurement of an MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the MTBR-tau243 concentration is elevated as compared to a control sample, e.g., compared to a an individual who does not have Alzheimer’s disease (AD), and / or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to an individual who has AD; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject in conjunction with a therapeutically effective dose of an anti-tau antibody, e.g., E2814.

[0300]

[0297] In some embodiments, the disorder (e.g., disease) is Alzheimer’s disease (AD). In some embodiments, the disorder is early AD. In some embodiments, the disorder is pre- AD. In some embodiments, the disorder is a neurological disorder (e.g., a neurodegenerative disorder or disease) characterized by Ap peptide-containing soluble and / or insoluble Ap aggregates. Exemplary disorders include but are not limited to Down’s Syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and Lewy Body Dementia.

[0301]

[0298] In some embodiments, treating the disorder comprises at least one of inhibiting the disorder, slowing progression of the disorder, delaying progression, arresting its development, reversing progression of disorder (e.g., reversing aggregation of Ap fibrils and / or tau), preventing the onset or development of the disorder, relieving or ameliorating one or more symptoms or underlying condition(s) of the disorder, curing the disorder, improving one or more clinical metrics, or preventing reoccurrence of one or more symptoms of the disorder. In some embodiments, treating a disorder comprises at least one of reducing a brain Ap level, reducing a brain tau level, reducing tau tangles, slowing an increase in brain tau level, slowing tau tangle formation, improving cognition, and altering biomarkers associated with AD pathology.

[0302]

[0299] In some embodiments, the method of treating the disorder further comprises steps of monitoring treatment efficacy and / or adjusting a treatment regimen. In some embodiments, the method further comprises, after steps of a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody such as lecanemab, applying further step c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject. In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0303]

[0300] In some embodiments, the further therapeutically effective dose is an adjusted dose (e.g., the size of the dose, the frequency of administration, and / or the route of administration is adjusted as compared to the treatment first administered to the subject). In some embodiments, the further therapeutically effective dose is an adjusted dose administered as part of an initiation dosing regimen, wherein both the treatment first administered to the subject and the further therapeutically effective dose are part of the initiation dosing regimen.

[0304]

[0301] In some embodiments, the further therapeutically effective dose of the anti-Ap protofibril antibody (e.g., lecanemab) is administered as part of a maintenance dosing regimen, e.g., a maintenance dosing regimen that follows an initiation dosing regimen.

[0302] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0305]

[0303] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0306]

[0304] In some embodiments, elevated levels of MTBR-tau243-256 in a sample (e.g., a CSF sample or preferably a blood sample) from a subject as compared to a sample from a control indicate that the subject has AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI.

[0307] Switch to a maintenance dosing regimen

[0308]

[0305] In some embodiments, an initiation dosing regimen is a dosing regimen in which a dose of the anti-Ap protofibril antibody (e.g., lecanemab), e.g., a therapeutically effective dose, is administered at a regular dosing interval on a repetitive basis. A therapeutically effective dose may be an initiation dose, a treatment dose, or a first dose. In an initiation dosage regimen (also called an initiation dosing regimen) the initiation dose of the anti-Ap protofibril antibody may be administered at an interval (e.g., daily, weekly, biweekly, or monthly), for a period of time, e.g., until the subject shows evidence of improved AD pathology and / or slowed progression of AD. An initiation dosing regimen may comprise administration of one or more therapeutically effective doses which differ from each other, e.g., a first therapeutically effective dose and a further therapeutic effective dose that has been changed from (e.g., adjusted relative to) the first therapeutically effective dose.

[0309]

[0306] In some embodiments, a maintenance dosing regimen is a dosing regimen in which a dose of the anti-Ap protofibril antibody (e.g., lecanemab), e.g., a therapeutically effective dose, is administered at a regular dosing interval on a repetitive basis in order to maintain therapeutically effective concentrations of the anti-Ap protofibril antibody in the subject and / or to maintain or continue to reduce levels of Ap protofibril in the brain of the treated subject. In some embodiments, the maintenance dosing regimen is sufficient to maintain reduced concentrations of MTBR-tau243 in biofluids (e.g., CSF or blood) of the treated subject. In some embodiments, the maintenance dosing regimen comprises intravenously administering lecanemab at a dose of 10 mg / kg relative to the weight of the subject, once every 4 weeks. In some embodiments, the maintenance dosing regimen comprises subcutaneously administering lecanemab at a dose of 360 mg or 250 mg once every week. The therapeutically effective dose administered according to a maintenance dosing regimen may be called a maintenance dose and may be administered at a regular interval on a repetitive basis. In some embodiments, each maintenance dose of the anti-Ap protofibril antibody may be administered daily, weekly, biweekly, or monthly. In some embodiments, the maintenance dose may be a dose that differs from the initiation dose. For example, the maintenance dose may be an adjusted dose in which the size of the dose, the frequency of administration, and / or the route of administration is adjusted as compared to one or more doses in the initiation dosing regimen.

[0310]

[0307] In some embodiments, the method of treating the subject comprises administration of the treatment (e.g., a therapeutically effective dose of the anti-Ap protofibril antibody) according to an initiation dosing regimen, after which the subject is switched to a maintenance dosing regimen.

[0311]

[0308] In some embodiments, one or more different steps or measurements may trigger the switch from the initiation dosing regimen to the maintenance dosing regimen.

[0312]

[0309] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

[0313]

[0310] In some embodiments, the subject is switched to a maintenance dosing regimen when additional biomarker measurements show evidence of improved AD pathology and / or slowed progression of AD. In some embodiments, the additional biomarker measurement is at least one of a decrease in amyloid or tau positron emission tomography (PET); an increase in cerebrospinal fluid level of Ap42 and / or AP42 / 40 ratio; a decrease in cerebrospinal fluid level of total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np- tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), cerebrospinal fluid level of neurogranin, and / or cerebrospinal fluid level of neurofilament light peptide (NfL); and a change in blood biomarkers as measured in the serum or plasma (e.g. increased levels of Ap42 and / or AP42 / 40 ratio; decreased plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-tau!81 / np-tau!81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light (NfL), as compared to the biomarker measurement(s) obtained from a control sample. In some embodiments, the control sample may be a sample from an individual who has AD. In some embodiments, the control sample may be a sample from the subject prior to treatment. In some embodiments, the control sample may be a sample from an individual who did not receive a therapeutically effective dose of an Ap protofibril antibody, e.g., a subject who receives no treatment, or a subject who receives a placebo. In some embodiments, the control sample is a sample from an individual who did not receive lecanemab. In some embodiments, a control is a reference measurement, e.g., an averaged measurement that combines population data from more than one subject and is representative of a subject who does not receive treatment.

[0314]

[0311] In some embodiments, the subject is switched to a maintenance dosing regimen when a decrease in tau PET SUVr is measured in the subject as compared to control sample, e.g., a sample from an individual who has AD or a sample from the subject prior to treatment.

[0315]

[0312] In some embodiments, the subject is switched to a maintenance dosing regimen when a low tau PET level as measured by PET SUVr is detected in the subject, e.g., a tau PET SUVr of about 1.1, preferably about 1.06, as measured with a MK6240 PET scan, e.g., of whole cortical gray matter. In some embodiments, the maintenance dosing regimen comprises administering a maintenance dose that maintains a tau PET SUVr level at or below 1.06.

[0316]

[0313] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

[0317]

[0314] In some embodiments, the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody.

[0318]

[0315] Exemplary dosing regimens comprising administration of initiation doses and maintenance doses of the anti-Ap protofibril antibody are disclosed in International Application No. PCT / US2024 / 033125, the contents of which are incorporated herein.

[0319]

[0316] Exemplary routes of administration of the anti-Ap protofibril antibody may be intravenous, subcutaneous, or a combination of both. In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject. In some embodiments, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

[0320]

[0317] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a different (e.g., lower) frequency of administration than the initiation dose. In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks.

[0321]

[0318] In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[0322]

[0319] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a dose of the anti-Ap protofibril antibody differs from (e.g., is lower than) the initiation dose.

[0323]

[0320] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg. For example, if the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg, the maintenance dosing regimen may comprise subcutaneous administration of the anti- Ap protofibril antibody at a therapeutically effective dose of 500 mg, 360 mg, or 250 mg. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 500 mg, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[0324]

[0321] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a different (e.g., a lower) frequency of administration than the initiation dose.

[0325]

[0322] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

[0326]

[0323] Following the switch to the maintenance dosing regimen as described herein, the maintenance dosing regimen may comprise a route of administration than the initiation dose.

[0324] In some embodiments, the initiation dosing regimen comprises intravenous administration of one or more initiation doses of the anti-Ap protofibril antibody, while the maintenance dosing regimen comprises subcutaneous administration of one or more maintenance doses of the anti-Ap protofibril antibody. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of one or more initiation doses of the anti-Ap protofibril antibody, while the maintenance dosing regimen comprises intravenous administration of one or more maintenance doses of the anti-Ap protofibril antibody.

[0327]

[0325] In some embodiments, the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when the MTBR-tau243 concentration in a biofluid sample (e.g., a CSF or blood sample) from the subject is reduced when compared to a control sample (e.g., a control sample from a subject who has AD, or a reference measurement obtained from the subject prior to treatment with the anti-Ap protofibril antibody). In some embodiments, the subject is switched after 18 months of administration of the anti-Ap protofibril antibody according to the initiation dosing regimen, e.g., if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample after 18 months. In some embodiments, the subject is switched after 24 months of administration of the anti-Ap protofibril antibody according to the initiation dosing regimen, e.g., if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample after 24 months.

[0328]

[0326] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered biweekly, after which the subject is switched to a maintenance dosing regimen comprising intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered monthly. In some embodiments, the initiation dosing is administered for 18 months or for 24 months, if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample.

[0329]

[0327] In some embodiments, initiation dosing regimen comprises intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered biweekly, after which subject is switched to a maintenance dosing regimen comprising subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 500 mg, 360 mg, or 250 mg, administered weekly. In some embodiments, the initiation dosing is administered for 18 months or for 24 months, if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample. In some embodiments, the subcutaneous doses are administered using a vial-syringe. In some embodiments, the subcutaneous doses are administered using an auto-injector.

[0330]

[0328] In some embodiments, initiation dosing regimen comprises subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, after which the subject is switched to a maintenance dosing regimen comprising subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 360 mg or 250 mg, administered weekly. In some embodiments, the initiation dosing is administered for 18 months or for 24 months, if the MTBR-tau243 concentration in the biofluid from the sample is reduced compared to a control sample. In some embodiments, the subcutaneous doses are administered using a vial-syringe. In some embodiments, the subcutaneous doses are administered using an auto-injector.

[0331]

[0329] In some embodiments, initiation dosing regimen comprises subcutaneous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 500 mg, administered weekly, after which the subject is switched to a maintenance dosing regimen comprising intravenous administration of the anti-Ap antibody (e.g., lecanemab) at a dose of 10 mg / kg relative to the weight of the subject, administered monthly. In some embodiments, the subcutaneous doses are administered using a vial-syringe. In some embodiments, the subcutaneous doses are administered using an auto-injector.

[0332] Combination therapy

[0333]

[0330] In some embodiments, the initiation dosing regimen further comprises administration of at least one Alzheimer’s disease medication other than the anti-Ap protofibril antibody.

[0334]

[0331] In some embodiments, the initiation dosing regimen comprises administration of a therapeutically effective dose of an anti-tau antibody sequentially or simultaneously with administration of the anti-Ap protofibril antibody.

[0335]

[0332] In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the anti-tau antibody is E2814.

[0336]

[0333] In some embodiments, the anti-Ap protofibril antibody is lecanemab. In some embodiments, the anti-Ap protofibril antibody lecanemab comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Ap protofibril antibody lecanemab comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

[0337]

[0334] In some embodiments, the anti-Ap protofibril antibody comprises the CDRs of lecanemab. In some embodiments, the anti-Ap protofibril antibody comprises the variable regions of lecanemab.

[0338]

[0335] In some embodiments, the anti-tau antibody E2814 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), and SEQ ID NO: 17 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). In some embodiments, the anti-tau antibody E2814 comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

[0339]

[0336] In some embodiments, the anti-tau antibody comprises the CDRs of E2814. In some embodiments, the anti-tau antibody comprises the variable regions of E2814.

[0340]

[0337] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

[0341]

[0338] In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose between 500 mg - 4500 mg (e.g., 500 mg, 750 mg, 1000 mg, 1500 mg, 3000 mg, 4500 mg). For example, in some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 750 mg once every 4 weeks. In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 1500 mg once every 4 weeks. In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 3000 mg once every 4 weeks. In some embodiments, the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose of 4500 mg once every 4 weeks. In some embodiments, the anti-tau antibody is intravenously administered at a dose of 750 mg once every four weeks for 12 weeks, a dose of 1500 mg once every four weeks for 12 weeks, a dose of 3000 mg once every four weeks for 12 weeks, and a dose of 4500 mg once every four weeks for 12 weeks.

[0339] In some embodiments, the initiation dosing regimen comprises pre-dosing with the anti-tau antibody (e.g., E2814) before the first administration of the anti-Ap protofibril antibody (e.g., lecanemab). In some embodiments, the subject receiving pre-dosing with the anti-tau antibody has pre- AD (e.g., the subject is asymptomatic for AD).

[0342]

[0340] In some embodiments, the initiation dosing regimen comprises pre-dosing with the anti-Ap protofibril antibody (e.g., lecanemab) before the first administration of the anti-tau antibody (e.g., E2814). In some embodiments, the subject receiving pre-dosing with the anti- Ap antibody has AD (e.g., early AD).

[0343]

[0341] In some embodiments, pre-dosing with the anti-tau antibody (e.g., E2814) comprises administration of a therapeutically effective dose of the anti-tau antibody for 52 weeks before the first administration of the anti-Ap protofibril antibody. In some embodiments, after 52 weeks of administration of the anti-tau antibody, the anti-Ap protofibril antibody is administered for 52 weeks.

[0344]

[0342] In some embodiments, pre-dosing with the anti-Ap protofibril antibody comprises administration of a therapeutically effective dose of the anti-Ap protofibril antibody for 52 weeks before the first administration of the anti-tau antibody. In some embodiments, after 52 weeks of administration of the anti-Ap protofibril antibody, the anti-tau antibody is administered for 52 weeks.

[0345]

[0343] Exemplary embodiments of a combination therapy combining an anti-Ap protofibril antibody and an anti-tau antibody are disclosed in International Application Nos. PCT / IB2021 / 000937 and PCT7US2022 / 079509, each of which are incorporated by reference herein.

[0346]

[0344] In some embodiments, the subject may be administered a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab) but a measurement of a MTBR- tau243 concentration in a biofluid sample from the subject indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial. For example, if the MTBR-tau243 concentration remains elevated compared to a reference / threshold or control sample (e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), then a therapeutically effective dose of an anti-tau antibody (e.g., E2814) may be administered. In some embodiments, administration of the anti-Ap protofibril is discontinued when the anti-tau antibody is administered. In some embodiments, administration of the anti-Ap protofibril antibody is continued when the anti-tau antibody is administered.

[0345] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0347]

[0346] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in tCSF or plasma.

[0348]

[0347] In some embodiments, elevated levels of MTBR-tau243-256 in a sample (e.g., a CSF sample or preferably a blood sample) from a subject as compared to a sample from a control indicate that the subject has AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI.

[0349]

[0348] In some embodiments, the subject is administered a therapeutically effective dose of an anti-Ap protofibril antibody (e.g., lecanemab), until the MTBR-tau243-256 level (e.g., in a plasma or CSF sample) indicates that the subject has later stage AD, e.g., in Braak stage V or VI, and then a therapeutically effective dose of an additional agent, e.g., an anti-tau antibody (e.g., E2814) is also administered, e.g., in combination or in lieu of the lecanemab.

[0350]

[0349] In some embodiments, a subject may be administered an anti-tau antibody (e.g., E2814) when a measurement of an E-MTBR-tau243 concentration in a biofluid sample from the subject is not elevated relative to a control. In some embodiments, lecanemab is administered in conjunction once a measurement of an E-MTBR-tau243 concentration in a biofluid sample from the subject is elevated relative to a control.

[0351]

[0350] In some embodiments, a subject may be administered a therapeutically effective dose of lecanemab, e.g., as a pre-treatment, but a measurement of a MTBR-tau243 concentration in a biofluid sample from the subject indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial, e.g., when the E-MTBR- tau243 concentration in a biofluid sample from the subject indicates a patient has reached Braak Stages V or VI. In some embodiments, if the MTBR-tau243 concentration remains elevated compared to a reference / threshold or control sample (e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD), even after administration of the anti-Ap protofibril antibody, then a therapeutically effective dose of an anti-tau antibody (e.g., E8214) may be administered. In some embodiments, administration of the anti-Ap protofibril antibody is discontinued when the anti-tau antibody is administered, e.g., when the E-MTBR-tau243 concentration in a biofluid sample from the subject indicates a patient has reached Braak Stages V or VI. In some embodiments, administration of the anti-Ap protofibril antibody is continued when the anti-tau antibody is administered.

[0352]

[0351] In some embodiments, the MTBR-tau243 species is a peptide fragment such as MTBR-tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR- tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0353]

[0352] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0354]

[0353] In some embodiments, elevated levels of MTBR-tau243-256 in a sample (e.g., a blood sample) from a subject as compared to a sample from a control indicate that the subject has AD in Braak stages III, IV, V, or VI, e.g., stage V or stage VI. Accordingly, in some embodiments, the subject is administered a therapeutically effective dose of an anti-tau antibody (e.g., E2814), but the MTBR-tau243-256 level indicates that the subject has AD in Braak stage III, IV, V, or VI, so then a therapeutically effective dose of anti-Ap protofibril antibody (e.g., lecanemab) may be administered.

[0355]

[0354] In some embodiments, a subject may be initially administered a therapeutically effective dose of lecanemab, based on a determination of levels of p-tau217 (and / or p- tau217R) in a biofluid sample from the subject (e.g., when levels of p-tau217 and / or p- tau217R are elevated as compared to the levels of p-tau217 and / or p-tau217R in a biofluid sample from a control, e.g., an individual who does not have AD). In some embodiments, after a period of time, a measurement of a MTBR-tau243 level in a biofluid sample from the subject (e.g., an elevated level relative to a healthy control or as compared to the level in a sample taken from the patient at an earlier time point) indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial. For example, the MTBR- tau243 concentration in a biofluid sample from the subject may be elevated as compared to the MTBR-tau243 concentration in a biofluid sample from a control (e.g., an individual who does not have AD, even after the subject has received the anti-Ap protofibril antibody, e.g., indicating that the subject has reached Braak Stages V or VI. In some embodiments, the at least one additional treatment comprises an anti-tau antibody (e.g., E8214). In some embodiments, the p-tau217 levels are reduced by treatment with lecanemab, but the MTBR- tau243 concentration is elevated as compared to the MTBR-tau243 concentration in a biofluid sample from a control (e.g., an individual who does not have AD). In some embodiments, adding the anti-tau antibody (e.g., E8214) leads to a reduction or slowing of the increase in the MTBR-tau243 concentration.

[0356]

[0355] In some embodiments, the subject is switched from an initiation dosing regimen as described herein to a maintenance dosing regimen when a further measurement of MTBR- tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD, wherein the maintenance dosing regimen comprises administering at least one maintenance dose of an anti-Ap protofibril antibody (e.g., lecanemab), at least one maintenance dose of the anti-tau antibody, or both. In some embodiments, the maintenance dosing regimen comprises administering at least one maintenance dose of lecanemab, e.g., by intravenous administration or subcutaneous administration at the doses and intervals described herein. In some embodiments, the maintenance dosing regimen comprises administering at least one maintenance dose of E2814. In some embodiments, the maintenance dosing regimen comprises administration of at least one maintenance dose of the E2814 and administration of at least one maintenance dose of lecanemab. In some embodiments, the maintenance dosing regimen maintains reduced levels of MTBR-tau243, amyloid, and / or tau.

[0357]

[0356] In some embodiments, the maintenance dosing regimen comprises administration of both the anti-tau antibody (e.g., E2814) and the anti-Ap protofibril antibody (e.g., lecanemab) according to a maintenance dosing regimen. In some embodiments, the maintenance dosing regimen comprises administration of the anti-tau antibody (e.g., E2814) according to a maintenance dosing regimen, while administration of the anti-Ap protofibril antibody (e.g., lecanemab) is not altered from the initiation dosing regimen. In some embodiments, the maintenance dosing regimen comprises administration of the anti-Ap protofibril antibody (e.g., lecanemab) according to a maintenance dosing regimen, while administration of the anti-tau antibody (e.g., E2814) is not altered from the initiation dosing regimen. For example, in an exemplary initiation dosing regimen, E2814 may be intravenously administered at a therapeutically effective dose of 750 mg - 4500 mg

[0358] (e.g. ,1500 mg or 3000 mg), once every 4 weeks, while lecanemab may be intravenously administered at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject, once every 2 weeks. In a further exemplary initiation dosing regimen, E2814 may be intravenously administered at a therapeutically effective dose of 750 mg - 4500 mg (e.g.,1500 mg), once every 4 weeks, while lecanemab may be subcutaneously administered at a therapeutically effective dose of 720 mg or 500 mg, once every week. At a later time, reduced levels of a biomarker (e.g., MTBR-tau243 concentration) may indicate that the subject may be switched to a maintenance dosing regimen for lecanemab. In some embodiments, the maintenance dosing regimen may comprise intravenous administration of lecanemab at a dose of 10 mg / kg, once every 4 weeks, without changing the dosing regimen for E2814. In some embodiments, the maintenance dosing regimen may comprise subcutaneous administration of lecanemab at a dose of 360 mg or 250 mg, once every week, without changing the dosing regimen for E2814.

[0359]

[0357] In some embodiments, a subject is selected for treatment with an initiation dosing regimen comprising administration of lecanemab and / or the anti-tau antibody (e.g., E2814), based on a measurement of an elevated MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject, as compared to a sample from a control.

[0360]

[0358] In some embodiments, the biomarker p-tau217 and / or p-tau217R may be used to select a treatment comprising administration of a therapeutically effective dose of an anti-Ap protofibril antibody such as lecanemab (e.g., according to an initiation dose as disclosed herein). In some embodiments, during the course of treatment, a measurement of a MTBR- tau243 (e.g., a MTBR-tau243 species such as tryptic MTBR-tau243 or E-MTBR-tau243) concentration in a biofluid sample from the subject indicates that administration of at least one additional Alzheimer’s disease medication may be beneficial. For example, if the MTBR- tau243 concentration remains elevated or increases compared to the MTBR-tau243 concentration from a reference / threshold or control sample (e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD), then a therapeutically effective dose of an anti-tau antibody (e.g., E2814) may be administered. In some embodiments, administration of the anti-Ap protofibril is discontinued when the anti- tau antibody is administered. In some embodiments, administration of the anti-Ap protofibril antibody is continued when the anti-tau antibody is administered. In some embodiments, administration of the anti-Ap protofibril antibody is continued at a maintenance dosing regimen when the anti-tau antibody is administered

[0361]

[0359] In some embodiments, a combination of MTBR-tau243 and p-tau217R may be used to select a subject for treatment with an anti-Ap protofibril antibody (e.g., lecanemab) and an anti-tau antibody (e.g., E2814).

[0360] In some embodiments, E2814 is administered in conjunction with lecanemab, e.g., wherein the lecanemab is administered subcutaneously. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg / mL SC formulation). In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg / mL SC formulation). In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg / mL SC formulation). In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 500 mg of lecanemab is administered subcutaneously once weekly using an autoinjector device (e.g., as 2 consecutive injections of 250 mg (2x1.25 mL of 200 mg / mL SC formulation).

[0362]

[0361] In some embodiments, E2814 is administered in conjunction with lecanemab, e.g., wherein the lecanemab is administered intravenously. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 2 weeks.

[0363]

[0362] In some embodiments, E2814 is administered in conjunction with lecanemab, e.g., wherein the lecanemab is administered intravenously. In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks.

[0364]

[0363] In some embodiments, the subject is switched to a maintenance dosing regimen of lecanemab, for example, if one or more measurements of MTBR-tau243 taken during the course of the combination treatment indicate that the treatment is effective or after at least 18 months of treatment with lecanemab. In some embodiments, the subject is switched to a maintenance dosing regimen of lecanemab if the level of p-tau217 and / or p-tau217R decreases, and / or a change is observed in another measurement known to reflect lecanemab efficacy, such as an increase in the AP42 / 40 ratio, a decrease in p-taul81, p-tau205, p-tau231, total tau, amyloid centiloid, and / or tau PET SUVR. In some embodiments, the maintenance dosing regimen is 360 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 250 mg of lecanemab administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, the maintenance dosing regimen is 10 mg / kg of lecanemab administered intravenously once every 4 weeks.

[0365]

[0364] Exemplary maintenance dosing regimens of lecanemab may be administered in combination with E2814. For example, in some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 360 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly.

[0366]

[0365] In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 250 mg of lecanemab is administered subcutaneously (e.g., using an autoinjector device) once weekly.

[0367]

[0366] In some embodiments, 3000 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 1500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 750 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks. In some embodiments, 500 mg of E2814 is administered intravenously once every 4 weeks and 10 mg / kg of lecanemab is administered intravenously once every 4 weeks.

[0368]

[0367] In some embodiments, the MTBR-tau243 is a peptide fragment such as MTBR- tau243-254 (tryptic MTBR-tau243) or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, the MTBR-tau243 species is CSF MTBR-tau243. In some embodiments, the MTBR-tau243 species is CSF E-MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma MTBR-tau243. In some embodiments, the MTBR-tau243 species is plasma E-MTBR-tau243.

[0369]

[0368] In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255. In some embodiments, the MTBR-tau243 species is a peptide fragment listed in Table 9. Any of these peptides may be measured in CSF or plasma.

[0370]

[0369] In some embodiments, elevated levels of MTBR-tau243 (e.g., tryptic MTBR- tau243 and / or E-MTBR-tau243) in a sample (e.g., a blood sample) from a subject as compared to a sample from a control (e.g., an individual who does not have AD) indicate that the subject has early AD, e.g., in Braak stages I, II, or III, whereupon the subject is administered treatment comprising lecanemab first, and then administered a combination of lecanemab and the anti-tau antibody, e.g., once a level of tryptic MTBR-tau243 and / or E- MTBR-tau243 indicates a patient has progressed to Braak stages III, IV, V, or VI, e.g., stage V or stage VI. In some embodiments, levels of MTBR-tau243-256 in a sample (e.g., a blood sample) from a subject that are not elevated as compared to a sample from a control indicate that the subject has pre- AD or early AD, e.g., Braak stages I, II, or III, whereupon the subject is administered treatment comprising the anti-tau antibody first. In some embodiments, the subject is later administered a combination of lecanemab and the anti-tau antibody, e.g., once the level of MTBR-tau243 is elevated in a sample from the patient, as compared to a control level. Assay for MTBR-tau243 in biofluids

[0371]

[0370] In some embodiments, a measurement of MTBR-tau243 concentration is obtained from a biofluid sample from a subject. In some embodiments, the biofluid sample is CSF. In some embodiments, the biofluid sample is blood. Accordingly, in some embodiments, MTBR-tau243 is CSF MTBR-tau243. In some embodiments, MTBR-tau243 is CSF E- MTBR-tau243. In some embodiments, MTBR-tau243 is CSF tryptic MTBR-tau243. In some embodiments, MTBR-tau243 is plasma MTBR-tau243. In some embodiments, MTBR- tau243 is plasma E-MTBR-tau243. In some embodiments, MTBR-tau243 is plasma tryptic MTBR-tau243.

[0372]

[0371] In some embodiments, MTBR-tau243 may be identified in a CSF sample by LC / MS. In some embodiments, tau species from CSF obtained from a subject are immunoprecipitated with a domain-specific anti-tau antibody, followed by analysis by LC / MS to calculate CSF biomarker levels (Horie et al., Nat Med, 2023; 29, 1954-1963) or plasma biomarker levels (Horie et al., Nat Med, doi: 10.1038 / s41591-025-03617-7). A chemical extraction method may be used after immunoprecipitation (Horie et al., Brain, 2021; 144(2): 515-527). The CSF MTBR-tau243 level may be expressed as a concentration, e.g., in pg / mL. Exemplary methods for detecting cleaved fragments of tau may be found in WO2024044637A2, the contents of which are incorporated herein by reference in their entirety.

[0373]

[0372] In some embodiments, the MTBR-tau243 concentration obtained from the sample from the subject is compared to a MTBR-tau243 concentration obtained from a control sample. In some embodiments, the control sample is from an individual who does not have Alzheimer's disease. For example, the individual may be a healthy subject. In some embodiments, the control sample is a reference measurement may be an average of measurements taken from more than one reference subject.

[0374] Additional biomarkers

[0375]

[0373] In some embodiments, the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment.

[0376]

[0374] In some embodiments, the change and / or difference in the measurement is selected from (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), neurogranin, and / or neurofilament light chain (NfL), and (d) decreased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0377]

[0375] In some embodiments, the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology during and / or after treatment.

[0378]

[0376] In some embodiments, the change and / or difference in the measurement is selected from (a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) increased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), neurogranin, and / or neurofilament light chain (NfL), and (d) increased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0379]

[0377] In some embodiments, the subject shows a change and / or difference in a measurement of MTBR-tau243, in combination with one or more additional biomarkers associated with AD pathology prior to treatment. For example, the subject may show elevated levels of MTBR-tau243, in combination with one or more of (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of ratio of A 1- 42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np- taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), neurogranin, and / or neurofilament light chain (NfL), and (d) decreased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p- tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p- taul81 / np-taul81, p-tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). In some embodiments, the combination of biomarkers comprises E-MTBR-tau243 and at least one of p-tau205 / np-tau205 and p-tau217 / np-tau217.

[0380]

[0378] In some embodiments, different biomarkers are used to detect different stages of AD progression. The different biomarkers may be used in combination. In some embodiments, the combination of biomarkers may be used to diagnose, select a patient for treatment, or stage AD. In some embodiments, the combination of biomarkers is MTBR- tau243 and an AP42 / 40 ratio, where a reduced AP42 / 40 ratio compared to a control indicates a later disease stage. In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau205 (e.g., a ratio of p-tau205 / np-tau205), where the ratio of p-tau205 level may increase earlier in disease progression than the MTBR-tau243 and can be used as an indicator of earlier disease stage. In some embodiments, the combination of biomarkers is MTBR- tau243 and p-tau231 (e.g., a ratio of p-tau231 / np-tau231). In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau217 (e.g., a ratio of p-tau217 / np- tau217). For example, high levels of p-tau217 / np-tau217 and MTBR-tau243 from a subject as compared to a control may indicate a late stage of AD, e.g., Ap+, CDR >1, or Braak stage III or higher. In some embodiments, high levels of p-tau217 / np-tau217 but little or no increase in MTBR-tau243 levels in a subject as compared to a control indicates an earlier Braak stage, e.g., stage I or stage II. In some embodiments, when the combination of biomarkers indicates early AD, the patient is administered lecanemab. In some embodiments, when the combination of biomarkers indicates more advanced AD (e.g., Braak stage, e.g., stages V or VI), the patient is administered lecanemab and a second agent, e.g., an anti-tau agent (e.g., E2814).

[0381]

[0379] In some embodiments, the combination of biomarkers may be used to monitor AD treatment. Increases in the biomarkers may indicate disease progression, e.g., Ap+, CDR >1, or Braak stage III or higher. In some embodiments, the combination of biomarkers is MTBR- tau243 and an AP42 / 40 ratio. In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau217 (e.g., a ratio of p-tau217 / np-tau217). In some embodiments, the combination of biomarkers is MTBR-tau243 and p-tau205 (e.g., a ratio of p-tau205 / np- tau205). In some embodiments, the combination of biomarkers is MTBR-tau243 and p- tau231 (e.g., a ratio of p-tau23 l / np-tau231). For example, a patient may be administered lecanemab and monitored for levels of p-tau217 / np-tau217 and MTBR-tau243. In some embodiments, increased levels of p-tau217 / np-tau217 but little or no increase in MTBR- tau243 levels in a subject as compared to a control may indicate an earlier Braak stage, e.g., stage I or stage II.

[0382]

[0380] In some embodiments, the MTBR-tau243 species in the combination is a peptide fragment such as MTBR-tau243-254 or MTBR-tau243-256 (E-MTBR-tau243). In some embodiments, MTBR-tau243-256 may be deamidated, for example, on residue N255.

[0383] Amyloid PET

[0384]

[0381] PET imaging enables visualization of amyloid plaques in the brain, which were previously detected only by examining the brain at autopsy. Amyloid PET is a valuable tool for diagnosing AD and monitoring progression of the disease, as it has a high predictive accuracy for the presence of AD pathology (Hansson et al., Nature Medicine, 2021. 27: 954- 963; Therriault et al., Nature Reviews Neurology, 2024. 20: 232-244). Amyloid PET may be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably a blood or CSF marker, e.g. MTBR-tau243 in blood or CSF.

[0385]

[0382] As used herein, the term “Amyloid PET” refers to Amyloid positron emission tomography imaging. In some embodiments, PET imaging (also referred to as a PET scan) is performed to assess for amyloid pathology. In some embodiments, amyloid PET is assessed with a PET tracer and uses the same tracer in follow-up assessments. In some embodiments, the amyloid PET tracer may be florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and / or flutametamol (e.g., 18F-Flutemetamol (Vizamyl®)).In some embodiments, the PET imaging uses a florbetapir tracer. In some embodiments, the PET imaging uses a flutemetamol tracer. In some embodiments, the PET imaging uses a florbetaben tracer. Other exemplary amyloid PET tracers may be [1 lC]PiB or [18F]NAV4694 (flutafuranol).

[0386]

[0383] Amyloid positron emission tomography (PET) imaging can be used to confirm the presence of amyloid pathology in the brain of early AD subjects in the screening phase of the study and / or to evaluate the effects of the at least one anti-Ap antibody on amyloid levels in the brain, both by whole brain analysis (e.g., the average of 5-6 cortical regions) and brain region analysis. In some embodiments, the PET scan uses florbetaben (e.g., 18F -Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and / or flutametamol (e.g., 18F- Flutemetamol (Vizamyl®)). In some embodiments, the PET scan uses florbetapir. In some embodiments, the PET scan uses a flutemetamol tracer. In some embodiments, the PET scan uses a florbetaben tracer. In some embodiments, amyloid plaque load can be identified by a PET imaging uptake visual read, e.g., by a trained radiologist. In some embodiments, 2 readers (1 designated as Primary Reader) visually assess the images to determine whether the scan is positive or negative for amyloid. In further embodiments, four regions of the brain are assessed for uptake of the imaging agent: the temporal lobes, the occipital lobes, the prefrontal cortex, and the parietal cortex and a positive amyloid scan has either 1 region with intense gray matter uptake that is greater than the white matter uptake and extends to the outer edges of the brain, or 2 regions with areas of reduced gray -white contrast. In further embodiments, if disagreement occurs between 2 readers, both meet to review the scan for a consensus read.

[0387]

[0384] In some embodiments, amyloid plaque load can be identified by a standard uptake value ratio (SUVr) as compared to a reference region. Methods for calculating amyloid PET SUVr are known in the art and may include those described herein. One exemplary method for quantitative analysis (e.g, computing) of SUVr is the PMOD PNEURO Biomedical Image Quantification Software (PMOD Technologies, Zurich, Switzerland. In some embodiments, PET images are first assessed for subject movement in the X, Y, and Z planes and corrected for motion, if needed, before individual images (e.g., 5-minute emission frames) are averaged, e.g., using a PMOD Averaging Function (PET frames averaged to increase the signal to noise ratio). In some embodiments, corresponding MRIs from subjects are prepared (e.g., using matrix size reduction processing, cropping of the MRI to include only the brain, segmentation to separate images into binary maps of gray matter, white matter, and CSF, and stripping the image of skull leaving only brain mask). In some embodiments, the averaged PET images and prepared MRIs are matched using the PMOD Matching Function, placing the images in the same orientation. In some embodiments, a Brain Normalization function, e.g., as provided by PMOD software, is used along with Brain Norm and Rigid Matching transformation matrices, to produce an averaged PET. In some embodiments, this averaged PET which is normalized to the MNInst space (Senjem et al, 2005) that is in the same orientation as the subject’s segmented MRI for quantitative analysis. In some embodiments, the PMOD Mask Function is used to mask the brain and zero the image outside of the mask to create a Normalized Gray Matter PET and a Normalized White Matter PET. Standard uptake values (SUVs) may be calculated for all gray matter mapped regions and the 3 white matter regions (pons, cerebellar white, and subcortical white) using PMOD software calculated using the normalized PET, subject weight, and injected dose of tracer to arrive at the units of SUVs. In some embodiments, the SUVr is the ratio of the global cortical average as compared to a reference region of choice. In some embodiments, a whole cerebellum mask is used as the reference region. In some embodiments, the reference region is subcortical white matter, derived whole cerebellum, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and composite reference regions consisting of cerebellar cortex, pons subcortical white matter, and cerebella white matter.

[0388]

[0385] In some embodiments, the amyloid beta plaque levels in the brain are evaluated using PET imaging. In some embodiments, the PET imaging uses an amyloid PET tracer. In some embodiments, the PET imaging uses florbetaben (e.g., 18F-Florbetaben (Neuraceq®)), florbetapir (e.g., 18F-Florbetapir (Amyvid®)), and / or flutametamol (e.g., 18F-Flutemetamol (Vizamyl®))In some embodiments, the PET imaging uses a florbetapir tracer. In some embodiments, the PET imaging used a flutemetamol tracer. In some embodiments, the PET imaging uses a florbetaben tracer. In some further embodiments, different tracers may yield different results. In some embodiments, the adjusted mean reduction threshold is dependent upon the tracer used.

[0389]

[0386] In some embodiments, a subject’s brain amyloid level is determined by visual reads of amyloid PET images and expressed as a PET standard uptake value ratio (SUVr value). In some embodiments, a brain amyloid level is reduced after administration of an anti- Ap protofibril antibody (e.g., lecanemab), as described herein.

[0390]

[0387] In some embodiments, MTBR-tau243 may be a proxy for amyloid PET in a subject, wherein increased levels of MTBR-tau 243 (e.g., tryptic MTBR-tau243 and / or E- MTBR-tau243 from CSF and / or plasma) in a subject over time indicate increased amyloid PET.

[0391] Tau PET

[0392]

[0388] PET imaging enables visualization of tau accumulation in the brain, which was previously detected only by examining the brain at autopsy. Tau PET is a valuable tool for diagnosing AD and monitoring progression of the disease, particularly as the tau NFT burden is strongly correlated with severity of clinical AD symptoms (Hansson et al., Nature Medicine, 2021. 27: 954-963; Therriault et al., Nature Reviews Neurology, 2024. 20: 232- 244). Tau PET may be used in conjunction with other biomarker measures, including any of those disclosed herein, preferably a blood or CSF marker, e.g. MTBR-tau243 in blood or CSF.

[0393]

[0389] Tau PET also correlates strongly with MTBR-tau243, supporting the use of MTBR-tau243 as a proxy for tau PET. In some embodiments, the use of MTBR-tau243 may reduce the need for tau PET measurements. In some embodiments, MTBR-tau243 may be used as a single marker measure for effects of amyloid and / or tau antibodies on tau accumulation, simplifying biofluid assays. In some embodiments, MTBR-tau243 may be used with an anti-Ap protofibril antibody (e.g., lecanemab) to track the effects of the antibody on tau pathology.

[0394]

[0390] As used herein, “tau PET” refers to tau positron emission tomography. In some embodiments, PET imaging (e.g., a PET scan) is performed to assess tau pathology.

[0395]

[0391] In some embodiments, tau PET is assessed with a PET tracer and uses the same tracer in follow-up assessments. In some embodiments, the tau PET tracer may be an arylquinoline derivatives (e.g., [18F]THK5317 and [18F]THK5351), a pyridoindole derivative (e.g., [18F]AV-1451 also known as [18F]-flortaucipir), or a phenyl / pyridinyl- butadienyl-benzothiazone / benzothiazolium (PBB) derivative such as [11C]PBB3. In some embodiments, the PET tracer is [18F]-RO-948, [18F]-PI-2620, [18F]-JNJ-311, and [18F]- GTP1.

[0396]

[0392] Tau positron emission tomography (PET) imaging can be used to confirm the presence of tau pathology in the brain of early AD subjects in the screening phase of the study and / or to evaluate the effects of the at least one anti-Ap protofibril antibody on amyloid levels in the brain, both by whole brain analysis (e.g., the average of 5-6 cortical regions) and brain region analysis (e.g., in a temporal brain region). In some embodiments, the PET scan uses a [18F]MK-6240 (florquinitau) tracer. In some embodiments, tau load can be identified by a PET imaging uptake visual read, e.g., by a trained radiologist. In embodiments, regions of the brain are assessed for uptake of the imaging agent. In some embodiments, the temporal region is assessed for a tau PET level. In some embodiments, the frontal region is assessed for a tau PET level. In some embodiments, the parietal region is assessed for a tau PET level. In some embodiments, the occipital region is assessed for a tau PET level. In some embodiments, the cingulate region is assessed for a tau PET level. In some embodiments, the temporal region comprises the medial temporal region. In some embodiments, the medial temporal region comprises the hippocampus, the entorhinal cortex, the parahippocampus, and / or the anterior medial / lateral temporal lobes. In some embodiments, the temporal region comprises the meta-temporal region. In some embodiments, the meta-temporal region comprises the amygdala, the entorhinal cortex, the parahippocampus, the middle / interior and posterior temporal lobe, and / or the fusiform region. In some embodiments, the temporal region comprises the temporal lobe. In some embodiments, the temporal lobe comprises the superior anterior / posterior temporal lobe, the middle / inferior temporal lobe, the posterior temporal lobe, and / or the fusiform cortex. In some embodiments, the whole cortical gray matter is assessed for a tau PET level. In some embodiments, the reference region used for assessing a tau PET level is the ventral cerebellum (Cb).

[0397]

[0393] In some embodiments, a “tau PET level” can be identified by a standard uptake value ratio (SUVr) as compared to a reference region as measured by tau PET imaging. As used herein, a “tau PET level”, “tau level in a brain” and “tau load” are used interchangeably. As used herein a tau PET level refers to a measurement of a level of tau in a brain region, e.g., a temporal region, by PET. Methods for calculating tau PET SUVr are known in the art and may include those described herein. In some embodiments, a Standard Uptake Value Ratio Quantitative analysis of amyloid levels is completed using PMOD PNEURO Biomedical Image Quantification Software (PMOD Technologies, Zurich, Switzerland). In some embodiments, PET images are first assessed for subject movement in the X, Y, and Z planes and corrected for motion, if needed, before individual images (e.g., 5-minute emission frames) are averaged, e.g., using a PMOD Averaging Function (PET frames averaged to increase the signal to noise ratio). In some embodiments, corresponding MRIs from subjects are prepared (e.g., using matrix size reduction processing, cropping of the MRI to include only the brain, segmentation to separate images into binary maps of gray matter, white matter, and CSF, and stripping the image of skull leaving only brain mask). In some embodiments, the averaged PET images and prepared MRIs are matched using the PMOD Matching Function, placing the images in the same orientation. In some embodiments, a Brain Normalization function, e.g., as provided by PMOD software, is used along with Brain Norm and Rigid Matching transformation matrices, to produce an averaged PET. In some embodiments, this averaged PET which is normalized to the MNInst space (Senjem et al, 2005) that is in the same orientation as the subject’s segmented MRI for quantitative analysis. In some embodiments, the PMOD Mask Function is used to mask the brain and zero the image outside of the mask to create a Normalized Gray Matter PET and a Normalized White Matter PET. Standard uptake values (SUVs) may be calculated for all gray matter mapped regions and the 3 white matter regions (pons, cerebellar white, and subcortical white) using PMOD software calculated using the normalized PET, subject weight, and injected dose of tracer to arrive at the units of SUVs. In some embodiments, the SUVr is the ratio of the global cortical average as compared to a reference region of choice. In some embodiments, a whole cerebellum mask is used as the reference region. In some embodiments, the reference region is subcortical white matter, ventral cerebellum, derived whole cerebellum, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and composite reference regions consisting of cerebellar cortex, pons subcortical white matter, and cerebella white matter.

[0398]

[0394] In some embodiments, a tau PET level is assessed with a PET tracer. In some embodiments, the PET tracer is [18F]MK-6240. In some embodiments, a tau PET level can be used to classify patients as having different levels of tau. For example, in some embodiments, a patient may be classified as having a low level of tau if the tau PET level is below a threshold value. The threshold value may be identified as tau levels in the whole cortex, or, alternatively, in a particular region of the interest. In some embodiments, the threshold value may be a tau PET level measured in the whole cortex (e.g., whole cortical gray matter). In some embodiments, the threshold values are cut-offs for classifying a patient as having a low tau PET level, an intermediate tau PET level, or a high tau PET level. In some embodiments, a patient may be classified as having a low level of tau if a level of tau as measured in a particular region of the interest, e.g., whole cortical gray matter, by PET using, e.g., an MK tracer, is below about 1.1, e.g., below about 1.0. In some embodiments, a patient may be classified as having a low level of tau if the tau PET level as measured using an MK tracer is below 1.06. In some embodiments, a patient may be classified as having an intermediate level of tau if the tau PET level as measured by MK tracer is between about 1.1 and 3.0, or between 1.06 and 2.91. In some embodiments, a patient may be classified as having a high level of tau if the tau PET level as measured by MK tracer is above about 3.0, e.g., above 2.91. In some embodiments, the thresholds for tau PET levels are <1.06 (low levels), 1.06 to 2.91 (intermediate levels), and > 2.91 (high levels), when the tau PET levels are determined in the whole cortex, e.g., using the PET tracer is [18F]MK-6240. In some embodiments, cut-offs may be determined according to tau PET levels in a particular brain region. As would be understood by one of ordinary skill in the art, the threshold values for classifying patients as having low, intermediate, or high tau PET levels may vary based on the methodology used to determine a tau level in the brain, e.g., depending on the tau PET methodology and tracer used in the tau PET imaging. In some embodiments, the threshold value may be determined using a common scale for tau PET which reflects analysis methods and / or measurements obtained with different tau PET tracers.

[0399]

[0395] In some embodiments, MTBR-tau243 may be a proxy for tau PET in a subject, wherein increased levels of MTBR-tau 243 (e.g., tryptic MTBR-tau243 and / or CSF E- MTBR-tau243 from CSF and / or plasma) in a subject over time indicate increased tau PET. Subjects having AD, suspected of having AD, or at risk of developing AD

[0400]

[0396] Subjects treated herein include those having AD or suspected of having AD. In some embodiments, the subject shows changes (e.g., an increase, a decrease, a change in the rate and / or extent of an increase, or a change in the rate and / or extent of the decrease) in one or more biomarkers associated with AD pathology (e.g., the biomarkers described above), as compared with a reference measurement. In some embodiments, the reference measurement may be a measurement taken from the same subject, e.g., at an earlier point in time, or a measurement in a part of the subject’s body, tissue, or fluids where the biomarkers levels do not change in response to AD pathology. In some embodiments, the reference measurement may be a measurement taken from another subject, such as a healthy control subject, or may be an average of measurements taken from more than one reference subject.

[0401]

[0397] In some embodiments, the subject may show a change and / or a difference in a measurement of MTBR-tau243 prior to treatment, e.g., an increase in MTBR-tau243 as compared to the reference measurement, e.g., as compared to an earlier measurement in the subject or as compared to a control subject who does not have AD.

[0402]

[0398] In some embodiments, in addition to or in lieu of an MTBR-tau243 measurement, the subject may show a change and / or a difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment, e.g., one or more of (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) decreased cerebrospinal fluid levels of Api-42 (e.g., a decreased ratio of Api-42 / 1-40) and / or increased total total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau23 l / np-tau231), neurogranin, and / or neurofilament light chain (NfL), and (d) decreased blood serum or plasma levels of Api-42 (e.g., a decreased ratio of Api-42 / 1-40 in the plasma or serum), and / or increased total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL), as compared to a reference measurement (e.g., measurement from a healthy control). In some embodiments, the subject may show a change in the ratio of phosphorylated to nonphosphorylated Tau 217 (P-Tau217 / NP-Tau217 ratio, also called P-Tau217R or pTau217R) in blood plasma or serum, e.g., the ratio may be increased in subjects who have, are suspected of having, or are at risk of developing AD. Without being bound by theory, biomarkers as disclosed herein may be effective for predicting amyloid PET status (Rissman et al., 2024, Alzheimers & Dementia, 20(2): 1214-1224; Janelidze et al., 2022, Alzhimer’s & Dementia, 18:283-293) and for detecting and diagnosing AD (Hampel et al., 2023, Neuron, 111(18):2781-2799). In some embodiments, at least one of p-tau217 / np-tau217, AP42 / AP40, and p-taul81 / np-taul81 may be used to predict amyloid PET status. In some embodiments, a measurement of p-tau217 and / or AP42 / AP40 may be used to predict amyloid PET status. In some embodiments, a combination of p-tau217 and AP42 / AP40 may be used to predict amyloid PET status. In some embodiments, the ratios of p-tau217 / np-tau217 and AP42 / AP40 may be used in combination to predict amyloid PET status. In some embodiments, MTBR- tau243, e.g., MTBR-tau243-254 or MTBR-tau243-256 (E-MTBR-tau243) or MTBR-tau243- 256 (deamidated, e.g., on residue N255) may be used in combination with one or more of p- tau217 / np-tau217, AP42 / AP40, p-taul81 / np-taul81, p-tau205 / np-tau205, and p-tau231 / np- tau231 to predict amyloid PET status.

[0403]

[0399] In some embodiments, the subject is amyloid-positive, e.g., as indicated by a PET assessment, a CSF assessment of AP(l-42), MRI, and / or retinal amyloid accumulation.

[0404]

[0400] In some embodiments, a subject has AD, e.g., has been diagnosed with AD. For example, the subject may have been diagnosed with (a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and / or has been diagnosed as having mild Alzheimer’s disease dementia; (b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; (c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; (d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an informant; (e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or (f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

[0405]

[0401] In some embodiments, the subject has early AD. The subject with early AD may have symptoms ranging in severity from mild cognitive impairment due to AD - intermediate likelihood to mild Alzheimer’s disease dementia. In some embodiments, subjects with early AD have MMSE scores of 22 to 30 and Clinical Dementia Rating (CDR) global range 0.5 to 1.0.

[0402] In some embodiments, the subject has a low tau PET level in a global brain measurement, for example, as measured by tau PET. A low level of tau PET may refer to a low level of tau aggregation as imaged by PET scan imaging, e.g., a low level of cortical tau aggregation. In some embodiments, a subject with low tau PET also has accumulation of tau in certain brain regions, e.g., one or more early Braak regions or a composite of regions where tau accumulates in early AD. In some embodiments, a subject may be classified as having a low level of tau if a level of tau as measured by PET using an MK tracer (e.g., MK6240) is below about 1.1, e.g., below about 1.0. In some embodiments, a patient may be classified as having a low level of tau if the tau PET level as measured using an MK tracer is below 1.06. In some embodiments, a patient may be classified as having an intermediate level of tau if the tau PET level as measured by MK tracer is between about 1.1 and 3.0, e.g., between 1.06 and 2.91. In some embodiments, a patient may be classified as having a high level of tau if the tau PET level as measured by MK tracer is above about 3.0, e.g., above 2.91.

[0406]

[0403] In some embodiments, a subject is suspected of having AD, e.g., based on one or more biomarkers and / or cognitive symptoms of dementia.

[0407]

[0404] In some embodiments, a subject is at risk for developing AD but has not yet exhibited cognitive symptoms of dementia.

[0408]

[0405] In some embodiments, a subject may have risk factors for AD, wherein the risk factors are related to age or genetic mutations. In some embodiments, the subject is ApoE4- positive. In some embodiments, the subject is at least 65 years old, e.g., 65 to 80 years old. In some embodiments, the subject is 55 to 64 years old and has at least one risk factor chosen from: (i) a first degree relative diagnosed with dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing. In some embodiments, a subject at risk for AD has elevated brain amyloid, e.g., as measured by and / or confirmed by PET assessment, but does not exhibit any detectable cognitive symptoms. In some embodiments, a subject at risk for AD has a change in a biomarker such as amyloid PET; tau in the brain, e.g., as measured by positron emission tomography (PET), cerebrospinal fluid levels of one or more of Api-42 (or a ratio of Ap 1-42 / 1 -40 in the cerebrospinal fluid), total tau, phosphorylated tau (e.g., p- taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non- phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), neurogranin, and neurofilament light chain (NfL), and / or a change in a blood serum or plasma levels of one or more of Api-42 (or a ratio of Api-42 / 1-40), total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL), relative to a control subject or population.

[0409]

[0406] In some embodiments, a subject at risk for developing AD may have pre- AD (also referred to as preclinical AD, in which subjects are cognitively unimpaired but have elevated amyloid in the brain, e.g., as based on a change in one or more biomarkers associated with AD pathology). For example, the subject may show a change in one or more biomarkers associated with AD pathology, but no cognitive impairment, e.g., as measured by clinical symptoms of AD. In some embodiments, the subject has a Global Clinical Dementia Rating (CDR) score of 0. In some embodiments, the subject has a Mini -Mental State Examination (MMSE) score greater than or equal to 27, with educational adjustments. In some embodiments, the subject has a Wechsler Memory Scale-IV Logical Memory (subscale) II (WMS-IV LMII) score better than one standard deviation below age-adjusted mean in the WMS-IV LMII; namely a score of greater than 15 for a subject of age ranging from 50 to 64 years, of greater than 12 for a subject of age ranging from 65 to 69 years, of greater than 11 for a subject of age ranging from 70 to 74 years, of greater than 9 for a subject of age ranging from 75 to 79 years, and of greater than 7 for a subject of age ranging from 80 to 90 years.

[0410]

[0407] In some embodiments, a subject at risk for developing AD has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

[0411]

[0408] In some embodiments, the subject has a mutation in APP.

[0412]

[0409] In some embodiments, the subject has a dominantly inherited Alzheimer’s disease (DIAD).

[0413]

[0410] In some embodiments, the subject has mild-to-moderate AD, e.g., where mild AD may be associated with Mini-Mental State Examination [MMSE] scores >20) and may be characterized by forgetfulness and difficulties with activities of daily living (ADLs). Moderate AD may be associated with MMSE scores of about 10-19 and may be characterized by marked memory loss and a requirement for significant assistance with ADLs.

[0414]

[0411] In some embodiments, the subject has AD at a late Braak stage, e.g., stage III or higher. Anti-Ap protofibril antibodies

[0415]

[0412] In some embodiments, an anti-Ap protofibril antibody used in the methods disclosed herein is an antibody capable of binding to an Ap protofibril, or an antigen binding fragment thereof. In some embodiments, the anti-Ap protofibril antibody is lecanemab, and comprises one or more of the sequences listed in Tables 1-4, e.g., comprising a complete set of 6 complementarity determining regions (CDRs) and / or a complete set of variable regions and / or a complete set of heavy and light chain sequences from the tables. In some embodiments, the anti-Ap protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-Ap protofibril antibody comprises human heavy and light chain variable region frameworks. In some embodiments, the anti-Ap protofibril antibody comprises a human IgGl heavy chain constant region, and a human Ig kappa light chain constant region. In some embodiments, the anti-Ap protofibril antibody comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 9 and a light chain comprising an amino acid sequence of SEQ ID NO: 10. “CDRs” used herein in the context of an antibody sequence or structure refers to complementarity determining regions, that provide the main determinants of antigen binding. Generally, the antigen-binding site has six CDRs; three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3). The CDRs may be determined according to the Kabat numbering scheme, which may be determined by according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991, hereafter referred to as “Kabat report”).

[0416]

[0413] In some embodiments, the at least one anti-Ap protofibril antibody comprises a human constant region. In some embodiments, the human constant region of the at least one anti-Ap protofibril antibody comprises a heavy chain constant region chosen from IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variation thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region is chosen from IgGl and allelic variations thereof. The amino acid sequence of human IgGl constant region is known in the art and set out in SEQ ID NO: 11.

[0417]

[0414] In some embodiments, the human constant region of the at least one anti-Ap antibody comprises a light chain constant region chosen from K-k-chain constant regions and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region is chosen from K and allelic variations thereof. The amino acid sequence of human K chain constant region is known in the art and set out in SEQ ID NO: 12.

[0418]

[0415] In some embodiments, the at least one anti-Ap protofibril antibody is lecanemab (also BAN2401, LEQEMBI, or lecanemab-irmb)). The terms “BAN2401” and “lecanemab” are used interchangeably and refer to a humanized IgGl monoclonal version of mAbl58, which is a murine monoclonal antibody raised to target protofibrils and disclosed in WO 2007 / 108756 and Journal of Alzheimer’s Disease 43: 575-588 (2015). Lecanemab comprises three heavy chain complementarity determining regions as described in Table 1 : (HCDR1, HCDR2, and HCDR3) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3) and is described in WO 2007 / 108756 and in Journal of Alzheimer’s Disease 43:575-588 (2015). Lecanemab comprises (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8 (Table 2). The full length sequences of heavy chain and light chain of Lecanemab are set forth in SEQ ID NOs: 9 and 10 and are described in WO 2007 / 108756 and in Journal of Alzheimer’s Disease 43:575-588 (2015).

[0419]

[0416] In some embodiments, the anti-Ap protofibril antibody to be used in treatment is present in a concentration of at least 80 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration of at least 100 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration of at least 200 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration of at least 250 mg / mL. In some embodiments, the antibody is present in a concentration ranging from 80 mg / mL to 300 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 85 mg / mL to 275 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 90 mg / mL to 250 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 95 mg / mL to 225 mg / mL. In some embodiments, the anti-Ap protofibril antibody is present in a concentration ranging from 100 mg / mL to 200 mg / mL. In some embodiments, the antibody is present in a concentration of 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, or 300 mg / mL. In some embodiments, the antibody is present in a concentration of 100 mg / mL. In some embodiments, the antibody is present in a concentration of 200 mg / mL. In some embodiments, the antibody is present in a concentration of 250 mg / mL. In some embodiments, the antibody is present in a concentration of 300 mg / mL. In some embodiments, the antibody is lecanemab.

[0420]

[0417] In some embodiments, the anti-Ap protofibril antibody may be administered intravenously, subcutaneously, or a combination of both. In some embodiments, the anti-Ap protofibril antibody is intravenously administered at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject, once every 2 weeks. In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered at a therapeutically effective dose (e.g., 500 mg) once every week. Additional exemplary dosages and dosing regimens are described below in Section D.

[0421]

[0418] As used herein, a “fragment” or “antigen binding fragment” of an anti-Ap protofibril antibody comprises a portion of the antibody, for example comprising an antigenbinding or a variable region thereof. In some embodiments, an antibody (e.g., an anti-Ap protofibril antibody) as used herein may refer to a full-length antibody comprising variable and constant regions, and / or an antigen-binding fragment of an antibody, e.g., a fragment comprising CDRs of the heavy and light chain, the heavy and light chain variable regions, the heavy and light chains of the antibody, and / or any fragments, variations, or alternative formats thereof. Accordingly, in any embodiment disclosed herein, a full-length antibody or a fragment of the antibody (e.g., an antigen-binding fragment) may be used, preferably a full antibody such as lecanemab. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and singlechain antibody molecules.

[0422]

[0419] In some embodiments, the anti-Ap protofibril antibody (e.g., lecanemab, or an antigen-binding fragment thereof) reduces cerebral amyloid angiopathy (CAA), amyloid beta peptide deposits in the walls of small to medium blood vessels in the central nervous system and meninges. Anti-Tau Antibodies

[0423]

[0420] In some embodiments, the anti-tau antibody administered herein is an anti-tau antibody or antigen binding fragment thereof that is capable of binding to human tau. In some embodiments, the anti-tau antibody is E2814.

[0424]

[0421] In some embodiments, the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3), as defined by Kabat (Table 6). In some embodiments, the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22 (e.g., as defined by Kabat or IMGT). In some embodiments, the anti-tau antibody comprises a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22 (Table 7).

[0425]

[0422] In some embodiments, the anti-tau antibody comprises the CDRs of E2814. In some embodiments, the anti-tau antibody comprises the variable regions of E2814.

[0426]

[0423] In some embodiments, the anti-tau antibody comprises a human constant region. In some embodiments, the human constant region comprises a heavy chain constant region chosen from IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variation thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 23 (Table 8).

[0427]

[0424] In some embodiments, the human constant region of the anti-tau antibody comprises a light chain constant region chosen from K and X-chain constant regions and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO: 24 (Table 8).

[0428]

[0425] In some embodiments, the anti-tau antibody comprises E2814 or an antigen binding fragment thereof. E2814 is disclosed in US 2019 / 0112364 Al as clone 7G6- HCzu25 / LCzul8, the sequences of which are incorporated by reference herein.

[0429]

[0426] In some embodiments, the anti-tau antibody is any of those disclosed in US 2019 / 0112364 Al, the disclosure of which is fully incorporated herein by reference. In some embodiments, the anti-tau antibody comprises the CDR and / or variable region sequences from antibody clone 7G6-HCzu25 / LCzul8 as disclosed in US 2019 / 0112364 Al, the sequences of which are incorporated by reference herein. In some embodiments, the anti-tau antibody is produced by antibody-producing cells deposited with the American Type Culture Collection (10801 University Blvd., Manassas, Va. 20110-2209) on Oct. 11, 2017 with Accession No. PTA-124524.

[0430]

[0427] In some embodiments, the anti-tau antibody is administered twice daily. In some embodiments, the anti-tau antibody is administered once daily. In some embodiments, the anti-tau antibody is administered weekly. In some embodiments, the anti-tau antibody thereof is administered twice weekly. In some embodiments, the anti-tau antibody is administered three times weekly. In some embodiments, the anti-tau antibody is administered every 2 weeks. In some embodiments, the anti-tau antibody is administered every four weeks or monthly.

[0431]

[0428] In some embodiments, the anti-tau antibody is administered at a dose ranging from 200 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 500 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1000 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1500 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 3000 mg to 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 3000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 1500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 1000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg to 500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 200 mg, 500 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, or 4500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 750 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 1500 mg. In some embodiments, the anti-tau antibody is administered at a dose of 3000 mg. In some embodiments, the anti-tau antibody is administered at a dose of 4500 mg.

[0432]

[0429] In some embodiments, an anti-Ap protofibril antibody is administered in conjunction with the anti-tau antibody, wherein anti-Ap protofibril antibody is administered every two weeks at a dose of 10 mg / kg and the anti-tau antibody is administered every four weeks at a dose of 1500 mg.

[0433]

[0430] A further aspect of the present disclosure relates to methods comprising optional administration of the anti-tau antibody (e.g., E2814) in conjunction with administration of an anti-Ap protofibril antibody, e.g., when the anti-Ap protofibril antibody is administered to a subject based on a measurement of a MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample. In some embodiments, the MTBR-tau243 concentration in the biofluid sample from the subject is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD). In some embodiments, the anti-Ap protofibril antibody may be administered simultaneously with or sequentially to the anti-tau antibody. In some embodiments, a subject may be pretreated with the anti-Ap protofibril antibody before the measurement of the MTBR-tau243 concentration is obtained and before the anti-tau antibody is administered.

[0434]

[0431] In some embodiments, the anti-tau antibody (e.g., administered in conjunction with the anti-Ap protofibril antibody) is administered until a change in the level of a biomarker in a sample is observed (e.g., a decrease in MTBR-tau243) in a biofluid sample (e.g., a CSF or blood sample) relative to the level in a sample taken from the subject prior to administration. In some embodiments, MTBR-tau243 can be measured in a sample taken from a subject at one point in time, and a second sample can be taken from a subject at a later point in time to measure the change in MTBR-tau243 in a subject. In some embodiments, the level of MTBR- tau243 in a sample taken from a subject after administration is reduced relative to the level of MTBR-tau243 in a sample taken from the subject before administration.

[0435]

[0432] In some embodiments, administration of the anti-tau antibody (e.g., administered in conjunction with the anti-Ap protofibril antibody) is increased due to an increase in the amount of MTBR-tau243 in a subject. In some embodiments, administration of the anti-tau antibody is decreased due to a decrease in the amount of MTBR-tau243 in a subject. Methods for measuring MTBR-tau243 in CSF are known in the art, such as immunoassays and mass spectrometry (Horie et al., 2023. Nat Med 29, 1954-1963).

[0436]

[0433] In some embodiments, the anti-tau antibody (e.g., administered in conjunction with the anti-Ap protofibril antibody) is administered until a change in the spread of tau as measured by PET is detected. In some embodiments, Tau PET can be used to confirm the presence of and / or measure the amount of tau in the brain of AD subjects. In some embodiments, a tau PET scan can be taken at one point in time, and a second tau PET scan can be taken at a second point later in time to measure the spread of tau in a subject. In some embodiments, administration of the anti-tau antibody is increased due to tau spread as measured by PET is observed in a patient. In some embodiments, the tau PET is MK-6240 Tau PET.

[0434] In some embodiments, MTBR-tau243 may be measured in addition to, or instead of, tau PET.

[0437]

[0435] As used herein, a “fragment” or “antigen binding fragment” of an anti-tau antibody comprises a portion of the antibody, for example comprising an antigen-binding or a variable region thereof. In some embodiments, an antibody (e.g., an anti-Ap protofibril antibody) as used herein may refer to a full-length antibody comprising variable and constant regions, and / or an antigen-binding fragment of an antibody, e.g., a fragment comprising CDRs of the heavy and light chain, the heavy and light chain variable regions, the heavy and light chains of the antibody, and / or any fragments, variations, or alternative formats thereof. Accordingly, in any embodiment disclosed herein, a full-length antibody or a fragment of the antibody (e.g., an antigen-binding fragment) may be used, preferably a full antibody such as E2814. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and single-chain antibody molecules.

[0438] Treatment Regimens and Routes of Administration

[0439]

[0436] As described herein, administration of a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody may comprise administration of one or more doses of the anti-Ap protofibril antibody according to an initiation dosing regimen. In some embodiments, one or more doses of the anti-Ap protofibril antibody may be administered according to a maintenance dosing regimen. In some embodiments, administration of a treatment according to a treatment regimen (also called a dosage regimen or dosing regimen) may comprise administration of one or more doses of the anti-Ap protofibril antibody according to an initiation dosage regimen and optionally, administration of one or more doses of the anti-Ap protofibril antibody according to a maintenance dosage regimen.

[0440]

[0437] In some embodiments, the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject, administered once every 2 weeks. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg, administered once every week.

[0441]

[0438] In some embodiments, the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks.

[0439] In some embodiments, the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg. For example, if the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg, the maintenance dosing regimen may comprise subcutaneous administration of the anti- Ap protofibril antibody at a therapeutically effective dose of 500 mg, 360 mg, or 250 mg. In some embodiments, the initiation dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 500 mg, and the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

[0442]

[0440] Additional variations of the initiation dosing regimen and maintenance dosing regimen are described herein.

[0443]

[0441] In some embodiments, the anti-Ap protofibril antibody may be administered daily, once weekly, also called “weekly”, or every other week, also called “biweekly”, or monthly, also called “every 4 weeks.” In some embodiments, the anti-Ap protofibril antibody may be administered intravenously and / or subcutaneously. In some embodiments, a dosage regimen comprises administration of at least one initiation dose (also called a treatment dose) and at least one maintenance dose. In some embodiments, the dosing regimen comprises administration of at least one dose of the anti-Ap protofibril antibody via one route of administration. In some embodiments, the dosing regimen comprises administration of at least one dose of the anti-Ap protofibril antibody via more than one route of administration (e.g., initially administering an antibody intravenously and then switching to subcutaneous administration).

[0444]

[0442] In some embodiments, the anti-Ap protofibril antibody is administered intravenously, e.g., by an injection into a peripheral vein. In an upper extremity, the median basilic or cephalic veins of the arm or the metacarpal veins in the hand’s dorsum may be used. In a lower extremity, the dorsal venous plexus of the foot may be used.

[0445]

[0443] In some embodiments, the anti-Ap protofibril antibody is administered subcutaneously. In a subcutaneous injection, the anti-Ap protofibril antibody is injected into the tissue layer between the skin and muscle, such as a fatty tissue just below the skin. In some embodiments, the subcutaneous administration is injected into the abdomen (e.g., at or under the level of the belly button), thigh (e.g., front of the thigh), or upper arm (e.g., back or side of the upper arm). In some embodiments, a volume of the injection administered subcutaneously is less than 2 mL.

[0444] In some embodiments, the anti-Ap protofibril antibody is subcutaneously administered using a vial and syringe (also called “vial / syringe” or “syringe / vial” or “SC Vial”). For example, the anti-Ap protofibril antibody in a subcutaneous formulation may be removed from a vial into a syringe and then injected from the syringe into the subject.

[0446]

[0445] In some embodiments, the anti-Ap protofibril antibody is administered using an autoinjector (also called an “auto-injector,” “Al,” “Al Device,” or “SC Al”). An exemplary auto-injector is the YpsoMate™ 2.25 mL Al Device, which has been approved in the United States (US) and Europe as a presentation for Ajovy® (fremanezumabv-frm). In some embodiments, an autoinjector may comprise a plastic PLAJEX™ syringe, a tapered needle (24G-29G), a V spring, a spring force, and component colors. It may be a single-use, disposable injection device consisting of a housing with a content viewing window, a spring activated mechanism, and integrated needle safety feature. In some embodiments, a 2.25 mL PLAJEX™ syringe may be prefilled with the anti-Ap protofibril antibody. At least one Al Device may be needed to administer the dose of the anti-Ap protofibril antibody.

[0447]

[0446] In some embodiments, the anti-Ap protofibril antibody is administered intravenously for at least one dose, and subcutaneously for at least one dose. For example, the anti-Ap protofibril antibody (e.g., LECANEMAB) may be administered to a subject intravenously, e.g., once weekly, for a period of time, such as 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 months, after which the antibody may be administered subcutaneously. In some embodiments, the anti-Ap protofibril antibody may be administered subcutaneously using a vial-syringe, and then later administered subcutaneously using an Al. In some embodiments, the anti-Ap protofibril antibody may be administered subcutaneously using a vial-syringe or an Al, and then later administered intravenously.

[0448]

[0447] In some embodiments, the method of treatment comprises switching between an intravenous or subcutaneous dose, or from an initiation to a maintenance dose, at a set time point (e.g., after 18 months or after 24 months). In some embodiments, the method of treatment comprises using a biomarker level to determine switching between an intravenous or subcutaneous dose or from an initiation to a maintenance dose, e.g., when measured at or after a set time point (e.g., after 18 months or after 24 months). In some embodiments, a maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections).

[0449]

[0448] In some embodiments, the anti-Ap protofibril antibody is lecanemab.

[0450]

[0449] In some embodiments, lecanemab is supplied as a solution for intravenous use and is a preservative-free, sterile, clear to opalescent and colorless to pale yellow solution for intravenous use by infusion after dilution. In some embodiments, LEQEMBI may be supplied in single-dose vials available in concentration of 500 mg / 5 mL (100 mg / mL) or 200 mg / 2 mL (100 mg / mL). In some embodiments, each mL of solution contains 100 mg of lecanemab- irmb and arginine hydrochloride (42.13 mg), histidine (0.18 mg), histidine hydrochloride monohydrate (4.99 mg), polysorbate 80 (0.50 mg), and Water for Injection at an approximate pH of 5.0. In some embodiments, LEQEMBI is diluted in 250 mL of 0.9% Sodium Chloride Injection, USP. In some embodiments, a dosage of LEQEMBI i...

Claims

CLAIMS1. A method of treating a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; and b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), and / or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., comparable to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

2. The method of claim 1, further comprising: in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; and in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a p-tau217 concentration in a control sample, or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

3. The method of claim 1 or claim 2, further comprising: c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is elevated as compared to the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration is comparable to a rate of increasein a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject.

4. The method of claim 1 or claim 2, further comprising c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after administering the treatment; d) determining that the second MTBR-tau243 concentration is less than the first MTBR-tau243 concentration, or the rate of increase from the first MTBR-tau243 concentration to the second MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated; and e) administering a further therapeutically effective dose of the anti-Ap protofibril antibody to the subject, wherein the further therapeutically effective dose of the anti-Ap protofibril antibody is administered according to a maintenance dosing regimen.

5. A method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for treatment if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), or if the MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

6. The method of claim 5, further comprising: in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject; in step b), selecting the subject for treatment if the p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample.

7. A method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and / or if the first MTBR-tau243 concentration is comparable to a positive control sample, e.g., compared to a MTBR-tau243 concentration in an individual who has AD; and c) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, wherein a decrease in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration, and / or a rate of increase from the first MTBR- tau243 concentration to the first MTBT-tau243 concentration is less than a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

8. The method of claim 7, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample from the subject;in step b), administering to the subject the treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration is elevated compared to a p-tau217 concentration in the control sample or if the first p-tau217 concentration is comparable to a p-tau217 concentration in the positive control sample; and in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample, wherein a decrease in the second p-tau217 concentration as compared to the first p-tau217 concentration or a decrease in the rate of increase from the first p-tau217 concentration to the second p-tau217 concentration as compared to the rate of increase in the positive control indicates a reduction in tau tangles.

9. A method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a MTBR-tau243 concentration in a biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the MTBR-tau243 concentration to a control sample, e.g., a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD) and / or comparing the MTBR-tau243 concentration to a positive control, e.g., a MTBR-tau243 concentration in an individual who has AD; and c) adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody if the MTBR-tau243 concentration differs from the control sample or if the MTBR- tau243 concentration differs from the positive control sample, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

10. The method of claim 9, further comprising: in step a), obtaining a measurement of a p-tau217 concentration in the biofluid sample from the subject;in step b), comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the control sample and / or comparing the p-tau217 concentration and the MTBR-tau243 concentration in the sample to a p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample; and in step c), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody, if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the control sample or if the p-tau217 concentration and the MTBR-tau243 concentration in the sample differ from the p-tau217 concentration and the MTBR-tau243 concentration in the positive control sample.

11. The method of any one of claims 1-10, wherein the control is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

12. The method of any one of claims 1-11, wherein the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

13. A method of monitoring treatment efficacy in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second MTBR-tau243 concentration as compared to first MTBR-tau243 concentration is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences ofSEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

14. The method of claim 13, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first MTBR-tau243 concentration to a second MTBR-tau243 concentration in an individual who has AD and is not treated, indicates an effective treatment.

15. The method of claim 13, wherein a lack of a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, as compared to a rate of increase in a placebo control, indicates a non-effective treatment.

16. The method of any one of claims 13-15, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration is an indicator of treatment efficacy.

17. The method of claim 16, wherein a decrease from the first p-tau217 concentration to the second p-tau217 concentration, or reduction in a rate of increase from the first p-tau217 concentration to the second p-tau217 concentration, as compared to a rate of increase in a placebo control sample, e.g., a rate of increase from a first p-tau217 to a second tau217 concentration in an individual who has AD and is not treated, indicates an effective treatment.

18. The method of claim 16, wherein a lack of a decrease from the first p-tau217 concentration to the second p-tau217 concentration and from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a lack of a reduction in a rate of increase between the first and second p-tau217 concentrations and MTBR-tau243 concentrations, as compared to rates in a placebo control, indicates a non-effective treatment.

19. A method of detecting a decrease in a brain Ap level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease from the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, or a reduction in a rate of increase from the first MTBR-tau243 concentration to the second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

20. The method of claim 19, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; andin step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change in the second p-tau217 concentration as compared to first p- tau217 concentration indicates a decrease of the brain Ap level in the subject.

21. A method of detecting a decrease in a brain tau level in a subject having, suspected of having, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first and second MTBR-tau243 concentrations, wherein a decrease in the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, or a reduction in a rate of increase between the first and second MTBR-tau 243 concentrations as compared to a rate of increase in a placebo sample, e.g., a rate of increase in samples from an individual who has AD and who is not treated, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

22. The method of claim 21, further comprising: in step a), obtaining a measurement of a first p-tau217 concentration in the first biofluid sample; in step b), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step c), comparing the first p-tau217 concentration to the second p-tau217 concentration, wherein a change from the first p-tau217 concentration to the second p-tau217 concentration indicates a decrease of the brain tau level in the subject23. The method of claim 21 or claim 22, wherein a decrease in a brain tau level is a reduction in tau tangles.

24. The method of any one of claims 1-23, wherein the treatment with the anti-Ap protofibril antibody comprises administration of a therapeutically effective dose of the anti- Ap protofibril antibody according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen.

25. The method of claim 24, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject is at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

26. The method of claim 24, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen when a further measurement of p-tau217 and a further measurement of MTBR-tau243 concentration in a further biofluid sample, e.g., a CSF or blood sample, from the subject are at or below a threshold, e.g., a level seen in a control sample from an individual who does not have AD.

27. The method of any one of claims 24-26, wherein the subject is switched to a maintenance dosing regimen when at least one of: a decrease in amyloid or tau positron emission tomography (PET); an increase in cerebrospinal fluid level of AP42 and / or AP42 / 40 ratio; a decrease in cerebrospinal fluid level of total tau, cerebrospinal fluid level of neurogranin, and / or cerebrospinal fluid level of neurofilament light peptide (NfL); and a change in blood biomarkers as measured in the serum or plasma (e.g. increased levels of Ap42 and / or AP42 / 40 ratio; decreased plasma levels of plasma total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), glial fibrillary acidic protein (GFAP), and / or neurofilament light (NfL)) is detected in a sample from the subject as compared to a control disease sample, e.g., a sample from an individual who has AD.

28. The method of any one of claims 24-27, wherein the subject is switched to a maintenance dosing regimen when a decrease in tau PET SUVr is measured in the subject as compared to control sample, e.g., a sample from an individual who has AD.

29. The method of any one of claims 24-28, wherein the subject is switched to a maintenance dosing regimen when a low tau PET level as measured by PET SUVr is detected in the subject, e.g., a tau PET SUVr of about 1.1, preferably about 1.06, as measured with a MK6240 PET scan, e.g., of whole cortical gray matter.

30. The method of claim 29, wherein the maintenance dosing regimen comprises administering a maintenance dose that maintains a tau PET SUVr level at or below 1.06.

31. The method of any one of claims 24-30, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

32. The method of any one of claims 24-31, wherein the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody.

33. The method of any one of claims 24-32, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject.

34. The method of any one of claims24-33, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

35. The method of claim 33 or 34, wherein the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effectivedose once every 4 weeks, preferably as an intravenous administration at 10 mg / kg relative to the weight of the subject.

36. The method of any one of claims 24-34, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

37. The method of any one of claims 24-32 or 36, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

38. The method of claim 36 or 37, wherein the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

39. The method of any one of claims 36-38, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

40. The method of any one of claims 24-39, wherein at least one of the initiation dosing regimen and the maintenance dosing regimen further comprises administration of a therapeutically effective dose of an anti-tau antibody, e.g., E2814, sequentially or simultaneously with administration of the anti-Ap protofibril antibody.

41. The method of claim 40, wherein the anti-tau antibody is E2814.

42. The method of claim 41, wherein the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

43. The method of claim 40 or claim 41, comprising intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., 500, 750, 1000, 1500, 3000, 4500 mg).

44. The method of any one of claims 40-43, wherein the anti-tau antibody is administered prior to the first administration of the anti-Ap protofibril antibody, optionally wherein the subject has pre- AD (e.g., is asymptomatic for AD).

45. The method of any one of claims 30-43, wherein the anti-Ap antibody is administered prior to the first administration of the anti-tau antibody, optionally wherein the subject has AD (e.g., early AD).

46. The method of any one of claims 1-45, wherein the MTBR-tau243 concentration is quantified by LC / MS.

47. The method of any one of claims 1-46, wherein the biofluid sample is CSF.

48. The method of any one of claims 1-47, wherein the biofluid sample is blood.

49. The method of any one of claims 1-48, wherein the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment.

50. The method of claim 49, wherein the change and / or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205,p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

51. The method of any one of claims 1-50, wherein the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology during and / or after treatment.

52. The method of claim 51, wherein the change and / or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

53. The method of claim 52, wherein the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

54. The method of any one of claims 1-53, wherein the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR-SB; or e) delays clinical decline as measured by an ADAS-Cog.

55. The method of any one of claims 1-54, wherein the method further comprises monitoring for ARIA, e.g., ARIA-E and / or ARIA-H, e.g., as observed by MRI.

56. The method of any one of claims 1-55, wherein the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

57. The method of claim 56, wherein the subject has a mutation in APP.

58. The method of any one of claims 1-57, wherein the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

59. The method of any one of claims 1-58, wherein the subject is ApoE4-positive.

60. The method of any one of claims 1-59, wherein the subject is 65 to 80 years old.

61. The method of any one of claims 1-60, wherein the subject is 55 to 64 years old and has at least one risk factor chosen from:(i) a first degree relative diagnosed with dementia onset before age 75;(ii) at least one apolipoprotein E4 variant (APOE4) allele; and(iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

62. The method of any one of claims 1-61, wherein the subject is amyloid positive.

63. The method of claim 62, wherein the subject is amyloid positive based on a PET assessment, a CSF assessment of A0(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), a CSF assessment of the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np- taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and / or a blood biomarker assessment (e.g. a plasma A 1- 42 / 1-40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p- tau217, and / or p-tau231), and / or the plasma ratio of phosphorylated tau / non-phosphorylatedtau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np- tau231)).

64. The method of any one of claims 1-63, wherein the subject has Alzheimer’s disease.

65. The method of any one of claims 1-64, wherein the subject has early Alzheimer’s disease.

66. The method of any one of claims 1-65, wherein the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and / or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

67. The method of any one of claims 1-66, wherein the subject is suspected of having AD.

68. The method of any one of claims 1-67, wherein the subject is a subject at risk for developing AD.

69. The method of claim 68, wherein the subject at risk for developing AD has preAlzheimer’s disease (pre- AD).

70. The method of claim 68 or claim 69, wherein the subject does not have cognitive impairment.

71. The method of any one of claims 1-70, wherein the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

72. The method of claim 71, wherein the anti-Ap protofibril antibody is lecanemab.

73. The method of any one of claims 40-72, wherein the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

74. The method of claim 73, wherein the anti-tau antibody is E2814.

75. The method of any one of claims 1-74, wherein the MTBR-tau243 is MTBR-tau243- 254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

76. The method of any one of claims 1-74, wherein the MTBR-tau243 is MTBR-tau243- 254.

77. The method of any one of claims 1-74, wherein the MTBR-tau243 is MTBR-tau243- 256.

78. The method of any one of claims 1-74, wherein the MTBR-tau243 MTBR-tau243-256 (deamidation on 255N).

79. A method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the first p-tau217 concentration and / or the first MTBR-tau243 concentration are elevated compared to a first control sample, e.g., a sample from an individual who does not have AD;c) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p- tau217 concentration and the second MTBR-tau243 concentration are elevated compared to the first p-tau217 concentration and the second MTBR-tau243 concentration, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

80. A method of treating or preventing Alzheimer’s disease (AD) in a subject having, suspected of having AD, or at risk for developing AD, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or a blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., a p-tau217 concentration in an individual who does not have AD; c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or a blood sample, from the subject after the first treatment; and d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., a MTBR-tau243 concentration in an individual who does not have AD; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences ofSEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

81. The method of claim 80, further comprising: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

82. The method of claim 80 or claim 81, further comprising: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 and the MTBR- tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

83. A method of selecting a subject having, suspected of having, or at risk for developing AD for treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the first p-tau217 concentration and / or the first MTBR-tau243 concentration are elevated compared to a controlsample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the second MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

84. A method of selecting a subject having, suspected of having, or at risk for developing AD for a treatment with an anti-Ap protofibril antibody and an anti-tau antibody, comprising: a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) selecting the subject for a first treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; and d) selecting the subject for a second treatment comprising administration of a therapeutically effective dose of the anti-Ap protofibril antibody and a therapeuticallyeffective dose of an anti-tau antibody if the MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD), optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

85. The method of claim 84, further comprising: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample; and in step b), selecting the subject for the first treatment with the anti-Ap protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

86. The method of claim 84 or claim 85, further comprising: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample; and in step d), selecting the subject for a second treatment with the anti-tau antibody if the second p-tau217 concentration and the MTBR-tau243 concentration are elevated compared to a control sample, e.g., a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

87. A method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising:a) obtaining a measurement of a first p-tau217 concentration and a measurement of a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the first p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the second p- tau217 concentration and the second MTBR-tau243 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD; e) optionally obtaining a measurement of a third p-tau217 concentration and a third MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the third p-tau217 concentration as compared to the second p-tau217 concentration and in the third MTBR-tau243 concentration as compared to the second MTBR-tau243 concentration, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

88. A method of reducing tau tangles in a subject having, suspected of having, or at risk for developing Alzheimer’s disease (AD), comprising:a) obtaining a measurement of a p-tau217 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject; b) administering to the subject a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody if the p-tau217 concentration is elevated compared to a control sample, e.g., compared to a p-tau217 concentration in an individual who does not have Alzheimer’s disease (AD); c) obtaining a measurement of a MTBR-tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject after the first treatment; d) administering to the subject a second treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody and an anti-tau antibody if the MTBR- tau243 concentration is elevated compared to a control sample, e.g., compared to a MTBR- tau243 concentration in an individual who does not have Alzheimer’s disease (AD); e) obtaining a measurement of a second MTBR-tau243 concentration in a third biofluid sample from the subject after the second treatment, wherein a decrease in the second MTBR-tau243 concentration after the second treatment as compared to the MTBR-tau243 concentration after the first treatment, indicates a reduction in tau tangles, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

89. The method of claim 88, further comprising: in step a), obtaining a measurement of a first MTBR-tau243 concentration in the first biofluid sample from the subject; and in step b), administering to the subject a first treatment comprising a therapeutically effective dose of an anti-amyloid P (AP) protofibril antibody if the p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample, e.g., ap-tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

90. The method of claim 88 or claim 89, further comprising: in step c), obtaining a measurement of a second p-tau217 concentration in the second biofluid sample from the subject after the treatment; and in step d), administering to the subject a second treatment comprising a therapeutically effective dose of an anti-tau antibody if the second p-tau217 concentration and the first MTBR-tau243 concentration are elevated compared to a control sample e.g., a p- tau217 concentration and a MTBR-tau243 concentration in an individual who does not have AD.

91. The method of any one of claims 83-90, wherein the first control sample and / or the second control sample are obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

92. The method of any one of claims 83-90, wherein the second control sample is obtained from the subject after the first treatment and prior to the second treatment.

93. A method of preventing or treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for developing AD, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject who is receiving a first treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody; b) comparing the first p-tau217 concentration and the first MTBR-tau243 to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); c) adjusting the treatment regimen to further administer a therapeutically effective amount of an anti-tau antibody if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample,optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and optionally wherein the anti-tau antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3).

94. The method of claim 93, further comprising d) obtaining a measurement of a third p-tau217 concentration and a third MTBR- tau243 concentration in a third biofluid sample, e.g., a CSF or blood sample, from the subject; e) comparing the third p-tau217 concentration and the third MTBR-tau243 concentration to a control sample, e.g., a tau-217 concentration and a MTBR-tau243 concentration in an individual who does not have Alzheimer’s disease (AD); and f), adjusting the treatment regimen, e.g., by changing the size of the dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody and / or the anti-tau antibody, if the p-tau217 concentration and the MTBR-tau243 concentration are elevated as compared to the control sample.

95. The method of claim 93 and claim 94, wherein the control sample is obtained from an individual who does not have AD, from an individual who has AD is at an earlier stage than the subject, or from a reference measurement indicating amyloid negative status.

96. The method of any one of claims 93-95, wherein the positive control sample is obtained from an individual who has AD, from an individual who has AD at the same stage or at a later stage than the subject, from a subject who has AD but is not receiving treatment, or from a reference measurement indicating amyloid-positive status.

97. A method of monitoring treatment efficacy in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a change in the second p-tau217 concentration and a change in the second MTBR-tau243 concentration, as compared to the first p-tau217 concentration and the first MTBR-tau243 concentration, is an indicator of treatment efficacy, optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

98. The method of claim 97, wherein a decrease or reduction in increase in the second p- tau217 concentration as compared to the first p-tau217 concentration and / or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates an effective treatment.

99. The method of claim 97, wherein a lack of a decrease or lack of a reduction in increase in the second p-tau217 concentration as compared to the first p-tau217 concentration and / or in the second MTBR-tau243 concentration as compared to the first MTBR-tau243 concentration indicates a non-effective treatment.

100. A method of detecting a decrease in a brain Ap level in a subject having, suspected of having AD, or at risk for developing AD, who is receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising:a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p- tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration indicates a decrease of a brain Ap level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

101. A method of detecting a decrease in a brain tau level in a subject receiving a treatment comprising a therapeutically effective dose of an anti-Ap protofibril antibody, comprising: a) obtaining a measurement of a first p-tau217 concentration and a first MTBR-tau243 concentration in a first biofluid sample, e.g., a CSF or blood sample, from the subject prior to the treatment; b) obtaining a measurement of a second p-tau217 concentration and a second MTBR- tau243 concentration in a second biofluid sample, e.g., a CSF or blood sample, from the subject during or after the treatment; and c) comparing the first p-tau217 concentration to the second p-tau217 concentration and comparing the first MTBR-tau243 concentration to the second MTBR-tau243 concentration, wherein a decrease between the second p-tau217 concentration and the first p- tau217 concentration and a decrease between the second MTBR-tau243 concentration and the first MTBR-tau243 concentration, indicates a decrease of a brain tau level in the subject; optionally wherein the anti-Ap protofibril antibody comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and threelight chain complementarity determining regions (LCDR1 , LCDR2, and LCDR3) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

102. The method of claim 101, wherein a decrease in a brain tau level is a reduction in tau tangles.

103. The method of any one of claims 79-102, wherein the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen if the subject receives treatment with an anti -tau antibody.

104. The method of any one of claims 79-103, wherein the treatment comprising a therapeutically effective dose of the anti-Ap protofibril antibody is administered according to an initiation dosing regimen, optionally after which the subject is switched to a maintenance dosing regimen of the anti-Ap protofibril antibody.

105. The method of claim 104, wherein the maintenance dosing regimen of the anti-Ap protofibril antibody is administered if a subject receives a treatment with an anti -tau antibody.

106. The method of claim 104 or claim 105, wherein the subject is switched from an initiation dosing regimen to a maintenance dosing regimen of the anti-Ap protofibril antibody at least 6 months (e.g., 6 months, or 12 months, or 18 months, or 24 months, or 36 months) after the start of the initiation dosing regimen.

107. The method of any one of claims 104-106, wherein the maintenance dosing regimen differs from the initiation dosing regimen in the size of dose, the frequency of administration, and / or the route of administration of the anti-Ap protofibril antibody.

108. The method of any one of claims 104-107, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose of 10 mg / kg relative to the weight of the subject.

109. The method of any one of claims 104-108, wherein the initiation dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 2 weeks.

110. The method of claim 108 or 109, wherein the maintenance dosing regimen comprises intravenous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every 4 weeks, preferably as an intravenous administration at 10 mg / kg relative to the weight of the subject.

111. The method of any one of claims 104-107, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 720 mg or 500 mg.

112. The method of any one of claims 104-107 or 111, wherein the initiation dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose once every week.

113. The method of claim 111 or claim 112, wherein the maintenance dosing regimen comprises subcutaneous administration of an anti-Ap protofibril antibody at a therapeutically effective dose of 360 mg or 250 mg.

114. The method of any one of claims 111-113, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Ap protofibril antibody at a therapeutically effective dose once every week.

115. The method of any one of claims 79-96, wherein the second treatment comprises administration of a therapeutically effective dose of the anti-tau antibody E2814.

116. The method of claim 115, wherein the initiation dosing regimen comprises intravenous administration of E2814 at a therapeutically effective dose once every 4 weeks.

117. The method of claim 115 or claim 116, comprising intravenous administration of E2814 at a therapeutically effective dose between 500-4500 mg (e.g., 500, 750, 1000, 1500, 3000, or 4500 mg).

118. The method of any one of claims 1-117, wherein the MTBR-tau243 concentration is quantified by LC / MS.

119. The method of any one of claims 1-118, wherein the biofluid sample is CSF.

120. The method of any one of claims 1-119, wherein the biofluid sample is blood.

121. The method of any one of claims 1-120, wherein the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology prior to treatment with the anti-Ap protofibril antibody.

122. The method of claim 121, wherein the change and / or difference in the measurement is selected from: a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), c) decreased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) decreased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or increased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

123. The method of any one of claims 1-122, wherein the subject shows a change and / or difference in a measurement of one or more biomarkers associated with AD pathology during and / or after treatment with the anti-tau antibody.

124. The method of claim 123, wherein the change and / or difference in the measurement is selected from: a) decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a centiloid measure of about 20-40, e.g., a centiloid measure of about 20-32), b) decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c) increased cerebrospinal fluid levels of ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p- tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, neurogranin, and / or neurofilament light chain (NfL), and d) increased blood serum or plasma levels of a ratio of Api-42 / 1-40 and / or decreased total tau, phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

125. The method of claim 124, wherein the decreased amyloid in the brain is an adjusted mean change from baseline in amyloid PET SUVr of at least about 0.10, or 0.15, or 0.20.

126. The method of any one of claims 1-125, wherein the treatment a) delays clinical decline as determined by ADCOMS; b) delays clinical decline as determined by ADAS MCI-ADL; c) delays clinical decline as determined by modified iADRS; d) delays clinical decline as measured by a CDR-SB; or e) delays clinical decline as measured by an ADAS-Cog.

127. The method of any one of claims 1-126, wherein the method further comprises monitoring for ARIA, e.g., ARIA-E and / or ARIA-H, e.g., as observed by MRI.

128. The method of any one of claims 1-127, wherein the subject has a genetic mutation for a dominantly inherited Alzheimer’s disease, e.g., wherein the subject a genetic mutation in at least one of three genes — PSEN1, PSEN2, or APP.

129. The method of claim 128, wherein the subject has a mutation in APP.

130. The method of any one of claims 1-129, wherein the subject has a family history of Alzheimer’s disease, e.g., a history of a family member being diagnosed with Alzheimer’s disease before the age of 60.

131. The method of any one of claims 1-130, wherein the subject is ApoE4-positive.

132. The method of any one of claims 1-131, wherein the subject is 65 to 80 years old.

133. The method of any one of claims 1-132, wherein the subject is 55 to 64 years old and has at least one risk factor chosen from:(i) a first degree relative diagnosed with dementia onset before age 75;(ii) at least one apolipoprotein E4 variant (APOE4) allele; and(iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to said administration.

134. The method of any one of claims 1-133, wherein the subject is amyloid positive.

135. The method of claim 134, wherein the subject is amyloid positive based on a PET assessment, a CSF assessment of A0(l-42), a CSF assessment of total tau, a CSF assessment of phosphorylated tau (e.g., p-taul81, p-tau205, p-tau217, and / or p-tau231), a CSF assessment of the ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np- taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np-tau231), MTBR-tau243, MRI, retinal amyloid accumulation, and / or a blood biomarker assessment (e.g. a plasma A 1- 42 / 1-40 ratio, plasma total tau, plasma phosphorylated tau (e.g., p-taul81, p-tau205, p- tau217, and / or p-tau231), and / or the plasma ratio of phosphorylated tau / non-phosphorylated tau (e.g., p-taul81 / np-taul81, tau205 / np-tau205, p-tau217 / np-tau217 and / or tau231 / np- tau231)).

136. The method of any one of claims 1-135, wherein the subject has Alzheimer’s disease.

137. The method of any one of claims 1-136, wherein the subject has early Alzheimer’s disease.

138. The method of any one of claims 1-137, wherein the subject has been diagnosed with a) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood and / or has been diagnosed as having mild Alzheimer’s disease dementia; b) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by National Institute of Aging - Alzheimer’s Association (NIA-AA) core clinical criteria; c) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment; d) mild cognitive impairment due to Alzheimer’s disease - intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last1 year before treatment, e.g., as corroborated by an informant; e) mild Alzheimer’s disease dementia by the NIA-AA core clinical criteria for probable Alzheimer’s disease dementia; or f) mild Alzheimer’s disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.

139. The method of any one of claims 1-135, wherein the subject is suspected of having AD.

140. The method of any one of claims 1-135, wherein the subject is a subject at risk for developing AD.

141. The method of claim 140, wherein the subject at risk for developing AD has preAlzheimer’s disease (pre- AD).

142. The method of claim 140 or claim 141, wherein the subject does not have cognitive impairment.

143. The method of any one of claims 1-142, wherein the anti-Ap protofibril antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 8.

144. The method of claim 143, wherein the anti-Ap protofibril antibody is lecanemab.

145. The method of any one of claims 79-96, wherein the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 21 and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 22.

146. The method of claim 145, wherein the anti-tau antibody is E2814.

147. The method of any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-254, MTBR-tau243-256, or MTBR-tau243-256 (deamidation on 255N).

148. The method of any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-254.

149. The method of any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-256.

150. The method of claim any one of claims 79-146, wherein the MTBR-tau243 is MTBR- tau243-256 (deamidation on 255N).

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