Methods of Treatment Using Tau PET Levels

Abstract

Disclosed herein are methods for diagnosing, selecting, monitoring, and treating subjects having or suspected of having Alzheimer's disease (AD) or another disorder associated with amyloid accumulation in the brain using tau PET levels.

Description

[Technical Field]

[0001]

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 63 / 385,188, filed November 28, 2022; 63 / 506,576, filed June 6, 2023; 63 / 513,797, filed July 14, 2023; and 63 / 592,515, filed October 23, 2023.

[0002] [Field]

[0002] Described herein are methods for treating Alzheimer's disease (AD) in a subject, involving the use of measurements of tau PET levels in regions of the subject's brain. Tau PET levels can be used to determine the stage of AD in a subject, identify subjects who will receive treatment for AD, select treatments and regimens, monitor treatment efficacy, and / or predict clinical outcomes of treatments. [Background technology]

[0003] [background]

[0003] Alzheimer's disease (AD) is a progressive neurodegenerative disorder of unknown etiology and is the most common form of dementia in the elderly. In 2006, there were 26.6 million cases of AD worldwide (range: 11.4 million to 59.4 million) (Brookmeyer, R., et al., Forecasting the global burden of Alzheimer's Disease. Alzheimer Dement. 2007;3:186-91), while more than 5 million people in the United States reportedly lived with AD (Alzheimer's Association, Alzheimer's Association report, 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94). By 2050, the global prevalence of AD is projected to increase to 106.8 million (range: 47.2-221.2 million), while in the United States alone the prevalence is estimated to be 11-16 million (Brookmeyer, supra, and 2010 Alzheimer's disease facts and figures, supra).

[0004]

[0004] The disease generally progresses slowly, with a global decline in cognitive function that renders end-stage subjects bedridden. AD subjects typically survive only 3 to 10 years after symptom onset, although extreme cases of 2 and 20 years have been known. (Hebert, LE, et al., Alzheimer's disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122.) Despite the fact that death rates from AD are significantly underestimated because death certificates rarely attribute the cause of death to AD, AD is the seventh leading cause of all deaths in the United States and the fifth leading cause of death among Americans over 65 years of age. (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94.)

[0005]

[0005] AD poses a significant economic burden throughout developed countries, with substantial impacts on health care systems and national treasuries, as well as on patients and their families. In the United States alone, the total cost in 2010 was estimated at $172 billion, including $123 billion for Medicare and Medicaid.

[0006]

[0006] Histologically, this disease is characterized by senile plaques found primarily in the association cortex, limbic system, and basal ganglia. The main component of these plaques is amyloid beta peptide (Aβ). Aβ exists in various conformational states (monomers, oligomers, protofibrils, and insoluble fibrils). The details of the mechanistic link between the development of Alzheimer's disease and Aβ production are unknown. However, several anti-amyloid beta antibodies (also called "anti-Aβ antibodies") are currently undergoing clinical trials as potential therapeutic agents for Alzheimer's disease.

[0007] Despite recent developments in treatments for AD, including those targeting Aβ, there remains a need for better monitoring of treatment, including more sophisticated measurements of markers predictive of treatment responsiveness or measurements of response to treatment. Such markers may include a combination of different measurements.

[0008]

[0008] Accordingly, disclosed herein are improved methods for selecting, monitoring, and treating patients (also referred to as "subjects") with AD. In some embodiments, treatments including anti-Aβ protofibril antibodies, such as BAN2401, can result in a reduction in the rate of tau accumulation, e.g., in brain regions such as the temporal region, compared to control patients, as measured by tau PET levels, also referred to as "tau-PET" levels (e.g., as measured by tau PET imaging). In some embodiments, this correlates with a reduction in cerebral amyloid burden and improved cognitive outcomes in the subjects. Without being bound by theory, tau PET levels (e.g., tau PET standardized uptake value ratio (SUVr, also referred to as "SUVR")) can be used in various embodiments as a minimally invasive and / or additional biomarker to refine measurements of treatment efficacy and / or enable monitoring and treatment decisions. Such decisions may include whether to increase or decrease the amount of anti-Aβ protofibril antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, and / or whether to discontinue treatment with the anti-Aβ protofibril antibody. Summary of the Invention

[0009] [overview]

[0009] One aspect of the present disclosure relates to a method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising: (a) selecting a subject having low levels of tau in whole brain measurements (low tau PET levels), preferably as measured by tau PET; and (b) administering a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to the subject.

[0010] In some embodiments, treating AD includes, for example, reducing, slowing, and / or reversing the decline in a measure of cognitive function in a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody compared to a control. In some embodiments, the measure of cognitive function in a treated subject is compared to a baseline measure obtained from the same subject before treatment or to a reference control. In some embodiments, the decline occurs between the time cognitive function is first measured (e.g., the baseline measure) and one or more later time points at which cognitive function is measured again. In some embodiments, the later time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measure. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject not receiving treatment or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measure, such as a mean measure that combines population data from two or more subjects and is representative of subjects not receiving treatment. In some embodiments, the baseline measurement is a measurement taken before initiating treatment in the subject, e.g., treatment with an anti-Aβ protofibril antibody. In some embodiments, the measure of cognitive function is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL.

[0011] In some embodiments, treating AD includes, for example, causing a change (e.g., slowing, delay, or reduction) in at least one marker of AD pathology in a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody compared to a control. In some embodiments, the change in the marker occurs between the time the marker is first measured (e.g., a baseline measure) and one or more later time points at which the marker is measured again. In some embodiments, the later time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measure. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject not receiving treatment or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measure, such as a mean measure that combines population data from two or more subjects and is representative of subjects not receiving treatment. In some embodiments, the marker is plasma Aβ42 / 40 ratio, plasma p-tau181 level, plasma GFAP level, and / or plasma NfL level.

[0012] In some embodiments, the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio as measured by an adjusted mean change from baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.009. In some embodiments, the change is observed after the Aβ protofibril antibody has been administered over a period of time. For example, the plasma Aβ42 / 40 ratio may increase by about 0.003 after about 6 months of treatment with the Aβ protofibril antibody, by about 0.006 after about 12 months, by about 0.007 after about 18 months, by about 0.008 after about 21 months, or by about 0.009 after about 24 months. In some embodiments, the increase in plasma Aβ42 / 40 ratio from baseline is greater in subjects receiving lecanemab than in controls. In some embodiments, the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or greater.

[0013] In some embodiments, the Aβ protofibril antibody reduces plasma p-tau 181 by at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml, as measured by an adjusted mean change from baseline p-tau 181 levels. In some embodiments, the change is observed after the Aβ protofibril antibody has been administered over a period of time. For example, p-tau 181 may be reduced by about 0.2 pg / ml after about 6 months of treatment with the Aβ protofibril antibody, by 0.5 pg / ml after about 12 months, by 0.6 pg / ml after about 18 months, by 0.8 pg / ml after about 21 months, or by 0.8 pg / ml after about 21 months. In some embodiments, the reduction in plasma p-tau 181 from baseline is greater in subjects receiving lecanemab than in controls, hi some embodiments, the Aβ protofibril antibody reduces p-tau 181 levels to about 2.3 pg / mL or less, or about 2.2 pg / mL or less (e.g., as measured using a Quanterix Simoa p-tau assay).

[0014] In some embodiments, the Aβ protofibril antibody reduces plasma GFAP by at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml, as measured by an adjusted mean change from baseline GFAP levels. In some embodiments, the change is observed after the Aβ protofibril antibody has been administered over a period of time. For example, plasma GFAP may be reduced by about 20 pg / ml after about 6 months of treatment with the Aβ protofibril antibody, by about 30 pg / ml after about 12 months, by about 50 pg / ml after about 18 months, by about 80 pg / ml after about 21 months, and by about 60 pg / ml after about 24 months. In some embodiments, the reduction in plasma GFAP from baseline is greater in subjects receiving lecanemab than in controls.

[0015] In some embodiments, the Aβ protofibril antibody increases plasma NfL by less than about 2 pg / ml or less than about 3 pg / ml, as measured by an adjusted mean change from baseline NfL levels. In some embodiments, the change is observed after the Aβ protofibril antibody has been administered over a period of time. In some embodiments, the increase in plasma NfL from baseline is smaller in subjects receiving lecanemab than in controls. In some embodiments, plasma NfL in subjects receiving lecanemab is unchanged from baseline or decreases over time.

[0016] In some embodiments, the marker is tau PET level or amyloid PET level.

[0017] In some embodiments, the Aβ protofibril antibody reduces tau PET levels as measured by an adjusted mean change from baseline tau PET SUVr levels of less than about 0.1, e.g., 0.05. In some embodiments, the decrease in tau PET from baseline is greater in subjects receiving lecanemab than in controls.

[0018] In some embodiments, the Aβ protofibril antibody reduces amyloid PET levels to about 55, 40, 25, or 20 centiloids (CL). In some embodiments, the reduction in amyloid PET from baseline is greater in subjects receiving lecanemab than in controls.

[0019] In some embodiments, the Aβ protofibril antibody reduces tau PET and / or amyloid PET levels in regional brain regions. In some embodiments, the decrease in plasma p-tau181 from baseline is greater in subjects receiving lecanemab than in controls.

[0020] In some embodiments, the local brain region is an early Braak region (eg, Braak region I, II, or III).

[0021] In some embodiments, the early Braak region includes the transitional entorhinal cortex, the entorhinal cortex, the hippocampus, the amygdala, the parahippocampal gyrus, the fusiform gyrus, and / or the lingual gyrus.

[0022] In some embodiments, the local brain region is a complex of regions that accumulate tau in early AD.

[0023] In some embodiments, the complex region includes the temporal region, the medial temporal region, and / or the meta-temporal region.

[0024] In some embodiments, the local brain region is the medial temporal region (eg, the entorhinal cortex).

[0025]

[0025] In some embodiments, the subject has mild cognitive impairment or mild dementia.

[0026] In some embodiments, the subject is at risk of developing AD.

[0027] In some embodiments, the subject has or is suspected of having pre-AD.

[0028] In some embodiments, the subject has or is suspected of having early stage AD.

[0029]

[0029] In some embodiments, the subject has an amyloid PET level of <20CL, <40CL, or <60CL.

[0030] In some embodiments, the subject has an amyloid PET level of >20CL, >40CL, or >60CL.

[0031] In some embodiments, the subject has elevated amyloid (eg, is amyloid positive) as measured by amyloid PET.

[0032] In some embodiments, the subject has a p-tau 181 level of about 2.2-2.3 pg / mL or greater (eg, as measured using a Quanterix Simoa p-tau assay).

[0033] In some embodiments, the subject is an ApoE4 carrier.

[0034] In some embodiments, a low level of tau is a tau PET level (eg, tau-PET normalized uptake value ratio (SUVR)) below a threshold in a whole brain measurement.

[0035]

[0035] In some embodiments, the whole brain measurement is a measurement of tau PET in the entire cortical gray matter.

[0036]

[0036] In some embodiments, tau PET levels are measured using the MK6240 radiotracer.

[0037]

[0037] In some embodiments, the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by an MK6240 PET scan of whole cortical gray matter.

[0038]

[0038] In some embodiments, the subject has low levels of tau in whole-brain measurements (e.g., throughout the cortical gray matter) and higher levels of tau in local brain regions (e.g., medial temporal, meta-temporal, and / or temporal).

[0039] In some embodiments, the subject further exhibits tau in a regional brain region, eg, an early Braak region (eg, Braak region I, II, or III), as measured by tau PET.

[0040]

[0040] Another aspect of the present disclosure relates to a method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising: (a) selecting a subject having tau in a local brain region, preferably as measured by PET, and (b) administering a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to the subject.

[0041] In some embodiments, the local brain region is an early Braak region (eg, Braak region I, II, or III).

[0042] In some embodiments, the early Braak region includes the transitional entorhinal cortex, the entorhinal cortex, the hippocampus, the amygdala, the parahippocampal gyrus, the fusiform gyrus, and / or the lingual gyrus.

[0043] In some embodiments, the regional brain region is a complex of regions that accumulate tau in early AD.

[0044] In some embodiments, the complex region includes the temporal region, the medial temporal region, and / or the meta-temporal region.

[0045] In some embodiments, the local brain region is the medial temporal region (eg, the entorhinal cortex).

[0046]

[0046] In some embodiments, the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0047]

[0047] In some embodiments, the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

[0048]

[0048] In some embodiments, the anti-Aβ protofibril antibody comprises lecanemab.

[0049]

[0049] In some embodiments, a therapeutically effective dose of anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg of subject weight.

[0050]

[0050] In some embodiments, a therapeutically effective dose of anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250 to 720 mg.

[0051]

[0051] In some embodiments, the therapeutically effective dose is administered weekly.

[0052] In some embodiments, the therapeutically effective dose is administered every two weeks.

[0053] In some embodiments, the therapeutically effective dose is administered for at least 13 months, at least 18 months, or at least 24 months.

[0054] In some embodiments, the frequency of administration is reduced after 13 months of treatment, for example, to every 4, 6, 8, 10, or 12 weeks.

[0055] In some embodiments, the frequency of administration is reduced after 18 months of treatment, for example, to every 4, 6, 8, 10, or 12 weeks.

[0056] In some embodiments, the frequency of administration is reduced after 24 months of treatment, for example, to every 4, 6, 8, 10, or 12 weeks.

[0057] In some embodiments, the treatment further comprises administering at least one additional therapy for AD (eg, an anti-tau antibody such as E2814).

[0058] In some embodiments, the treatment further comprises administering an anti-tau antibody, preferably E2814.

[0059]

[0059] One aspect of the present disclosure relates to a method for selecting a subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody, the method comprising: (a) obtaining a tau PET level from a whole brain measurement of the subject; and (b) selecting the subject for treatment if the tau PET level is below a threshold level.

[0060]

[0060] In some embodiments, the whole brain measure is tau PET levels in the entire cortical gray matter.

[0061] In some embodiments, tau PET levels are measured using the MK6240 radiotracer.

[0062]

[0062] In some embodiments, the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, in an MK6240 PET scan of whole cortical gray matter.

[0063] [Enumerated Embodiments] 1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in a brain region of a subject; b. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. A second tau PET level is or has been measured in the subject; and d. administering a second therapeutically effective dose comprising an anti-Aβ protofibril antibody in an amount equal to or less than the first dose to subjects with a lower rate of tau PET increase compared to control subjects. A method comprising: 2. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in a brain region of a subject; b. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. A second tau PET level is or has been measured in the subject; and d. administering a second therapeutically effective dose comprising an anti-Aβ protofibril antibody in an amount equal to or greater than the first dose and / or administering a second therapeutic agent to subjects with a similar or higher rate of tau PET increase compared to control subjects. A method comprising: 3. The method of embodiment 2, wherein the second therapeutic agent comprises an anti-tau antibody. 4. The method of any one of embodiments 1-3, wherein the second tau PET level is measured at 13 months. 5. The method of any one of embodiments 1-3, wherein the second tau PET level is measured at 18 months. 6. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. measuring tau PET levels in the temporal region of the brain of a subject; b. administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. The subject has or has had a second tau PET level measured in the temporal region of the brain at 13 or 18 months after the first dose; and d. Continuing administration of anti-Aβ protofibril antibody to subjects whose tau PET levels, as assessed by tau PET SUVR in the temporal region, have not increased by more than 0.05-0.1 compared to pre-Aβ protofibril antibody measurements. A method comprising: 7. The method of embodiment 6, wherein the temporal region is a medial temporal region, a meta-temporal region, or a temporal region (e.g., a lateral temporal region). 8. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in the temporal region of the brain of a subject; and b. Administering a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to subjects with tau PET levels higher than those in subjects without AD. A method comprising: 9. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. administering a second therapeutically effective dose of an anti-Aβ protofibril antibody in an amount equal to or less than the first dose to a subject who has AD but has a lower rate of tau PET increase compared to a control subject not treated with the Aβ protofibril antibody. 9. The method of embodiment 8, further comprising: 10. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. The method of embodiment 8, further comprising administering a second therapeutically effective dose comprising an anti-Aβ protofibril antibody in an amount equal to or greater than the first dose to control subjects and / or subjects having a high tau PET increase rate relative to control subjects and / or tau PET levels that did not increase by more than 0.05-0.1 as assessed by tau PET SUVR in the temporal region. 11. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. The method of embodiment 8, further comprising administering a second therapeutic agent to subjects having a high tau PET increase rate compared to control subjects. 12. The method of embodiment 1, 2, 6, or 8-11, wherein the second tau PET level is measured at least 13 months after the first tau PET level measurement. 13. The method of embodiment 1, 2, 6, or 8-11, wherein the second tau PET level is measured at least 18 months after the first tau PET level measurement. 14. A method of treating Alzheimer's disease in a subject, comprising: a. Measuring tau PET levels in brain regions of subjects suspected of having pre-AD; and b. administering a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to subjects with tau PET levels higher than subjects without AD. Including, A method in which the subject exhibits at least one biomarker of AD (e.g., a reduced Aβ42 / 40 ratio compared to subjects without AD, e.g., a ratio below a threshold of about 0.092, and / or elevated p-tau217 levels compared to levels in subjects without AD), and optionally the subject is otherwise cognitively normal. 15. A method for reducing brain amyloid beta in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in a brain region of a subject; b. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. A second tau PET level is or has been measured in the subject; and d. administering a second therapeutically effective dose comprising an anti-Aβ protofibril antibody in an amount equal to or less than the first dose to subjects with a lower rate of tau PET increase compared to control subjects. A method comprising: 16. A method for reducing brain amyloid beta in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in a brain region of a subject; b. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. A second tau PET level is or has been measured in the subject; and d. administering a second therapeutically effective dose comprising an anti-Aβ protofibril antibody in an amount equal to or greater than the first dose and / or administering a second therapeutic agent to subjects with a similar or higher rate of tau PET increase compared to control subjects. A method comprising: 17. The method of any one of embodiments 10, 11, or 16, wherein the second therapeutic agent comprises an anti-tau antibody. 18. The method of any one of embodiments 15-17, wherein the second tau PET level is measured at 13 months or 18 months. 19. A method for reducing brain amyloid beta in a subject having or suspected of having AD, comprising: a. measuring tau PET levels in the temporal region of the brain of a subject; b. administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. The subject has or has had a second tau PET level measured in the temporal region of the brain at 13 or 18 months after the first dose; and d. Continuing to administer anti-Aβ protofibril antibodies to subjects whose tau PET levels have not increased by more than 0.05-0.1 as assessed by tau PET SUVR in the temporal region. A method comprising: 20. The method of embodiment 19, wherein the temporal lobe is the medial temporal lobe, the meta-temporal lobe, or the temporal lobe. 21. A method for reducing brain amyloid beta in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in the temporal region of the brain of a subject; and b. Administering a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to subjects with tau PET levels higher than those in subjects without AD. A method comprising: twenty two. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. administering a second therapeutically effective dose of an anti-Aβ protofibril antibody in an amount equal to or less than the first dose to subjects who have a lower rate of tau PET increase compared to control subjects. 22. The method of embodiment 21, further comprising: twenty three. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. administering a second therapeutically effective dose of an anti-Aβ protofibril antibody in an amount equal to or greater than the first dose to subjects who have a lower rate of tau PET increase compared to control subjects. 22. The method of embodiment 21, further comprising: twenty four. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. The method of embodiment 21, further comprising administering a second therapeutic agent to subjects having a lower tau PET increase rate compared to control subjects. twenty five. a. measuring a second tau PET level from the subject after the first sampling to determine a second tau PET level; and b. The method of embodiment 21, further comprising administering a second therapeutic agent to subjects having a high tau PET increase rate compared to control subjects. 26. A method for reducing brain amyloid beta in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in brain regions of subjects suspected of having pre-AD; and b. administering a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to subjects with tau PET levels that are higher than subjects without AD; A method in which the subject exhibits at least one biomarker of AD (e.g., a reduced Aβ42 / 40 ratio compared to subjects without AD, e.g., a ratio below a threshold of about 0.092 and / or elevated p-tau217 levels compared to levels in subjects without AD), but is cognitively normal. 27. The method of any one of embodiments 1-26, further comprising administering a second therapeutic agent in combination with the anti-Aβ protofibril antibody. 28. The method of embodiment 24, 25, or 27, wherein the second therapeutic agent is an anti-tau antibody. 29. The method of embodiment 28, wherein the anti-tau antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the 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 the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). 30. The method of embodiment 28 or 29, wherein 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. 31. The method of any one of embodiments 1 to 30, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 32. The method of any one of embodiments 1-31, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. 33. The method of any one of embodiments 1-32, wherein the subject has or is suspected of having pre-AD. 34. The method of embodiment 33, wherein the subject is administered an anti-tau antibody prior to the anti-Aβ protofibrils. 35. The method of any one of embodiments 1-32, wherein the subject has or is suspected of having early stage AD. 36. The method of embodiment 35, wherein the subject is administered anti-Aβ protofibrils prior to the anti-tau antibody. 37. The method of any one of embodiments 1-36, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg of the subject's weight. 38. The method of any one of embodiments 1-36, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250-720 mg. 39. The method of any one of embodiments 1-36, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises 360 mg subcutaneously. 40. The method of any one of embodiments 1-36, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises 720 mg subcutaneously. 41. A method for selecting a subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody, comprising: a. Measuring tau PET levels from a region of the subject's brain; and b. A method comprising selecting a subject for treatment if the tau PET level is higher than that of a subject not having AD. 42. The method of embodiment 41, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 43. The method of embodiment 41 or 42, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. 44. The method of any one of embodiments 41-43, wherein the tau PET level is about 1.4. 45. The method of any one of embodiments 41-43, wherein the tau PET level is about 1.5. 46. ​​A method for monitoring therapeutic efficacy in a subject having or suspected of having AD, comprising: a. administering to a subject a therapeutically effective dose of an anti-Aβ protofibril antibody; b. Measuring tau PET levels from a region of the subject's brain; and c. A method comprising comparing the tau PET level to a tau PET level from a subject before treatment, where a lower tau PET level compared to a control subject indicates effective treatment. 47. A method for monitoring therapeutic efficacy in a subject having or suspected of having AD, comprising: a. measuring tau PET levels in the temporal region of the brain of a subject; b. administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. The subject has or has had a second tau PET level measured in the temporal region of the brain at 13 or 18 months after the first dose; and d. A method comprising comparing the tau PET level to a tau PET level from the subject before treatment (a tau PET level that did not increase by more than 0.05-0.1 as assessed by tau PET SUVR in the temporal region indicates effective treatment). 48. The method of embodiment 46 or 47, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 49. The method of any one of embodiments 46-48, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. 50. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels in a brain region of a subject; b. administering to the subject a therapeutic dosing regimen comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; c. Measuring subsequent tau PET levels; and d. Determining that the subsequent tau PET level is lower than the control level and / or the tau PET level has not increased by more than 0.05-0.1, and switching to a maintenance dosing regimen. 51. The method of embodiment 50, wherein the subject has a tau PET level greater than 1.4 as assessed by tau PET SUVR. 52. The method of embodiment 50, wherein the subject has a tau PET level greater than 1.5 as assessed by tau PET SUVR. 53. The method of any one of embodiments 50-52, wherein the brain region is the temporal region. 54. The method of any one of embodiments 50 to 53, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 55. The method of any one of embodiments 50-54, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. 56. The method of any one of embodiments 50-55, wherein the switch to the maintenance dose occurs at least 6 months (e.g., 6 months, or 13 months, or 18 months) after initiation of the therapeutic dosing regimen or after the subject has converted to an amyloid-negative state, e.g., as determined by amyloid PET. 57. The method of any one of embodiments 50-55, wherein the therapeutic dosing regimen comprises weekly administration of the anti-Aβ protofibril antibody as an intravenous infusion at a therapeutically effective dose of 10 mg / kg of the subject's weight. 58. The method of any one of embodiments 50-55, wherein the therapeutic dosing regimen comprises administering the anti-Aβ protofibril antibody as an intravenous infusion every two weeks at a therapeutically effective dose of 10 mg / kg of the subject's weight. 59. The method of any one of embodiments 50-55, wherein the therapeutic dosing regimen comprises weekly subcutaneous administration of an anti-Aβ protofibril antibody at a therapeutically effective dose of 720 mg. 60. The method of any one of embodiments 50-55, wherein the therapeutic dosing regimen comprises weekly subcutaneous administration of an anti-Aβ protofibril antibody at a therapeutically effective dose of 360 mg. 61. The method of any one of embodiments 50-55, wherein the therapeutic dosing regimen comprises biweekly subcutaneous administration of an anti-Aβ protofibril antibody at a therapeutically effective dose of 720 mg. 62. The method of any one of embodiments 50-61, wherein the maintenance dosing regimen comprises biweekly intravenous infusions at a therapeutically effective dose of 10 mg / kg of subject weight. 63. The method of any one of embodiments 50-61, wherein the maintenance dosing regimen comprises monthly intravenous infusions at a therapeutically effective dose of 10 mg / kg of the subject's weight. 64. The method of any one of embodiments 50-61, wherein the maintenance dosing regimen comprises intravenous infusion every 3 months at a therapeutically effective dose of 10 mg / kg of the subject's weight. 65. The method of any one of embodiments 50-61, wherein the maintenance dosing regimen comprises administering an anti-Aβ protofibril antibody subcutaneously every other week at a therapeutically effective dose of 720 mg. 66. The method of any one of embodiments 50-61, wherein the maintenance dosing regimen comprises monthly subcutaneous administration of an anti-Aβ protofibril antibody at a therapeutically effective dose of 720 mg. 67. The method of any one of embodiments 50-61, wherein the maintenance dosing regimen comprises weekly subcutaneous administration of an anti-Aβ protofibril antibody at a therapeutically effective dose of 360 mg. 68. The method of any one of embodiments 50-67, wherein the maintenance dosing regimen comprises the same dosing regimen as the treatment regimen. 69. A method of monitoring therapeutic efficacy in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels from a brain region of a subject; b. measuring the level of a second biomarker from the subject; c. administering to the subject a therapeutically effective dose of an anti-Aβ protofibril antibody; d. measuring a second tau PET level from the region of the subject's brain after the first sampling; e. measuring a second level of a second biomarker from the subject after the first sampling; f. Comparing tau PET levels and levels of a second biomarker from a control subject, wherein lower tau PET levels and / or improved levels in the second biomarker compared to the control subject indicate effective treatment. 70. A method of monitoring therapeutic efficacy in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels from a brain region of a subject; b. measuring the level of a second biomarker from the subject; c. administering to the subject a therapeutically effective dose of an anti-Aβ protofibril antibody; d. measuring a second tau PET level from the region of the subject's brain after the first sampling; e. measuring a second level of a second biomarker from the subject after the first sampling; f. comparing the tau PET level to a tau PET level from the subject before treatment; g. Comparing the level of the second biomarker in the subject with the level of the biomarker from the subject before treatment, wherein a decreased rate of tau PET increase and / or an improvement in the level of the second biomarker compared to the control subject indicates effective treatment. 71. A method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels from a brain region of a subject; b. measuring the level of a second biomarker from the subject; c. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; d. measuring a second tau PET level in the subject after the first sampling; e. measuring the level of a second biomarker from the subject after the first sampling to determine a second level; and f. A method comprising administering a second therapeutically effective dose comprising the same or a lesser amount of anti-Aβ protofibril antibody as the first dose to a subject having a lower rate of tau PET increase and / or improvement in a second biomarker level compared to a control subject. 72. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Measuring tau PET levels from a brain region of a subject; b. measuring the level of a second biomarker from the subject; c. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; d. Measuring a second tau PET level in the subject after the first sampling; e. measuring the level of a second biomarker from the subject after the first sampling to determine a second level; and f. A method comprising administering a second therapeutically effective dose comprising an amount of anti-Aβ protofibril antibody equal to or greater than the first dose to a subject who has a high rate of tau PET increase and / or no improvement or worsening in a second biomarker level compared to a control subject. 73. The second biomarker is Volumetric MRI (vMRI) including whole brain volume, cortical thickness, total hippocampal volume, lateral ventricle volume, amyloid PET levels, fluorodeoxyglucose (FDG) PET levels, cerebrospinal fluid levels of Aβ1-42 and Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, neurogranin, neurofilament light chain (NfL), microtubule binding region (MTBR)-tau, or serum or plasma levels of Aβ1-42 and Aβ1-40. 73. The method of any one of embodiments 69-72, wherein the measured values ​​of tau include one or more of: Aβ1-42 to Aβ1-40 ratio (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and / or tau phosphorylated at 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). 74. The method of any one of embodiments 69-73, wherein the second biomarker is a combination of GFAP and / or p-tau217 and the ratio of Aβ1-42 to Aβ1-40. 75. The method of any one of embodiments 69-73, wherein lower levels of tau PET and lower levels of amyloid PET indicate effective treatment. 76. The method of any one of embodiments 69 to 73, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 77. The method of any one of embodiments 69-73, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. 78. The method of any one of embodiments 1-77, wherein the control subject has Alzheimer's disease, early Alzheimer's disease, or pre-Alzheimer's disease, and the control subject is not treated with an anti-Aβ protofibril antibody. 79. The method of any one of embodiments 1-78, wherein the brain region is the temporal lobe. 80. The method of any one of embodiments 1-78, wherein the brain region is the meta-temporal lobe. 81. The method of any one of embodiments 1-78, wherein the brain region is the medial temporal lobe. 82. The method of any one of embodiments 1-13, 15-25, or 27-88, wherein the subject has Alzheimer's disease. 83. The method of any one of embodiments 1-13, 15-25, or 27-88, wherein the subject has early Alzheimer's disease. 84. The method of any one of embodiments 1-83, wherein the subject has pre-Alzheimer's disease (pre-AD). 85. The method of any one of embodiments 1-84, wherein the subject has Alzheimer's disease, Down's syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, dementia with Lewy bodies, or another brain disease or condition having Aβ peptide-containing soluble and / or insoluble Aβ aggregates. 86. The subject is a. Has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate probability and / or mild Alzheimer's disease dementia; b. Mild cognitive impairment due to Alzheimer's disease - intermediate probability according to the National Institute of Aging-Alzheimer's Association (NIA-AA) Core Clinical Criteria; c. Mild cognitive impairment due to Alzheimer's disease - intermediate probability with a CDR global score of 0.5 and a memory box score of 0.5 or higher before treatment; d. Mild cognitive impairment due to Alzheimer's disease - intermediate probability, e.g., with a history of subjective memory decline with gradual onset and slow progression over the last year before treatment, as corroborated by the informant; e. Mild Alzheimer's disease dementia according to the NIA-AA Core Clinical Criteria for Probable Alzheimer's Disease Dementia; or f. The method of any one of embodiments 1-85, wherein the patient has been diagnosed with mild Alzheimer's disease dementia with a pre-treatment CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater. 87. The method of any one of embodiments 1-86, wherein the subject is amyloid-positive prior to administration, as indicated, for example, by PET assessment, CSF assessment of Aβ(1-42), MRI, retinal amyloid deposits, and / or specific behavioral / cognitive phenotype. 88. The method of any one of embodiments 1-87, wherein treatment is discontinued if tau PET levels increase by more than 0.05-0.1 compared to control subjects. 89. The method of any one of embodiments 1-88, wherein treatment is discontinued if it does not result in a lower rate of increase in tau PET levels compared to control subjects. 90. The method of any one of embodiments 1-37, 41-58, or 62-89, wherein the anti-Aβ protofibril antibody is administered as an intravenous infusion at a therapeutically effective dose of 10 mg / kg of the subject's weight. 91. The method of any one of embodiments 1-36, 40-56, 59, or 61-89, wherein the anti-Aβ protofibril antibody is administered subcutaneously at a therapeutically effective dose of 720 mg. 92. The method of any one of embodiments 1-36, 39, 41-56, 60, or 62-89, wherein the anti-Aβ protofibril antibody is administered subcutaneously at a therapeutically effective dose of 360 mg. 93. The method of embodiments 1-57, 59, 60, 62-92, wherein the therapeutically effective dose is administered weekly. 94. The method of embodiments 1-56, 58, 61-92, wherein the therapeutically effective dose is administered every two weeks. 95. The method of embodiments 1-94, wherein the frequency of administration is reduced after 13 months of treatment, for example, to a frequency of every 4, 6, 8, 10, or 12 weeks. 96. The method of any one of embodiments 90-92, wherein the therapeutically effective dose is reduced after 13 months of treatment. 97. The method of embodiments 1-96, wherein the frequency of administration is reduced after 18 months of treatment, for example, to a frequency of every 4, 6, 8, 10, or 12 weeks. 98. The method of any one of embodiments 90-92, wherein the therapeutically effective dose is reduced after 18 months of treatment. 99. The method of any one of embodiments 1 to 98, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 100. The method of any one of embodiments 1-99, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. 101. The method of any one of embodiments 1-100, wherein the subject is administered a second therapeutic agent sequentially or simultaneously. 102. The method of embodiment 101, wherein the second therapeutic agent is an anti-tau antibody. 103. The method of embodiment 102, wherein the anti-tau antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the 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 the amino acid sequences of SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). 104. The method of embodiment 102 or 103, wherein the anti-tau antibody or antigen-binding fragment thereof comprises a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22. 105. The method comprises: comparing the results of a subject's treatment with a subject's condition before treatment and / or compared to an untreated control subject; a. improvement or slowing of deterioration of one or more cerebrospinal fluid biomarkers, e.g., Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, neurogranin, neurofilament light chain (NfL), phosphorylated tau; and / or b. The method of any one of embodiments 1-104, wherein the method results in a reduced or slowed increase in plasma or serum biomarkers, such as Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and / or tau phosphorylated at 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). 106. Treatment a. Delays clinical deterioration as determined by ADCOMS; b. Delays clinical deterioration as determined by ADAS MCI-ADL; c. delays clinical deterioration as determined by the revised iADRS; d. delays clinical deterioration as measured by CDR-SB; or e. delaying clinical deterioration as measured by ADAS-Cog; The method of any one of embodiments 1 to 105. 107. The method of any one of embodiments 1-106, wherein the method further comprises monitoring for ARIA, e.g., ARIA-E and / or ARIA-H, e.g., as observed by MRI. 108. The method of any one of embodiments 1-107, wherein the method does not require a titration step before administering a first therapeutically effective dose of the anti-Aβ protofibril antibody to the subject. 109. The method of any one of embodiments 1-108, wherein the method results in at least 24% lower (e.g., at least 29% lower) cognitive decline as measured by ADCOMS compared to untreated subjects. 110. The method of any one of embodiments 1-109, wherein the method results in at least 26% lower (e.g., at least 27%) cognitive decline as measured by CDR-SB compared to untreated subjects. 111. The method of any one of embodiments 1-110, wherein the method results in at least 26% lower (e.g., at least 47% lower) cognitive decline as measured by ADAS-Cog14 compared to untreated subjects. 112. The method of any one of embodiments 1-111, wherein the method results in at least 37% less cognitive decline as measured by ADCS MCI-ADL compared to untreated subjects. 113. The method of any one of embodiments 1-112, wherein the method results in a decrease in PET SUVr of at least 0.2 from baseline as measured by amyloid beta PET compared to untreated subjects. 114. The method of any one of embodiments 1-113, wherein the method results in a decrease of at least 50 centiloids from baseline as measured by amyloid beta PET compared to untreated subjects. 115. The method of any one of embodiments 1-114, wherein the method results in an increase from baseline of plasma Aβ42 / 40 of at least 0.005 compared to untreated subjects. 116. The method of any one of embodiments 1-115, wherein the method results in a decrease of at least 1 pg / ml from baseline in plasma p-tau 181 compared to untreated subjects. 117. The method of any one of embodiments 1-116, wherein the method results in the subject being converted from amyloid-positive to amyloid-negative. 118. The method of any one of embodiments 1-117, wherein the method results in a reduction in the risk of progression to the next stage of AD, e.g., by at least 10%, at least 20%, at least 30%, at least 31%, as measured by the Clinical Dementia Rating (CDR) global score. 119. The method of any one of embodiments 109-118, wherein the outcome is measured at least 6 months after the first therapeutically effective dose. 120. The method of any one of embodiments 109-118, wherein the outcome is measured at least 12 months after the first therapeutically effective dose. 121. The method of any one of embodiments 109-118, wherein the outcome is measured at least 13 months after the first therapeutically effective dose. 122. The method of any one of embodiments 109-118, wherein the outcome is measured at least 18 months after the first therapeutically effective dose. 123. The method of any one of embodiments 109-122, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg of the subject's weight. 124. The method of any one of embodiments 109-123, wherein the therapeutically effective dose is administered every other week. 125. The method of any one of embodiments 109-122, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises 720 mg administered subcutaneously weekly. 126. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Selecting subjects with low levels of tau in whole brain measurements, preferably as measured by tau PET (low tau PET levels); and b. A method comprising administering to a subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. 127. The method of embodiment 126, wherein treating AD comprises reducing, slowing, and / or reversing the decline in measures of cognitive function. 128. The method of embodiment 127, wherein the measure of cognitive function is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL. 129. The method of embodiment 126, wherein treating AD comprises causing a change (e.g., slowing, delaying, or reducing) in at least one marker of AD pathology. 130. The method of embodiment 129, wherein the marker is plasma Aβ42 / 40 ratio, plasma p-tau181 level, plasma GFAP level, and / or plasma NfL level. 131. The method of embodiment 130, wherein the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio as measured by an adjusted mean change from baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.009. 132. The method of embodiment 130 or embodiment 131, wherein the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or greater. 133. The method of embodiment 130, wherein the Aβ protofibril antibody reduces plasma p-tau 181 by at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml, as measured by adjusted mean change from baseline p-tau 181 levels. 134. The method of embodiment 130, wherein the Aβ protofibril antibody reduces plasma GFAP by at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml, as measured by adjusted mean change from baseline GFAP levels. 135. The method of embodiment 130, wherein the Aβ protofibril antibody increases plasma NfL by less than about 2 pg / ml or less than about 3 pg / ml, as measured by adjusted mean change from baseline NfL levels. 136. The method of embodiment 129, wherein the marker is tau PET level or amyloid PET level. 137. The method of embodiment 136, wherein the Aβ protofibril antibody reduces tau PET levels as measured by an adjusted mean change from baseline tau PET SUVr level of less than about 0.1, e.g., 0.05. 138. The method of embodiment 136, wherein the Aβ protofibril antibody reduces amyloid PET levels to about 55, 40, 25, or 20 centiloids. 139. The method of embodiment 136, wherein the Aβ protofibril antibody reduces tau PET and / or amyloid PET levels in a local brain region. 140. The method of embodiment 139, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III). 141. The method of embodiment 140, wherein the early Braak region comprises the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. 142. The method of embodiment 139, wherein the local brain region is a complex of regions that accumulate tau in early AD. 143. The method of embodiment 142, wherein the complex region includes the temporal region, the medial temporal region, and / or the meta-temporal region. 144. The method of embodiment 139, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex, hippocampus, parahippocampal gyrus, and / or the temporal pole (medial and inferior lateral tip of the temporal lobe)). 145. The method of embodiment 126, wherein the subject has mild cognitive impairment or mild dementia. 146. The method of embodiment 126, wherein the subject is at risk of developing AD. 147. The method of embodiment 126, wherein the subject has or is suspected of having pre-AD. 148. The method of embodiment 126, wherein the subject has or is suspected of having early stage AD. 149. The method of embodiment 126, wherein the subject has an amyloid PET level of <20CL, <40CL, or <60CL. 150. The method of embodiment 126, wherein the subject has an amyloid PET level of >20CL, >40CL, or >60CL. 151. The method of embodiment 126, wherein the subject has elevated amyloid as measured by amyloid PET (e.g., is amyloid positive). 152. The method of embodiment 126, wherein the subject is an ApoE4 carrier. 153. The method of embodiment 126, wherein the low level of tau is a tau PET level (e.g., tau-PET standardized uptake value ratio (SUVR)) below a threshold in whole brain measurements. 154. The method of embodiment 153, wherein the whole-brain measurement is a measurement of tau PET in the entire cortical gray matter. 155. The method of embodiment 153 or 154, wherein tau PET levels are measured using the MK6240 radiotracer. 156. The method of any one of embodiments 153-155, wherein the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by an MK6240 PET scan of whole cortical gray matter. 157. The method of any one of embodiments 1-156, wherein the subject has low levels of tau in whole-brain measurements (e.g., throughout the cortical gray matter) and higher levels of tau in regional brain regions (e.g., medial temporal, meta-temporal, and / or temporal regions) as measured by tau PET. 158. The method of any one of embodiments 1-157, wherein the subject further exhibits tau in a regional brain region, e.g., an early Braak area (e.g., Braak area I, II, or III), as measured by tau PET. 159. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. Selecting subjects with tau in regional brain regions, preferably as measured by PET; and b. A method comprising administering to a subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. 160. The method of embodiment 159, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III). 161. The method of embodiment 160, wherein the early Braak region comprises the transitional entorhinal cortex, the entorhinal cortex, the hippocampus, the amygdala, the parahippocampal gyrus, the fusiform gyrus, and / or the lingual gyrus. 162. The method of embodiment 159, wherein the local brain region is a complex of regions that accumulate tau in early AD. 163. The method of embodiment 162, wherein the complex region includes the temporal region, the medial temporal region, and / or the meta-temporal region. 164. The method of embodiment 159, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex). 165. The method of any one of embodiments 1 to 164, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 166. The method of any one of embodiments 1-165, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. 167. The method of any one of embodiments 1-166, wherein the anti-Aβ protofibril antibody comprises lecanemab. 168. The method of any one of embodiments 1-167, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg of the subject's weight. 169. The method of any one of embodiments 1-167, wherein the therapeutically effective dose of anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250-720 mg. 170. The method of any one of embodiments 1-168, wherein the therapeutically effective dose is administered weekly. 171. The method of any one of embodiments 1-168, wherein the therapeutically effective dose is administered every two weeks. 172. The method of any one of embodiments 1-171, wherein the therapeutically effective dose is administered for at least 13 months, at least 18 months, or at least 24 months. 173. The method of embodiment 172, wherein the frequency of administration is reduced after 13 months of treatment, for example, to a frequency of every 4, 6, 8, 10, or 12 weeks. 174. The method of embodiment 172, wherein the frequency of administration is reduced after 18 months of treatment, for example, to a frequency of every 4, 6, 8, 10, or 12 weeks. 175. The method of embodiment 172, wherein the frequency of administration is reduced after 24 months of treatment, for example, to a frequency of every 4, 6, 8, 10, or 12 weeks. 176. The method of any one of embodiments 1-175, wherein the treatment further comprises administering at least one additional therapy for AD (e.g., an anti-tau antibody such as E2814). 177. The method of any one of embodiments 1-176, wherein the treatment further comprises administering an anti-tau antibody, preferably E2814. 178. A method for selecting a subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody, comprising: a. Obtaining tau PET levels from whole brain measurements in a subject; b. A method comprising selecting a subject for treatment if the tau PET level is below a threshold level. 179. The method of embodiment 178, wherein the whole-brain measure is tau PET levels in the entire cortical gray matter. 180. The method of embodiment 178 or 179, wherein tau PET levels are measured using the MK6240 radiotracer. 181. The method of embodiment 179, wherein the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by an MK6240 PET scan of whole cortical gray matter. 182. An anti-amyloid beta (Aβ) protofibril antibody for use in a method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the method is the method of any one of embodiments 126 to 181. 183. Use of an anti-amyloid beta (Aβ) protofibril antibody in the manufacture of a medicament for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the medicament is administered by the method of any one of embodiments 126 to 181. 184. A kit for carrying out a method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD according to any one of embodiments 126-181. 185. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use in a method for the treatment of Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the subject has low levels of tau in whole brain measurements, preferably as measured by tau PET (low tau PET levels). 186. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use in a method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the subject has tau in a regional brain region, preferably as measured by PET. 187. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-186, wherein treatment of AD comprises reducing, slowing, and / or reversing decline in measures of cognitive function. 188. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 187, wherein the measure of cognitive function is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL. 189. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-188, wherein treating AD comprises causing a change (e.g., slowing, delay, or reduction) in at least one marker of AD pathology. 190. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 189, wherein the marker is plasma Aβ42 / 40 ratio, plasma p-tau181 level, plasma GFAP level, and / or plasma NfL level. 191. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 190, wherein the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio as measured by an adjusted mean change from baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.009. 192. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 190-191, wherein the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or greater. 193. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 190-192, wherein the Aβ protofibril antibody reduces plasma p-tau 181 by at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml, as measured by adjusted mean change from baseline p-tau 181 levels. 194. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 190-193, wherein the Aβ protofibril antibody reduces plasma GFAP by at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml, as measured by adjusted mean change from baseline GFAP levels. 195. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 190-194, wherein the Aβ protofibril antibody increases plasma NfL by less than about 2 pg / ml or less than about 3 pg / ml, as measured by adjusted mean change from baseline NfL levels. 196. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 189-195, wherein the marker is tau PET levels or amyloid PET levels. 197. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-196, wherein the Aβ protofibril antibody reduces tau PET levels as measured by an adjusted mean change from baseline tau PET SUVr levels of less than about 0.1, e.g., 0.05. 198. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-197, wherein the Aβ protofibril antibody reduces amyloid PET levels by about 55, 40, 25, or 20 centiloids. 199. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 197-198, wherein the Aβ protofibril antibody reduces tau PET and / or amyloid PET levels in a local brain region. 200. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 199, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III). 201. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 200, wherein the early Braak region comprises the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus. 202. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 199, wherein the local brain region is a complex of regions that accumulate tau in early AD. 203. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 202, wherein the complex region comprises a temporal region, a medial temporal region, and / or a meta-temporal region. 204. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 199, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex, hippocampus, parahippocampal gyrus, and temporal pole (medial and inferior lateral tip of the temporal lobe)). 205. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-204, wherein the subject has mild cognitive impairment or mild dementia. 206. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-205, wherein the subject is at risk of developing AD. 207. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-206, wherein the subject has or is suspected of having pre-AD. 208. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-205, wherein the subject has or is suspected of having early stage AD. 209. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-208, wherein the subject has an amyloid PET level of <20 CL, <40 CL, or <60 CL. 210. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-208, wherein the subject has an amyloid PET level of >20CL, >40CL, or >60CL. 211. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-208, wherein the subject has elevated amyloid as measured by amyloid PET (e.g., is amyloid positive). 212. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-211, wherein the subject is an ApoE4 carrier. 213. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 or 187-212, wherein the low level of tau is a tau PET level (e.g., tau-PET normalized uptake value ratio (SUVR)) below a threshold in whole brain measurements. 214. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 213, wherein the whole brain measurement is a measurement of tau PET in the entire cortical gray matter. 215. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-214, wherein tau PET levels are measured using the MK6240 radiotracer. 216. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 or 187-215, wherein the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by MK6240 PET scan of whole cortical gray matter. 217. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 or 187-216, wherein the subject has low levels of tau in whole-brain measurements (e.g., throughout the cortical gray matter) and higher levels of tau in regional brain regions (e.g., medial temporal, meta-temporal, and / or temporal regions) as measured by tau PET. 218. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 or 187-217, wherein the subject further exhibits tau in a regional brain region, e.g., an early Braak region (e.g., Braak region I, II, or III), as measured by tau PET. 219. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 186 or 218, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III). 220. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 219, wherein the early Braak region comprises the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus. 221. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 186 or 218, wherein the local brain region is a complex of regions that accumulate tau in early AD. 222. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 221, wherein the complex region comprises a temporal region, a medial temporal region, and / or a meta-temporal region. 223. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 186 or 218, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex). 224. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 to 223, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 225. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 to 224, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. 226. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-225, wherein the anti-Aβ protofibril antibody comprises lecanemab. 227. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-226, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg of the subject's weight. 228. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-227, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250-720 mg. 229. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-228, wherein the therapeutically effective dose is administered weekly. 230. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibrillar antibody for use according to any of embodiments 185-229, wherein the therapeutically effective dose is administered every two weeks. 231. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-230, wherein the therapeutically effective dose is administered for at least 13 months, at least 18 months, or at least 24 months. 232. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 231, wherein the frequency of administration is reduced after 13 months of treatment, for example to a frequency of every 4, 6, 8, 10, or 12 weeks. 232. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 231, wherein the frequency of administration is reduced after 18 months of treatment, for example to a frequency of every 4, 6, 8, 10, or 12 weeks. 234. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to embodiment 231, wherein the frequency of administration is reduced after 24 months of treatment, for example to a frequency of every 4, 6, 8, 10, or 12 weeks. 235. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185-234, wherein the treatment further comprises administering at least one additional therapy for AD (e.g., an anti-tau antibody such as E2814). 236. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use according to any of embodiments 185 to 235, wherein the treatment further comprises administering an anti-tau antibody, preferably E2814. 237. Use of a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for the manufacture of a medicament for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the subject has low levels of tau in whole brain measurements, preferably as measured by tau PET (low tau PET levels). 238. Use of a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for the manufacture of a medicament for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the subject has tau in a regional brain region, preferably as measured by PET. 237. A method for diagnosing early stage Alzheimer's disease (AD) in a subject suspected of having AD and / or identifying a subject suspected of having Alzheimer's disease who is suitable for treatment with an anti-amyloid protofibril antibody, such as lecanemab, comprising: a. obtaining a first tau PET measurement from a global brain region and, optionally, a second tau PET measurement from a regional brain region in a subject; and b. A method of diagnosing AD in a subject and / or identifying a subject suitable for treatment with an anti-amyloid protofibril antibody, such as lecanemab, based on a first tau PET level in a whole-brain measurement that is below a threshold level, and optionally by the presence of tau PET in a regional brain region measurement (preferably the regional brain region includes one or more of an early Braak region (e.g., Braak region I, II, or III), a composite of regions that accumulate tau in early AD (e.g., the temporal region, the medial temporal region, and / or the meta-temporal region), or the medial temporal region (e.g., the entorhinal cortex, the hippocampus, the parahippocampal gyrus, and / or the temporal pole (the medial and inferior lateral tips of the temporal lobe)). 238. A method for predicting the prognosis of a subject having or suspected of having Alzheimer's disease, comprising: a. Obtaining tau PET levels from whole brain measurements in a subject; and b. comparing the tau PET level to a threshold tau PET level; The method, wherein subjects having tau PET levels that are below a threshold level are predicted to have an improved prognosis with respect to treating AD compared to subjects having tau PET levels that are equal to or greater than the threshold level. 239. The method of any of embodiments 237-238, wherein the whole brain measure is tau PET levels in the entire cortical gray matter. 240. The method of any of embodiments 237-239, wherein tau PET levels are measured using the MK6240 radiotracer. 241. The method of embodiment 240, wherein the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by an MK6240 PET scan of whole cortical gray matter. [Brief explanation of the drawings]

[0064] [Figure 1A] 1 shows plots of adjusted mean change from baseline tau PET SUVR (±standard error, SE) over time in subjects receiving lecanemab or placebo. [Figure 1B] 1 shows plots of adjusted mean change from baseline tau PET SUVR (±standard error, SE) over time in subjects receiving lecanemab or placebo. [Figure 2] 1 shows the effect of lecanemab administration on the entorhinal cortex of a subject. [Figure 3] 1 shows a plot of adjusted change from baseline tau PET SUVR at 18 months as a function of baseline tau PET SUVR. [Figure 4A] 1 shows the effect of lecanemab on tau PET SUVR in selected brain regions. [Figure 4B] 1 shows the effect of lecanemab on tau PET SUVR in selected brain regions. [Figure 4C] 1 shows the effect of lecanemab on tau PET SUVR in selected brain regions. [Figure 5]1 shows baseline tau PET SURV for the combined region in subjects receiving lecanemab and subjects receiving placebo. [Figure 6] Baseline tau PET SUVR is shown to be increased in subjects from clusters 1 to 4. [Figure 7A] FIG. 1 shows the effect of lecanemab on adjusted mean change from baseline in tau PET SUVR in subjects with different APOE4 status. [Figure 7B] FIG. 1 shows the effect of lecanemab on adjusted mean change from baseline in tau PET SUVR in subjects with different APOE4 status. [Figure 7C] FIG. 1 shows the effect of lecanemab on adjusted mean change from baseline in tau PET SUVR in subjects with different APOE4 status. [Figure 8A] 1 shows a comparison of the effect of lecanemab on adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele and subjects heterozygous for the APOE4 allele. [Figure 8B] 1 shows a comparison of the effect of lecanemab on adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele and subjects heterozygous for the APOE4 allele. [Figure 8C] 1 shows a comparison of the effect of lecanemab on adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele and subjects heterozygous for the APOE4 allele. [Figure 9A] The effect size of lecanemab on the adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele compared to subjects who are non-carriers and subjects heterozygous for the APOE4 allele will be compared. [Figure 9B]The effect size of lecanemab on the adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele compared to subjects who are non-carriers and subjects heterozygous for the APOE4 allele will be compared. [Figure 9C] The effect size of lecanemab on the adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele compared to subjects who are non-carriers and subjects heterozygous for the APOE4 allele will be compared. [Figure 9D] The effect size of lecanemab on the adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele compared to subjects who are non-carriers and subjects heterozygous for the APOE4 allele will be compared. [Figure 9E] The effect size of lecanemab on the adjusted mean change from baseline in tau PET SUVR in subjects homozygous for the APOE4 allele compared to subjects who are non-carriers and subjects heterozygous for the APOE4 allele will be compared. [Figure 10A] 1 shows the effect of lecanemab at 18 months across all brain regions and global tau burden (tau IQ) in subjects homozygous for APOE4 allele carriers. [Figure 10B] 1 shows the effect of lecanemab at 18 months across all brain regions and global tau burden (tau IQ) in subjects homozygous for APOE4 allele carriers. [Figure 10C] 1 shows the effect of lecanemab at 18 months across all brain regions and global tau burden (tau IQ) in subjects homozygous for APOE4 allele carriers. [Figure 11A] 1 shows the effect of lecanemab at 18 months in subjects who are non-carriers for APOE4. [Figure 11B] 1 shows the effect of lecanemab at 18 months in subjects who are non-carriers for APOE4. [Figure 11C]Shows the effect of lecanemab at 18 months in subjects who are non-carriers for APOE4. [Figure 12A] Shows the effect of lecanemab at 18 months in subjects who are carriers for APOE4. [Figure 12B] Shows the effect of lecanemab at 18 months in subjects who are carriers for APOE4. [Figure 12C] Shows the effect of lecanemab at 18 months in subjects who are carriers for APOE4. [Figure 13A] Shows the effect of lecanemab at 18 months in subjects who are heterozygous for APOE4. [Figure 13B] Shows the effect of lecanemab at 18 months in subjects who are heterozygous for APOE4. [Figure 13C] Shows the effect of lecanemab at 18 months in subjects who are heterozygous for APOE4. [Figure 14A] Shows the effect of lecanemab at 13 and 18 months in subjects from below the first quartile (<Q1) in brain regions and overall tau burden (tau IQ). [Figure 14B] Shows the effect of lecanemab at 13 and 18 months in subjects from below the first quartile (<Q1) in brain regions and overall tau burden (tau IQ). [Figure 14C] Shows the effect of lecanemab at 13 and 18 months in subjects from below the first quartile (<Q1) in brain regions and overall tau burden (tau IQ). [Figure 14D] Shows the effect of lecanemab at 13 and 18 months in subjects from below the first quartile (<Q1) in brain regions and overall tau burden (tau IQ). [Figure 14E] Shows the effect of lecanemab at 13 and 18 months in subjects from below the first quartile (<Q1) in brain regions and overall tau burden (tau IQ). [Figure 15A]Shows the effect of lecanemab in subjects from the first quartile (Q1) to the third quartile (<Q3) over the same time points and regions as in Figure 14. [Figure 15B] Shows the effect of lecanemab in subjects from the first quartile (Q1) to the third quartile (<Q3) over the same time points and regions as in Figure 14. [Figure 15C] Shows the effect of lecanemab in subjects from the first quartile (Q1) to the third quartile (<Q3) over the same time points and regions as in Figure 14. [Figure 15D] Shows the effect of lecanemab in subjects from the first quartile (Q1) to the third quartile (<Q3) over the same time points and regions as in Figure 14. [Figure 15E] Shows the effect of lecanemab in subjects from the first quartile (Q1) to the third quartile (<Q3) over the same time points and regions as in Figure 14. [Figure 16A] Shows the effect of lecanemab in subjects exceeding the third quartile (>Q3) over the same time points and regions as in Figures 14 and 15. [Figure 16B] Shows the effect of lecanemab in subjects exceeding the third quartile (>Q3) over the same time points and regions as in Figures 14 and 15. [Figure 16C] Shows the effect of lecanemab in subjects exceeding the third quartile (>Q3) over the same time points and regions as in Figures 14 and 15. [Figure 16D] Shows the effect of lecanemab in subjects exceeding the third quartile (>Q3) over the same time points and regions as in Figures 14 and 15. [Figure 16E] Shows the effect of lecanemab in subjects exceeding the third quartile (>Q3) over the same time points and regions as in Figures 14 and 1​​​​​​​​​ [Figure 20] 1 shows the adjusted mean change from baseline CDR-SB in Study 301. [Figure 21] 1 shows the adjusted mean change from baseline ADAS-Cog14 in study 301. [Figure 22] 1 shows the adjusted mean change from baseline ADCS MCI-ADL in Study 301. [Figure 23] 1 shows that lecanemab administration resulted in a reduction in brain amyloid beta plaques (adjusted mean change from baseline in amyloid beta PET centiroids) in Study 301. [Figure 24] Health-related quality of life scale - EQ-5D-5L (subject's health on the day) is shown. [Figure 25] Health-Related Quality of Life Scale-QOL-AD (subject total score) is shown. [Figure 26] Health-related Quality of Life Scale-QOL-AD (subject by proxy) is shown. [Figure 27] Health-Related Quality of Life Scale-Zarit Caregiver Burden Scale-Study partner burden (total score) shown. [Figure 28] Time to deterioration of global CDR score is shown. [Figure 29] CDR-SB: shows a gradient analysis using observed data and extrapolation up to 2 years. [Figure 30] 1 shows the changes in plasma GFAP levels upon treatment with lecanemab. [Figure 31] Averaged scans from patients in the tau PET substudy are shown. [Figure 32] 1 shows tau PET SUVr in the Braak stage region in subjects with low total cortical tau aggregation. [Figure 33A] Shown is the ordering by decreasing median baseline tau PET SUVr. [Figure 33B] Shown is the ordering by decreasing median baseline tau PET SUVr. [Figure 33C]Shown is the ordering by decreasing median baseline tau PET SUVr. [Figure 34] 1 shows regional tau PET SUVr from subjects in the low tau PET subgroup who are amyloid positive or negative based on the 30CL cutoff. [Figure 35] 1 shows regional tau PET SUVr from subjects in the low tau PET subgroup who are ApoE4 carriers or non-carriers. [Figure 36] Figure 1 shows that lecanemab slowed tau pathology in the medial temporal lobe, metatemporal lobe, and temporal lobe compared to placebo. [Figure 37] 1 summarizes the adjusted mean differences in tau pathology, as measured by tau-PET SUVr across brain regions, for patients receiving lecanemab compared to patients receiving placebo. [Figure 38] The efficacy of lecanemab on cognitive and functional outcomes in subjects from the entire early AD patient population studied in CLARITY, a representative tau PET substudy, and in subjects in the low tau and moderate-high tau subgroups. [Figure 39A] Figure 1 shows that lecanemab affects different brain regions in the low tau PET group compared to the moderate + high tau PET group. [Figure 39B] Figure 1 shows that lecanemab affects different brain regions in the low tau PET group compared to the moderate + high tau PET group. [Figure 40A] 1 shows the effect of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in subjects from the Clarity AD study. [Figure 40B] 1 shows the effect of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in subjects from the Clarity AD study. [Figure 41A] 1 shows the effect of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in subjects from the tau PET substudy. [Figure 41B]1 shows the effect of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in subjects from the tau PET substudy. [Figure 42A] 1 shows the effect of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in subjects with low tau PET levels. [Figure 42B] 1 shows the effect of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in subjects with low tau PET levels. [Figure 43] 1 shows the effect of lecanemab on CDR-SB in subjects with low tau PET levels at 18 months, showing the percentage of subjects with no CDR-SB decline and the percentage of subjects with CDR-SB improvement. [Figure 44] 1 shows amyloid PET levels and amyloid PET clearance in subjects from the tau PET substudy. [Figure 45A] 1 shows body fluid biomarkers in patients from the tau PET substudy. [Figure 45B] 1 shows body fluid biomarkers in patients from the tau PET substudy. [Figure 45C] 1 shows body fluid biomarkers in patients from the tau PET substudy. [Figure 45D] 1 shows body fluid biomarkers in patients from the tau PET substudy. [Figure 46] 1 shows the results of the CDR-SB measure in subjects from the early-start and late-start groups. [Figure 47] Figure 1 shows study results from the OLE in the context of an observational cohort. [Figure 48] 1 shows the results of the ADAS-Cog14 measure in subjects from the early-start and late-start groups. [Figure 49] 1 shows the results of the ADCS MCI-ADL measure in subjects from the early-start and late-start groups. [Figure 50] 1 shows the results of CDR-SB measurements in subjects from the low tau-PET subgroup up to 24 months. [Figure 51] 1 shows the results of ADAS-Cog14 measurements in subjects from the low tau-PET subgroup up to 24 months. [Figure 52] 1 shows the results of ADCS MCI-ADL measures in subjects from the low tau-PET subgroup up to 24 months. [Figure 53] 1 shows the effect of lecanemab on CDR-SB in subjects with low tau PET levels at 18-24 months, showing the percentage of subjects with no CDR-SB decline and the percentage of subjects with CDR-SB improvement. [Figure 54] Figure 1 shows the percentage of patients with lecanemab who showed either "no decline" or "improvement" in CDR-SB, ADAS-Cog14 and ADCS MCI-ADL analyses up to 24 months. [Figure 55] 1 shows that low tau PET levels are associated with lower levels of amyloid PET. [Figure 56A] Clinical outcomes in subjects with baseline amyloid PET <60 CL are shown. [Figure 56B] Clinical outcomes in subjects with baseline amyloid PET <60 CL are shown. [Figure 57A] 1 shows the results of biomarker analysis in patients receiving lecanemab for 24 months. [Figure 57B] 1 shows the results of biomarker analysis in patients receiving lecanemab for 24 months. DETAILED DESCRIPTION OF THE INVENTION

[0065] [Detailed explanation] [000120] The "amyloid hypothesis" proposes that amyloid beta (Aβ) peptides play a central role in the pathogenesis of AD. Specifically, it is hypothesized that neurodegeneration in AD may be caused by the deposition of Aβ plaques in brain tissue due to an imbalance between Aβ production and Aβ clearance, leading to the formation of neurofibrillary tangles containing tau protein. Aβ peptides generally exist in a dynamic continuum of conformational states, such that species tend to progress from monomeric Aβ to soluble Aβ assemblies ranging from low-molecular-weight oligomers to higher-molecular-weight protofibrils, and ultimately to insoluble fibrils (plaques). Targeting these soluble and insoluble Aβ tangles and plaques provides therapeutic benefits.

[0066] [000121] Several immunotherapies have been developed with the intention of reducing the amount of insoluble Aβ fibrils deposited in the brain. However, a simple correlation between the amount and progressive accumulation of insoluble amyloid plaques and the clinical course of AD has not been determined. While treatment strategies continue to focus on removing insoluble amyloid plaques, additional approaches to therapy may involve reducing toxic Aβ aggregates, such as protofibrils, which 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-β 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.)

[0067] [000122] In various embodiments, anti-Aβ protofibril antibodies, such as BAN2401 and other anti-Aβ protofibril antibodies, may be used to treat AD by slowing the progression of AD in subjects, such as those in early stages of the disease, where amyloid has been deposited in the brain but the downstream neurodegenerative cascade thought to be triggered by amyloid deposition is still relatively early in its process (i.e., where limited brain tissue loss has occurred and associated clinical deficits are minimal).

[0068] [A. Definition] [000123] The following are definitions of terms used in this application.

[0069] [000124] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0070] [000125] The phrase "and / or," as used herein, means "either or both" of conjunctively linked elements, i.e., elements that are presented conjunctively in some cases and disjunctively in other cases. Thus, as a non-limiting example, "A and / or B," when used with open-ended terms such as "comprising," can refer in some embodiments to A only (optionally including elements other than B); in other embodiments to B only (optionally including elements other than A); in still other embodiments to both A and B (optionally including other elements), etc.

[0071] [000126] As used herein, "at least one" means one or more of the elements in a list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combinations of elements in the list of elements. This definition also allows for elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements, may optionally be present. Thus, as a non-limiting example, "at least one of A and B" (or in other words "at least one of A or B" or in other words "at least one of A and / or B") can refer in one embodiment to at least one that optionally includes two or more As and no Bs (and optionally includes elements other than B); in another embodiment, it can refer to at least one that optionally includes two or more Bs and no As (and optionally includes elements other than A); in yet another embodiment, it can refer to at least one that optionally includes two or more As, and at least one that optionally includes two or more Bs (and optionally includes other elements); and so on.

[0072] [000127] As used herein, "about," when used in connection with a dose, amount, or ratio, includes the specified dose, amount, or ratio value, or a range of doses, amounts, or ratios that would be recognized by one of ordinary skill in the art as providing a therapeutic effect equivalent to that resulting from the specified dose, amount, or ratio. The term "about" may refer to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "about" means within 5% of a given value or range.

[0073] [000128] When a number is listed, either alone or as part of a numerical range, it is understood that the numerical value can vary above and below the stated value, up to a variance of + / - 10% of the stated value.

[0074] [000129] When a range of values ​​is recited herein, it is intended to encompass each value and subrange within that range. For example, "2.5 mg / kg to 10 mg / kg" is intended to encompass, for example, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 2.5 mg / kg to 3 mg / kg, 2.5 mg / kg to 4.5 mg / kg, 3 mg / kg to 4.5 mg / kg, 4.5 mg / kg to 8 mg / kg, 2.5 mg / kg to 9 mg / kg, etc.

[0075] [000130] As used herein, "adjusted mean change from baseline" refers to the use of statistical analysis to calculate the change in biomarker value over time. In some embodiments, a linear mixed-effects model (MMRM) is used to account for at least one additional covariate to determine the adjusted mean change from baseline.

[0076] [000131] Amyloid β1-42 (Aβ42) refers to the amyloid beta monomer of amino acids 1-42 of the full-length protein (Table 5, SEQ ID NO: 13). Amyloid β1-40 (Aβ1-40) refers to the amyloid beta monomer of amino acids 1-42 of the full-length protein (Table 5, SEQ ID NO: 14).

[0077] [000132] P-tau181 is human tau protein phosphorylated at threonine at position 181. P-tau217 is human tau protein phosphorylated at threonine at position 217. P-tau231 is human tau protein phosphorylated at threonine at position 231.

[0078] [000133] Total tau or t-tau, as used herein, is a measure of total tau in a sample, e.g., a CSF sample, a plasma sample, a serum sample.

[0079] [000134] Patients with "pre-symptomatic AD" or "pre-AD," as described herein, are cognitively normal individuals with moderate or elevated levels of amyloid in the brain and can be identified by an asymptomatic stage with or without memory complaints and emerging episodic memory and executive function deficits. Cognitively normal can include individuals with a CDR of 0 or cognitive test scores within the normal range (e.g., MMSE, International Shopping List Task, Logical Memory). Pre-symptomatic AD occurs before significant, irreversible neurodegeneration and cognitive impairment and is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence of clinical symptoms. Presymptomatic AD biomarkers that may indicate future onset of Alzheimer's disease include moderate or elevated levels of amyloid in the brain by amyloid PET (e.g., about 20-40 centimeter scale, e.g., about 20-32 centimeter scale), fluorodeoxyglucose (FDG) PET, or tau positron emission tomography (PET), cerebrospinal fluid levels of Aβ1-42 and / or Aβ1-42 / 1-40 ratio, cerebrospinal fluid levels of total tau, cerebrospinal fluid levels of microtubule binding domain (MTBR)-tau, cerebrospinal fluid levels of neurogranin, cerebrospinal fluid levels of neurofilament light chain (NfL), and serum or blood These may include, but are not limited to, one or more of the following blood biomarkers measured in plasma: levels of Aβ1-42, the ratio of two forms of amyloid-β peptide (Aβ1-42 / 1-40 ratio, e.g., a ratio of about 0.092 to 0.094 or less than about 0.092), plasma levels of plasma total tau (T-tau), phosphorylated tau (P-tau) isoforms (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and tau phosphorylated at 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NF1).For example, subjects treated with elenbecestat (E2609), a beta-site amyloid precursor protein-cleaving enzyme (BACE) inhibitor, who had a baseline positron emission tomography (PET) standardized uptake value ratio (SUVr) of 1.4 to 1.9 for amyloid, were found to have the greatest slowing of cognitive decline during treatment. See Lynch, S.Y. et al., "Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease," Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 have not shown sufficient cognitive decline to be detectable, whereas subjects with SUVr levels above 1.6 have been found to have amyloid levels that have reached saturation levels and appear to correlate with a plateau effect in which treatment does not result in change in cognitive measures. See Dhadda, S. et al., "Baseline florbetapir amyloid PET standard update value ratio (SUVr) can predict clinical progression in prodromal Alzheimer's disease (pAD)," Poster P4-291, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA.

[0080] [000135] "Early AD" or "early Alzheimer's disease," as used herein, is a continuum of AD severity ranging from mild cognitive impairment due to AD (intermediate likelihood) to mild Alzheimer's disease dementia. Subjects with early AD include subjects with mild Alzheimer's disease dementia, as defined herein, and subjects with mild cognitive impairment (MCI) due to AD, as defined herein (intermediate likelihood). In some embodiments, subjects with early AD have an MMSE score of 22-30 and a Clinical Dementia Rating Scale (CDR) global range of 0.5-1.0. Other methods for detecting early AD disease may utilize the tests and assays specified below, including the National Institute on Aging-Alzheimer's Association (NIA-AA) Core Clinical Criteria for probable Alzheimer's disease dementia in McKhann, GM et al., "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer Dement. 2011;7:263-9. Other methods include the CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, Revised iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, subjects with early stage AD have evidence of elevated amyloid or a positive amyloid burden in the brain, hi some embodiments, the elevated amyloid or positive amyloid burden in the brain is demonstrated and / or confirmed by PET assessment.In some embodiments, elevated amyloid or positive amyloid burden in the brain is indicated and / or confirmed by CSF assessment of markers such as Aβ1-42 (e.g., soluble CSF biomarker analysis). In some embodiments, elevated amyloid or positive amyloid burden in the brain is indicated and / or confirmed by measuring levels of p-tau181. In some embodiments, elevated amyloid or positive amyloid burden in the brain is indicated and / or confirmed by MRI. In some embodiments, elevated amyloid or positive amyloid burden in the brain is indicated by retinal amyloid deposits. In some embodiments, more than one assessment method is used.

[0081] [000136] "Amyloid" refers to unbranched, usually extracellular, fibrils found in vivo; in addition, the fibrils bind the dye Congo red and subsequently exhibit green birefringence when viewed between crossed polarizers. Amyloid-forming proteins have been identified and associated with serious diseases, including amyloid-β peptide (Aβ) associated with Alzheimer's disease (AD), islet amyloid polypeptide (IAPP) associated with type 2 diabetes, and prion protein (PrP) associated with spongiform encephalopathies. As used herein, "amyloid," "cerebral amyloid," and "amyloid-β peptide (Aβ)" are used interchangeably.

[0082] [000137] In some embodiments, the subject has "elevated amyloid" or "moderate amyloid." As one of skill in the art would recognize, amyloid levels from amyloid PET can be reported using the centiloid method in "centiloid" units (CL). (Klunk WE et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer's Dement. 2015;11:1-15 e1-4) The centiloid method measures tracer on a scale of 0 CL to 100 CL, where 0 is considered the anchor point and represents the mean in young healthy controls, and 100 CL represents the average amyloid burden present in subjects with mild to moderately severe dementia due to AD. (Id.) As known to one of skill in the art, the centiloid threshold may vary and may be refined, for example, based on new or additional scientific information. (See, e.g., http: / / www.gaain.org / centiloid-project). Elevated amyloid levels can be set relative to a baseline threshold in healthy controls determined according to methods known to those skilled in the art (POSA). For example, a centimeter value of 32.5 can be used as a threshold for "elevated amyloid," with "moderate amyloid" levels referring to Aβ amyloid PET in the range of 20 to 32.5 CL (e.g., 30 CL). In another example, a centimeter value of 40 can be used as a threshold for "elevated amyloid," with "moderate amyloid" levels referring to Aβ amyloid PET in the range of 20 to 40 CL.

[0083] [000138] As used herein, a subject with "mild Alzheimer's disease dementia" or "mild AD dementia" is one who meets the National Institute on Aging-Alzheimer's Association (NIA-AA) Core Clinical Criteria for probable Alzheimer's disease dementia in McKhann, GM et al., "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer Dement. 2011;7:263-9. Also included herein are subjects with a CDR score of 0.5-1.0 and a Memory Box score of 0.5 or greater at screening and baseline, as well as subjects who demonstrate a change in score on the Wechsler Memory Scale-Revised Logical Memory Subscale II (WMS-R LM II).

[0084] [000139] As used herein, a subject with "MCI due to AD (intermediate probability)" is one identified according to the NIA-AA Core Clinical Criteria for Mild Cognitive Impairment due to Alzheimer's Disease (intermediate probability) (see McKhann, supra). For example, a subject may be symptomatic but not demented, and may have evidence of cerebral amyloid pathology, making the subject less heterogeneous in cognitive and functional decline and more similar to mild Alzheimer's disease dementia subjects, as measured by the ADCOMS composite clinical score defined herein. Also included are subjects with a CDR score of 0.5 and a memory box score of 0.5 or greater at screening and baseline. Additionally, subjects who report a history of subjective memory decline with gradual onset and slow progression over the last year prior to screening, as corroborated by an informant, are also included herein. Memory decline and / or episodic memory impairment may be assessed in subjects by changes in scores on the Wechsler Memory Scale-Revised Logical Memory Subscale II (WMS-R LM II).

[0085] [000140] As used herein, a "control subject," "untreated AD subject," or "untreated control subject" is a subject who is not being treated or who has been treated for Alzheimer's disease. In some embodiments, the control subject has Alzheimer's disease. In some embodiments, the control subject has early Alzheimer's disease or pre-Alzheimer's disease. In some embodiments, the control subject has Alzheimer's disease and is not being treated with an anti-Aβ protofibril antibody.

[0086] [000141] The terms "patient" and "subject" are used interchangeably.

[0087] [000142] As used herein, "MMSE" refers to the Mini-Mental State Examination, a cognitive measure commonly used for screening purposes but often measured longitudinally in AD clinical trials, with a 30-point scale ranging from 0 (most impaired) to 30 (no impairment), with higher scores indicating less impairment and lower scores indicating more impairment. In some embodiments, seven items measuring orientation to time and place, registration, recall, attention, language, and drawing may be assessed as part of the MMSE score. (Folstein, M.F. et al., "Mini-mental state. A practical method for grading the cognitive state of patients for the clinician." J. Psychiatr. Res. 1975;12:189-98.)

[0088] [000143] As used herein, "ADAS-Cog" refers to the Alzheimer's Disease Assessment Scale-Cognitive Version. The ADAS-Cog is a cognitive scale widely used in Alzheimer's disease testing, with structured scales assessing memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational behavior (placing a letter in an envelope), and constructional behavior (copying a geometric design). (Rosen, W. Get al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984;141:1356-64.) Assessments of spoken language, language comprehension, paraphrase difficulty, ability to remember test instructions, mazes, and digit elimination may also be obtained. In some embodiments, the ADAS-Cog is a cognitive scale that assesses the Alzheimer's Disease Assessment Scale-Cognitive Version subscales. 14The ADAS-Cog14 is a cognitive assessment tool used to assess cognitive impairment and cognitive function. In some embodiments, a modified version may be used herein, scored from 0 to 90, with a score of 0 indicating no impairment and a score of 90 indicating maximal impairment. In some embodiments, the ADA-Cog14 tasks include memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational tasks (placing a letter in an envelope), constructional tasks (copying a geometric design), spoken language, language comprehension, paraphrase difficulty, ability to remember test instructions, mazes, and digit elimination (Rosen et al., 1984).

[0089] [000144] As used herein, "CDR-SB" refers to the Clinical Dementia Scale-Sum of Boxes. The CDR is a clinical scale that describes five degrees of impairment in ability in each of six categories of functioning, including memory, orientation, judgment and problem-solving, community activities, home life and hobbies, and self-care. (Berg, L. et al., "Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment." Ann. Neurol. 1988;23:477-84.) The sum of the boxes score provides a measure of change, where each category has a maximum possible score of 3 points, and the total score is the sum of the category scores, giving a total possible score of 0 to 18, with higher scores indicating more impairment.

[0090] [000145] As used herein, the terms "CDR Global," "Global CDR," and "Dementia CDR Global Rating" score are used interchangeably. As used herein, the CDR Global score is a rating of the degree of impairment obtained in each of the six categories of function from the six categories of the CDR scale, combined into one global rating of the Dementia CDR score (ranging from 0 to 3), where 0 indicates no cognitive impairment, 0.5 indicates mild cognitive impairment, and 1 to 3 indicate mild, moderate, and severe dementia, respectively. The Global CDR score can be used as a clinical measure of dementia severity. In some embodiments, the Global CDR score may be used to determine whether a patient has progressed or maintained their stage of AD, e.g., higher scores at subsequent assessments indicate progression of AD, while a stable score indicates no progression of AD.

[0091] [000146] As used herein, "ADCOMS" refers to the Alzheimer's Disease Composite Score, a composite clinical score based on analysis of four ADAS-Cog items (delayed word recall, orientation, word recognition, and translation difficulties), two Mini-Mental State Examination (MMSE) items (orientation to time and drawing), and all six CDR-SB items (self-care, community activities, home life and hobbies, memory, orientation, and judgment and problem solving), as discussed in the Examples and Wang, J. et al., "ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials." J. Neurol. Neurosurg. Psychiatry. 2016;87:993-999. ADCOMS was developed to be particularly sensitive to disease progression during the early stages of AD (i.e., pre-symptomatic AD or early AD).

[0092] [000147] In some embodiments, ADCOMS may be calculated using the following formula:

number

[0093] [000148] As used herein, "ADCS MCI-ADL" refers to the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical scale that assesses a patient's level of ability in six basic activities of daily living. Additional examples are discussed in Kreutzer J.S., DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, NY.

[0094] [000149] As used herein, "Revised iADRS" or "iADRS" refers to a composite tool that combines scores from the ADAS Cog14 (all items) and ADCS MCI-ADL (all items). The revised iADRS score can be used to assess disease progression: Revised iADRS score = [-1(ADAS-cog14)+90]+ADCS MCI-ADL.

[0095] [000150] As used herein, "ApoE4-positive" subject and "ApoE4 carrier" refer to a subject harboring the ε4 variant of the apolipoprotein E (APOE) gene. The ε4 variant is one of several major alleles of the apolipoprotein E gene. The gene is generally involved in fat metabolism. Apolipoprotein ε4 carriers have been found to have significantly higher amyloid burden compared to non-carriers. (Drzezga, A. et al., "Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer's disease." Neurology. 2009;72:1487-94.) In some embodiments, the subject treated herein is a heterozygous carrier of the apolipoprotein E ε4 gene allele. In some embodiments, the subject is a homozygous carrier of the apolipoprotein E ε4 gene allele. The terms "ApoE4 negative" and "ApoE4 non-carrier" are used interchangeably.

[0096] [000151] As used herein, whether an early stage AD subject is "amyloid positive" or "amyloid negative" can be determined based on the subject having a positive amyloid load. In some embodiments, a subject is determined to be amyloid positive or amyloid negative as shown by longitudinal positron emission tomography (PET) assessment of brain imaging agent (e.g., amyloid imaging agent or tau imaging agent) uptake. In some embodiments, a subject is determined to be amyloid positive or amyloid negative by assessment of tau PET imaging assessment. In some embodiments, a subject is "amyloid negative" if the PET SUVr negativity is below a threshold determined for the amyloid PET tracer. In some embodiments, the amyloid PET tracer can be florbetaben (e.g., 18F-florbetaben (Neuraceq®)), florbetapir (e.g., 18F-florbetapir (Amyvid®)), and / or flutametamol (e.g., 18F-flutametamol (Vizamyl®)). In some embodiments, the PET SUVr threshold for the amyloid PET tracer is about 1.17, and a measurement below this threshold can indicate that the subject is "amyloid negative." In some embodiments, the florbetapir amyloid PET SUVr threshold is about 1.17. In some embodiments, the florbetaben amyloid PET SUVr threshold is about 1.17. In some embodiments, the flutametamol amyloid PET The SUVr threshold is about 1.17. In some embodiments, a subject is determined to be amyloid positive or amyloid negative by assessment of the level of a biomarker (e.g., Aβ42 / 40 ratio) in a sample from the subject, either alone or in combination with another method, such as PET measurement of brain amyloid. In some embodiments, a subject is "amyloid negative" if the Aβ42 / 40 ratio in the sample is between 0.092 and 0.094 or about greater than 0.092 to 0.094, e.g., about 0.092. In some embodiments, a subject is "amyloid negative" if the Aβ42 / 40 ratio in the sample is greater than 0.092.In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by CSF assessment of the presence of amyloid pathology using assessment of markers such as p-tau 181, alone or in combination with another method, such as PET measurement of brain amyloid. In some embodiments, amyloid-positive and amyloid-negative may be determined by using qualitative visual interpretation of PET scans to classify subjects as having either "normal" or "abnormal" uptake based on PET image patterns. Interrogators are trained and certified to recognize brain PET images with abnormal or normal uptake patterns, or amyloid detection is achieved via semi-quantitative or quantitative approaches. In some embodiments, a threshold is set to quantitatively determine whether Aβ brain burden from biomarkers (e.g., serum or CSF) and / or PET scans indicates the subject is amyloid-positive or amyloid-negative. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by imaging methods. Imaging methods can be used to determine, calculate, or predict whether a subject is amyloid-positive or amyloid-negative even when the imaging method is not used to directly visualize amyloid. In some embodiments, the method uses MRI and / or combines MRI and other imaging modalities, such as PET. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by retinal amyloid deposits. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by behavioral / cognitive phenotype.

[0097] [000152] As will be appreciated by those skilled in the art, digital, computerized, and / or traditional (e.g., pen and paper) cognitive tests can be used to detect early cognitive changes that may indicate risk of developing mild cognitive impairment and / or dementia, and thus may be used to identify subjects in need of treatment as disclosed herein. Such tests can, for example, screen for cognitive impairment and potentially identify individuals with MCI. The tests can use artificial intelligence to analyze cognitive test results and determine whether a case of mild cognitive impairment will escalate to Alzheimer's disease within one year. Diagnosing the condition early, before symptoms begin to appear, can be used to assist physicians in earlier identification of subjects in need of treatment as disclosed herein, potentially delaying the onset or reducing the severity of neurodegenerative diseases.

[0098] [000153] As used herein, the term "treating" refers to any administration or application of a therapeutic agent for a disease or disorder in a subject, including inhibiting the disease, slowing the progression of the disease, delaying its progression, halting its occurrence, reversing the progression of the disease (e.g., reversing the accumulation of Aβ fibrils), preventing the onset or occurrence of the disease, alleviating or ameliorating one or more symptoms or underlying conditions of the disease, curing the disease, improving one or more clinical metrics, or preventing the recurrence of one or more symptoms of the disease. In some embodiments, treating AD in a subject involves administering, e.g., intravenously injecting, an anti-amyloid beta (Aβ) protofibril antibody. In some embodiments, treating AD in a subject involves administering, e.g., intravenously injecting, a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody.

[0099] [000154] As used herein, the term "infusion" refers to the effective administration of one or more agents, for example, over an infusion time of approximately 60 minutes. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibodies described herein are systemically administered to a human subject via infusion. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibodies are alternatively administered to a human subject, for example, by subcutaneous injection. In some embodiments, the subcutaneous injections are weekly injections. In some embodiments, the subcutaneous injections are biweekly injections. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibodies are administered to a human subject by intravenous infusion.

[0100] [000155] In some embodiments, the subject is administered a maintenance dose of treatment. As used herein, the term "maintenance dose" refers to a dose administered to a subject to maintain a desired therapeutic effect. In some embodiments, the maintenance dose is administered weekly, every two weeks, monthly, every two months, or every three months (quarterly yearly), or every 24 weeks (every six months or six months). In some embodiments, the maintenance dose comprises an anti-Aβ protofibril antibody. In some embodiments, the maintenance dose is administered as an intravenous infusion. In some embodiments, the intravenous infusion is a 10 mg / kg dose of BAN2401 administered every two weeks. In some embodiments, the maintenance dose is administered subcutaneously, orally, or intranasally. In some embodiments, the maintenance dose is administered subcutaneously.

[0101] [000156] In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarterly subcutaneous injection. In some embodiments, the maintenance dose is administered weekly or less frequently, for example, every 2 weeks (biweekly), every 4 weeks, every month, every 6 weeks, every 8 weeks (bimonthly), every 3 months (quarterly), or every 6 months (biannually). In some embodiments, the maintenance dose is administered as a biweekly subcutaneous injection of 720 mg. In some embodiments, the maintenance dose is administered as a biweekly subcutaneous injection of 720 mg comprising two simultaneous, e.g., sequential, injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation.

[0102] [000157] In some embodiments, the maintenance dose is administered one or more times. In some embodiments, the maintenance dose is administered at a lower dose and / or less frequently than during earlier courses of treatment.

[0103] [000158] In some embodiments, after switching to the maintenance dose, the subject's biomarker levels may indicate an increase in the level of amyloid in the brain. In some embodiments, after switching to the maintenance dose, the subject's biomarker levels may begin to worsen, for example, an increase in the plasma Aβ42 / 40 ratio indicates an increase in the level of amyloid in the brain. In some embodiments, the subject on the maintenance dose may have a decrease in the Aβ42 / 40 ratio. In some embodiments, the subject receives a maintenance dose selected such that the subject may have a decrease in the Aβ42 / 40 ratio, but the Aβ42 / 40 ratio may remain above the threshold for amyloid positivity, for example, for at least 1 year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0104] [000159] In some embodiments, after switching to the maintenance dose, the subject's biomarker levels, e.g., tau PET levels, may begin to increase or the rate of increase may increase. In some embodiments, such subjects may be returned to the treatment regimen. In some embodiments, the subject may remain on the maintenance dose, for example, if the increase remains below the tau PET levels or rate of increase seen in control subjects with AD who have not received the anti-Aβ protofibril antibody.

[0105] [000160] As used herein, the term "preventing" refers to obtaining a benefit or desired result, including, but not limited to, a prophylactic benefit. For a prophylactic benefit, a composition may be administered to a subject at risk of developing Alzheimer's disease, to a subject who has one or more preclinical symptoms of Alzheimer's disease but does not have clinical symptoms, or to a subject who reports one or more physiological symptoms of Alzheimer's disease even without a clinical diagnosis of Alzheimer's disease. As used herein, "prevention" can further include a therapeutic effect, which refers to the eradication or amelioration of the underlying condition being treated or one or more physiological symptoms associated therewith.

[0106] [000161] As used herein, the term "ARIA" refers to an amyloid-related imaging abnormality as assessed using MRI. In some embodiments, ARIA includes amyloid-related imaging abnormality edema / exudation (ARIA-E). In some embodiments, ARIA includes amyloid-related imaging abnormality hemorrhage (ARIA-H). In some embodiments, subjects with ARIA experience headache, confusion, and / or seizures, which may be used to identify subjects with ARIA or indicate further evaluation for ARIA. In some embodiments, ARIA is assessed at specified intervals during treatment. In some embodiments, ARIA is assessed when a subject is experiencing symptoms of ARIA. In some embodiments, the maximum serum concentration (Cmax) of an anti-Aβ protofibril antibody may be used as a predictor of risk of ARIA-E. In some embodiments, use of a subcutaneous formulation may result in a reduced risk of ARIA-E (e.g., due to a lower Cmax) compared to IV administration.

[0107] [000162] As used herein, the term "worsening clinical status" refers to a worsening of one or more clinical symptoms of AD. Methods for measuring clinical status may utilize the tests and assays specified herein. In some embodiments, the worsening clinical status is determined by a worsening of ADCOMS. In some embodiments, the worsening clinical status is determined by a worsening of MMSE. In some embodiments, the worsening clinical status is determined by a worsening of ADAS-Cog. In some embodiments, the worsening clinical status is determined by a worsening of FAQ. In some embodiments, the worsening clinical status is determined by a worsening of CDR-SB. In some embodiments, the worsening clinical status is determined by a worsening of Wechsler Memory Scale-IV Logical Memory (Subscale) I and / or (Subscale) II. In some embodiments, the worsening clinical status is determined by a worsening CDR score. In some embodiments, the worsening clinical status refers to a worsening of one or more biomarkers of AD or brain measurements (e.g., by PET or MRI), such as brain atrophy and / or amyloid accumulation.

[0108] [000163] As used herein, the term "blood sample" or "blood" refers to a sample of blood, including serum and / or plasma, from a human subject. In some embodiments, blood will be collected from the subject to evaluate potential biomarkers of AD, which may include amyloid fragments and isoforms, tau, and other protein biomarkers (e.g., neurofilament light chain or NfL), for association with AD diagnosis, amyloid or tau burden, or disease modification. In some embodiments, subjects are required to fast, if possible, prior to collection at weeks 96 and 216. In other embodiments and / or at other time points, subjects are not required to fast. Pre-AD biomarker levels that may indicate the onset of Alzheimer's disease include, but are not limited to, brain amyloid levels, cerebrospinal fluid levels of Aβ1-42, cerebrospinal fluid levels of total tau, cerebrospinal fluid levels of neurogranin, and cerebrospinal fluid levels of neurofilament light chain (NfL).

[0109] [B. Anti-Aβ protofibril antibody and tau PET levels] [000164] In various embodiments, disclosed herein are methods for selecting patients, treating, monitoring treatment, and making decisions regarding maintenance dosing in patients receiving an anti-amyloid beta protofibril antibody, such as BAN2401 (also referred to as an "anti-amyloid beta (Aβ) protofibril antibody" or "anti-Aβ protofibril antibody"). Without being bound by theory, it has surprisingly been found that effective treatment with an anti-amyloid protofibril antibody, such as BAN2401 (i.e., lecanemab), can result in a reduced rate of increase or an overall reduction in tau levels as measured by PET, for example, in the temporal region of the brain. In some embodiments, the method includes measuring tau PET levels from the subject. In some embodiments, the method includes measuring tau PET levels from the subject having or suspected of having AD in another sample before and / or during treatment (although it should be understood that additional doses may be administered between sampling time points). In some embodiments, the measurement includes measuring in the temporal region of the brain. In some embodiments, an increase in tau PET levels (e.g., in the temporal region) compared to a control subject (e.g., a subject without AD) indicates a subject suitable for treatment with an anti-Aβ protofibril antibody, such as BAN2401. In some embodiments, a decrease in tau PET levels and / or rate of increase after receiving one or more doses of an anti-Aβ protofibril antibody, such as BAN2401, indicates therapeutic efficacy. In some embodiments, if a decrease in tau PET levels or a decrease in the rate of increase in tau PET is detected, a subsequent therapeutic dose is given after a second sampling. In some embodiments, treatment may be titrated based on changes in tau PET levels.

[0110] [000165] In some embodiments, additional patient demographics, such as age and whether the subject is a carrier of the apolipoprotein E ε4 gene allele, may be used to select patients for treatment in combination with tau PET measurements, e.g., to predict amyloid positivity (e.g., West et al., Mol Neurodegen (2021) 16-30, Jansen et al., JAMA (2015) 1924-1938, Ossenkoppele et al., JAMA (2015) 1939-1950). In some embodiments, one or more additional biomarkers, e.g., one or more blood biomarkers (such as the ratio of Aβ42 to Aβ40 and / or p-tau181), may be used in combination with tau PET measurements. In some embodiments, age-normalized and / or apolipoprotein E ε4 gene allele-normalized measurements of tau PET and / or at least one additional biomarker from a subject are used to evaluate whether a sample (e.g., a plasma sample) from the subject indicates that the subject is suitable for treatment with a protofibrillar antibody such as BAN2401 (e.g., if the subject is amyloid-positive) and / or to monitor treatment. For example, in some embodiments, a patient who is a carrier of the apolipoprotein E ε4 gene allele may be considered amyloid-positive at a lower level of the biomarker than would be required to indicate amyloid positivity in a non-carrier subject. Similarly, in another example, an elderly subject may be considered amyloid-positive at a lower level of the biomarker than would be required to indicate positivity in a younger subject. In some embodiments, biomarker levels are used in a receiver operating characteristic (ROC) analysis to predict amyloid positivity. In some embodiments, additional patient demographics, such as age and whether the subject is a carrier of the apolipoprotein E ε4 gene allele, may be used along with biomarker levels in a ROC analysis to predict amyloid positivity. In some embodiments, the prediction of amyloid positivity in a patient is used to determine dosage or frequency of treatment.

[0111] [000166] In some embodiments, the methods disclosed herein include measuring tau PET levels from a subject having or suspected of having AD before treatment with an anti-Aβ protofibril antibody to identify patients suitable for treatment and / or measuring tau PET levels again in another sample during treatment to monitor treatment effectiveness (although it should be understood that additional doses may be administered between sampling time points). In some embodiments, if tau PET levels or the rate of increase decrease compared to a control subject, e.g., an AD subject not receiving an anti-Aβ protofibril antibody, treatment may be stopped and / or reduced (e.g., reduced frequency and / or dosage). In some embodiments, after treatment is stopped or reduced, additional measurements of tau PET levels may be made from the subject. In some embodiments, if tau PET levels increase compared to control subjects, treatment is resumed, the dosage increased, and / or the frequency of administration increased. In some embodiments, the dosage or frequency of treatment is increased, e.g., to return to the dosage and / or frequency used in the previous treatment before dose reduction and / or extended dose frequency was initiated. In some embodiments, the method includes measuring tau PET levels from the subject during treatment and again after treatment has stopped or the dosage or frequency of treatment has been reduced (it should be understood that additional doses may be administered between sampling time points). In some embodiments, if an increase in tau PET levels or rate of increase is detected, treatment is resumed or the dosage or frequency of treatment is increased compared to the dosage or frequency during the period when the level increased. In some embodiments, multiple measurements may be made during treatment before a decision to stop and / or decrease treatment is made based on a decrease in the rate of increase of tau PET levels compared to a control (e.g., based on a trend showing a decrease in the tau accumulation rate with each subsequent measurement). In some embodiments, multiple measurements may be made after treatment has been stopped or reduced, and a decision to resume and / or increase treatment may be made based on the tau PET levels (e.g., based on a trend showing an increase in the tau accumulation rate compared to a control).In some embodiments, after resuming treatment or increasing a treatment regimen, one or more additional measurements may consist of tau PET levels from the subject. In some embodiments, the tau PET level measurement is done in combination with measuring one or more additional biomarkers (e.g., using a decrease in amyloid PET SUVr as an indicator of amyloid plaque reduction during and / or after treatment). In some embodiments, treatment may be stopped if tau PET levels remain unchanged compared to controls, e.g., compared to untreated AD subjects. In some embodiments, treatment may be stopped due to poor therapeutic efficacy.

[0112] [000167] In some embodiments, any of the methods comprising measuring tau PET levels may further comprise measuring one or more additional biomarkers, or may comprise measuring one or more additional biomarkers instead of measuring tau PET levels. In some embodiments, any of the methods comprising measuring tau PET levels may further comprise measuring one or more additional biomarkers. In some embodiments, the additional biomarkers comprise volumetric MRI (vMRI), e.g., measuring whole brain volume, cortical thickness, total hippocampal volume, and / or lateral ventricle volume. In some embodiments, the one or more additional biomarkers comprise PET levels, such as amyloid PET levels and / or fluorodeoxyglucose (FDG) PET levels. In some embodiments, the one or more additional biomarkers comprise cerebrospinal fluid and / or blood levels of one or more biomarkers including Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 205 (P-tau205), tau phosphorylated at 217 (P-tau217), and tau phosphorylated at 231 (P-tau231)), neurogranin, neurofilament light chain (NfL), and / or microtubule-binding region (MTBR)-tau containing residue 243 (MTBR-tau243). In some embodiments, the one or more biomarkers comprise serum or plasma levels of biomarkers including Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 205 (P-tau205), tau phosphorylated at 217 (P-tau217), and tau phosphorylated at 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). In some embodiments, the one or more additional biomarkers comprise the microtubule-binding region of tau containing residue 243 (MTBR-tau243).Recent studies have shown that MTBR-tau243 expression in both CSF and plasma can correlate with tau PET levels, cognitive measures, and AD disease progression (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).

[0113] [000168] In some embodiments, provided herein are methods of reducing and / or slowing clinical deterioration in a subject, e.g., a subject with Alzheimer's disease, pre-AD, or early Alzheimer's disease, comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody (e.g., BAN2401) to a patient with a tau PET level greater than a subject without AD. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered in a therapeutically effective amount to a patient with a tau PET level greater than a subject without AD. In some embodiments, a decrease in the rate of increase of tau PET levels indicates a slowing of cognitive decline in the patient (e.g., a patient with pre-AD or early AD) compared to a decrease in the rate in the absence of treatment. In some embodiments, a decrease in the rate of tau accumulation indicates a slowing of cognitive decline in the patient (e.g., a patient with pre-AD or early AD) compared to a decrease in the rate in the absence of treatment. In some embodiments, a subject may be transitioned to a maintenance dosing regimen after a decrease in the rate of increase of tau PET is detected, e.g., when measured 18 months after initiation of treatment. In some embodiments, a subject may be transitioned to a maintenance dosing regimen after a decrease in the rate of increase of tau PET is detected in combination with a decrease in one or more additional biomarkers of AD progression, e.g., when measured 18 months after initiation of treatment.

[0114] [000169] In some embodiments, provided herein are methods of improving cognitive outcomes in subjects, e.g., subjects with Alzheimer's disease, pre-AD, or early Alzheimer's disease, comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody (e.g., BAN2401) to patients with tau PET levels greater than subjects without AD. Cognitive and functional decline can be measured by techniques known in the art, including scoring methods such as CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, revised iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered in a therapeutically effective amount to patients with tau PET levels greater than subjects without AD. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered at a therapeutically effective dose comprising an intravenous infusion of 10 mg / kg of the subject's body weight. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered at a therapeutically effective dose comprising a subcutaneous administration of 720 mg. In some embodiments, the method results in lower cognitive decline as measured by ADCOMS compared to untreated subjects. In some embodiments, the method results in at least 24% lower (e.g., at least 29% lower) cognitive decline as measured by ADCOMS compared to untreated subjects. In some embodiments, the method results in lower cognitive decline as measured by CDR-SB compared to untreated subjects. In some embodiments, the method results in at least 26% lower (e.g., at least 27% lower) cognitive decline as measured by CDR-SB compared to untreated subjects. In some embodiments, the method results in lower cognitive decline as measured by ADAS-Cogl4 compared to untreated subjects.In some embodiments, the method results in at least a 26% lower (e.g., at least a 47% lower) cognitive decline as measured by ADAS-Cogl4 compared to untreated subjects. In some embodiments, the method results in lower cognitive decline as measured by ADCS MCI-ADL compared to untreated subjects. In some embodiments, the method results in at least a 37% lower cognitive decline as measured by ADCS MCI-ADL compared to untreated subjects. In some embodiments, the method results in a reduced risk of progression to a subsequent stage of AD as measured by a CDR global score, e.g., a higher score at a subsequent assessment indicating progression to a next stage of AD, e.g., a stable score indicating remaining at the same stage of AD. In some embodiments, the results are measured at least 6 months after administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the results are measured at least 12 months after administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the results are measured at least 13 months after administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the results are measured at least 18 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0115] [000170] In some embodiments, provided herein are methods of treatment using tau PET levels or rate of change of tau PET levels from a region of the brain (e.g., the temporal region). For example, in some embodiments, the treatment involves intravenous or subcutaneous administration of an anti-Aβ protofibril antibody, e.g., BAN2401. In some embodiments, the method of treatment involves using biomarker levels, e.g., tau PET levels or rate of change of tau PET levels, to determine switching to a maintenance intravenous or subcutaneous dose at a set time point (e.g., after 18 months). In some embodiments, the method of treatment involves using biomarker levels, e.g., tau PET levels or rate of change of tau PET levels, in combination with one or more biomarker criteria (e.g., the ratio of Aβ1-42 to Aβ1-40 and / or p-tau181 measurements in a body fluid sample, e.g., a blood sample). In some embodiments, the combination includes amyloid PET measurements. In some embodiments, the combination includes serum or plasma GFAP measurements. In some embodiments, the same marker or combination of markers may be used to select patients for treatment with a protofibrillar antibody, e.g., BAN2401, by comparison with levels in control subjects, e.g., subjects without AD.

[0116] [000171] Anti-Aβ protofibril antibodies, such as BAN2401, can be formulated in pharmaceutical compositions as disclosed in PCT / IB2021 / 000155 (International Publication No. WO 2021 / 186245), which is incorporated herein by reference. In some embodiments, the composition comprises 80 mg / mL to 120 mg / mL BAN2401, 240 mM to 360 mM arginine, 0.03% w / v to 0.08% w / v polysorbate 80, and 30 mM to 70 mM citrate buffer. In some embodiments, the arginine is arginine, arginine hydrochloride, or a combination thereof. In some embodiments, the composition comprises a liquid dosage form comprising 100 mg / mL BAN2401, 50 mmol / L citrate, 350 mmol / L arginine, and 0.05% polysorbate 80. In some embodiments, the composition comprises 80 mg / mL to 240 mg / mL BAN2401, 140 mM to 260 mM arginine hydrochloride, 0.01% w / v to 0.1% w / v polysorbate 80, and 15 mM to 35 mM histidine buffer. In some embodiments, the composition comprises a liquid dosage form comprising 100 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.

[0117] [000172] In some embodiments, BAN2401 is formulated as disclosed in PCT / IB2021 / 000155 (International Publication No. WO 2021 / 186245), which is incorporated herein by reference. In some embodiments, the composition comprises 80 mg / mL to 240 mg / mL BAN2401, 140 mM to 260 mM arginine hydrochloride, 0.01% w / v to 0.1% w / v polysorbate 80, and 15 mM to 35 mM histidine buffer. In some embodiments, the composition comprises a liquid dosage form comprising 200 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.

[0118] [000173] In some embodiments, provided herein are methods of treatment comprising administering a therapeutically effective dose of an anti-Aβ protofibril antibody until a desired improvement in one or more biomarkers, e.g., tau PET levels or rate of change in tau PET levels, or another treatment outcome measure, is achieved. In some embodiments, treatment is continued until a desired improvement in one or more biomarkers or other treatment outcome measure is achieved, e.g., when tau PET levels have not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by tau PET SUVR in the temporal region. In some embodiments, treatment is continued until tau PET levels improve compared to untreated control subjects, and / or treatment is continued until the ratio of Aβ 1-42 to Aβ 1-40 increases in a bodily fluid sample, e.g., a blood sample. In some embodiments, treatment is continued until tau PET levels are improved compared to untreated control subjects and / or treatment is continued until the ratio of Aβ1-42 to Aβ1-40 in a bodily fluid sample, e.g., a blood sample, is 0.092 or greater. In some embodiments, treatment is continued until tau PET levels are improved compared to untreated control subjects and / or until the level of p-tau181 in a bodily fluid sample, e.g., a blood sample, is reduced. In some embodiments, treatment is continued until tau PET levels are improved compared to untreated control subjects and / or until amyloid PET SUVr negativity is below a threshold of about 1.17. In some embodiments, the amyloid PET tracer can be florbetaben (e.g., 18F-florbetaben (Neuraceq®)), florbetapir (e.g., 18F-florbetapir (Amyvid®)), and / or flutametamol (e.g., 18F-flutametamol (Vizamyl®)). In some embodiments, the PET SUVr threshold for the amyloid PET tracer is about 1.17, and a measurement below this threshold can indicate that the subject is "amyloid negative." In some embodiments, the florbetapir amyloid PET SUVr threshold is about 1.17. In some embodiments, the florbetaben amyloid PET SUVr threshold is about 1.17.In some embodiments, the flutemetamol amyloid PET SUVr threshold is about 1.17.

[0119] [000174] In some embodiments, the one or more biomarkers include serum or plasma GFAP measurements. In some embodiments, treatment is continued until the subject becomes amyloid-negative. In some embodiments, the subject will switch to a maintenance dose after achieving a desired improvement in one or more biomarkers, e.g., tau PET levels or other treatment outcome measures. In some embodiments, the maintenance dosing regimen may further include one or more additional therapies in addition to the anti-Aβ protofibril antibody, e.g., it may include administering E2814.

[0120] [000175] In some embodiments, provided herein are methods of treatment that include administering a therapeutically effective dose of an anti-Aβ protofibril antibody in combination with tau PET levels or rate of change of tau PET until a desired improvement in cognitive outcome or other treatment outcome measure is achieved in a subject, e.g., a subject with Alzheimer's disease, pre-AD, or early Alzheimer's disease. In some embodiments, the method of treatment includes administering a therapeutically effective dose of an anti-Aβ protofibril antibody until tau PET levels are improved compared to untreated control subjects and a desired improvement in cognitive outcome or other treatment outcome measure is achieved in the subject. In some embodiments, the method of treatment includes administering a therapeutically effective dose of an anti-Aβ protofibril antibody for at least 18 months, or until, e.g., a patient has a tau PET level that has increased by 0.05-0.1 or less as assessed by temporal tau PET SUVR and a desired improvement in cognitive outcome is achieved in the subject. Cognitive and functional decline can be measured by techniques known in the art, including scoring methods such as the CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, revised iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, a method of treatment comprising administering a therapeutically effective dose of an anti-Aβ protofibril antibody is continued until the method results in less cognitive decline as measured by the ADCOMS compared to untreated subjects. In some embodiments, the efficacy of a method of treatment may be assessed using a CDR global score, which may be used to determine whether a patient has progressed or maintained their AD stage during treatment, e.g., a higher score at subsequent assessments indicates progression of AD, whereas a unchanged score indicates no progression of AD. In some embodiments, the method of treatment continues until the method results in at least a 24% lower (eg, at least a 29% lower) cognitive decline as measured by ADCOMS compared to untreated subjects.In some embodiments, the method of treatment continues until the method results in less cognitive decline as measured by CDR-SB compared to untreated subjects. In some embodiments, the method of treatment continues until the method results in at least 26% less (e.g., at least 27% less) cognitive decline as measured by CDR-SB compared to untreated subjects. In some embodiments, the method of treatment continues until the method results in less cognitive decline as measured by ADAS-Cog14 compared to untreated subjects. In some embodiments, the method of treatment continues until the method results in at least 26% less (e.g., at least 47% less) cognitive decline as measured by ADAS-Cog14 compared to untreated subjects. In some embodiments, the method results in less cognitive decline as measured by ADCS MCI-ADL compared to untreated subjects. In some embodiments, the method results in at least 37% less cognitive decline as measured by ADCS MCI-ADL compared to untreated subjects. In some embodiments, the results are measured at least 6 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the results are measured at least 12 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the results are measured at least 13 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the results are measured at least 18 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0121] [000176] Methods of treatment involving intravenous administration of anti-Aβ protofibril antibodies are disclosed in PCT / US2022 / 073576 and PCT / US2022 / 079571, which are incorporated herein by reference. In some embodiments, treatment involves intravenously administering an anti-Aβ protofibril antibody (e.g., administering BAN2401 at 10 mg / kg) every other week, e.g., for at least 18 months, or until, e.g., the patient becomes amyloid-negative. In some embodiments, treatment involves intravenously administering an anti-Aβ protofibril antibody (e.g., administering BAN2401 at 10 mg / kg) every other week, e.g., for at least 18 months, or until, e.g., the patient becomes amyloid-negative, followed by switching to a maintenance dose. In some embodiments, the method of treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) for at least 18 months, or until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by temporal tau PET SUVR, followed by switching to a maintenance dose. In some embodiments, the method of treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) for at least 18 months, or until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by temporal tau PET SUVR, followed by switching to a maintenance dose. In some embodiments, the maintenance dose may be the same as the treatment dose, or it may involve a reduction in the dosage and / or frequency of administration.

[0122] [000177] Methods of treatment involving administration of subcutaneously administered anti-Aβ protofibril antibodies are disclosed in PCT / US2022 / 073576; PCT / US2022 / 079571; and PCT / US2022 / 041926, which are incorporated herein by reference. In some embodiments, treatment involves subcutaneously administering an anti-Aβ protofibril antibody (e.g., administering BAN2401 at 720 mg) weekly, e.g., for at least 18 months, or, e.g., until the patient is amyloid-negative. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401 (e.g., weekly subcutaneous injections of 720 mg of two simultaneous, e.g., sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) for at least 18 months, or until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401 (e.g., weekly subcutaneous injections of 720 mg of two simultaneous, e.g., sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) for at least 18 months, or until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., at a dose of 720 mg, for at least 18 months, or until the patient is amyloid-negative, followed by a switch to a weekly subcutaneous maintenance dose, e.g., a 360 mg dose. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., at a dose of 720 mg, for at least 18 months, or until the patient is amyloid-negative, followed by a switch to a biweekly subcutaneous maintenance dose, e.g., a 720 mg dose.In some embodiments, the method of treatment involves administering BAN2401 subcutaneously weekly (e.g., weekly subcutaneous injections of 720 mg of two simultaneous, e.g., sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) for at least 18 months, or until, e.g., the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by tau PET SUVR in the temporal region. In some embodiments, the method of treatment involves administering BAN2401 subcutaneously weekly (e.g., weekly subcutaneous injections of two simultaneous, e.g., 720 mg of two sequential, e.g., 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) for at least 18 months, or until, e.g., the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by tau PET SUVR in the temporal region. In some embodiments, the method of treatment involves switching to a maintenance dose, after administering BAN2401 subcutaneously weekly (e.g., weekly subcutaneous injections of two simultaneous, e.g., 720 mg of two sequential, e.g., 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) for at least 18 months, or until, e.g., the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by tau PET SUVR in the temporal region. In some embodiments, the maintenance dose may be the same as the therapeutic dose, or it may involve a reduction in dosage and / or frequency of administration.

[0123] [000178] In some embodiments, methods of treatment include using biomarker levels, e.g., tau PET levels or rate of change in tau PET levels, to determine switching to a maintenance intravenous or subcutaneous dose at a set time point (e.g., after 18 months). In some embodiments, a maintenance dose is administered after a treatment period. In some embodiments, treatment includes intravenously administering an anti-Aβ protofibril antibody followed by switching to an intravenous maintenance dose. In some embodiments, treatment includes intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) followed by switching to an intravenous maintenance dose, for example, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR. In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every other week (e.g., after administration of BAN2401 at 10 mg / kg), e.g., for at least 18 months or until tau PET levels improve compared to untreated control subjects, followed by a switch to an intravenous maintenance dose. In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every other week (e.g., after administration of BAN2401 at 10 mg / kg), e.g., for at least 18 months or until, e.g., the patient becomes amyloid-negative, followed by a switch to an intravenous maintenance dose. In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every other week, followed by a monthly intravenous maintenance dose (e.g., after administration of BAN2401 at 10 mg / kg), e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., tau PET levels have improved compared to untreated control subjects.In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every other week, followed by a quarterly intravenous maintenance dose (e.g., after administration of BAN2401 at 10 mg / kg), for example, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects. In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody, followed by a subcutaneous maintenance dose. In some embodiments, treatment involves intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) followed by a subcutaneous maintenance dose of, e.g., 720 mg administered weekly or every other week, 360 mg administered weekly, or 250 mg administered weekly, e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., tau PET levels are improved compared to untreated control subjects. In some embodiments, the intravenous maintenance dose is administered every two weeks. In some embodiments, the intravenous maintenance dose is administered every four weeks. In some embodiments, the intravenous maintenance dose is administered every six weeks. In some embodiments, the intravenous maintenance dose is administered every eight weeks (two months). In some embodiments, the intravenous maintenance dose is administered every three months (quarterly). In some embodiments, the intravenous maintenance dose is administered every 24 weeks (every 6 months or every 6 months). In some embodiments, treatment involves intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level has improved compared to untreated control subjects, followed by switching to a biweekly intravenous maintenance dose.

[0124] [000179] In some embodiments, methods of treatment include using biomarker levels, e.g., tau PET levels or rate of change of tau PET levels, to determine switching from a subcutaneous treatment dose to a subcutaneous maintenance dose. In some embodiments, the maintenance dose is administered as a subcutaneous injection of an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, treatment includes subcutaneously administering an anti-Aβ protofibril antibody followed by switching to a subcutaneous maintenance dose. In some embodiments, treatment includes subcutaneously administering 720 mg of an anti-Aβ protofibril antibody every other week (e.g., after administering sequential injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) followed by switching to weekly or biweekly subcutaneous injections of 720 mg, for example, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by tau PET SUVR in the temporal region. In some embodiments, treatment involves subcutaneous administration of an anti-Aβ protofibril antibody at 720 mg every other week (e.g., after administering sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation), for example, for at least 18 months or until tau PET levels improve compared to untreated control subjects, followed by switching to weekly or biweekly subcutaneous injections of 720 mg. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of a subcutaneous formulation of an anti-Aβ protofibril antibody. In some embodiments, the maintenance dose is administered as two simultaneous, e.g., weekly subcutaneous injections of 720 mg with sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as monthly subcutaneous injections of 720 mg, including two simultaneous, e.g., sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody subcutaneously at 720 mg weekly (e.g., after administering sequential injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation) for, e.g., at least 18 months, or until, e.g., the patient becomes amyloid-negative, followed by switching to biweekly subcutaneous injections of 720 mg.

[0125] [000180] In some embodiments, methods of treatment include using biomarker levels, e.g., tau PET levels or rate of change of tau PET levels, to determine switching from an intravenous treatment dose to a maintenance dose. In some embodiments, the maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections). In some embodiments, treatment includes intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) followed by switching to a subcutaneous maintenance dose, e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., the tau PET level has improved compared to an untreated control subject. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, followed by a weekly subcutaneous maintenance dose, for example, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, followed by a weekly subcutaneous maintenance dose of 720 mg, for example, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, followed by a switch to a subcutaneous maintenance dose of 720 mg every other week, e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., tau PET levels have improved compared to untreated control subjects.

[0126] [000181] In some embodiments, methods of treatment include using biomarker levels, e.g., tau PET levels or rate of change of tau PET levels, to determine switching from a subcutaneous treatment dose to a maintenance dose. In some embodiments, treatment includes subcutaneous administration of an anti-Aβ protofibril antibody, e.g., BAN2401, followed by switching to an intravenous maintenance dose. In some embodiments, treatment includes weekly subcutaneous administration of BAN2401, e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by tau PET SUVR in the temporal region, or until the tau PET level has improved compared to untreated control subjects, e.g., after two simultaneous, sequential injections of 720 mg (2 x 1.8 mL of 400 mg / 2 mL). In some embodiments, treatment involves administering BAN2401 subcutaneously weekly at a dose of, e.g., 720 mg, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects, for example, followed by a switch to a maintenance dose. In some embodiments, treatment involves administering BAN2401 subcutaneously weekly at a dose of, e.g., 10 mg / kg, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment, as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects, for example, followed by a switch to a biweekly intravenous maintenance dose of 10 mg / kg. In some embodiments, a subject's maintenance dose is administered in the same amount and / or frequency as the dose administered during the treatment period. In some embodiments, a subject's maintenance dose is 50% of the dose administered during the treatment period.

[0127] [000182] In some embodiments, patients are initiated on an intravenous maintenance dose, e.g., 10 mg / kg BAN2401 as disclosed above, followed by a subcutaneous maintenance dose, e.g., 720 mg subcutaneous injections comprising two simultaneous, e.g., 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous injections of the formulation. In some embodiments, patients are initiated on a subcutaneous maintenance dose, e.g., 720 mg subcutaneous injections comprising two simultaneous, e.g., 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous injections of the formulation, followed by an intravenous maintenance dose, e.g., 10 mg / kg BAN2401 as disclosed above.

[0128] [000183] In some embodiments, a patient is returned from the maintenance dose to the initial treatment dose when the patient is determined to be no longer amyloid negative, e.g., as assessed by blood, serum, or CSF biomarkers and / or as determined by amyloid PET SUVr.

[0129] [000184] In some embodiments, the maintenance dose for a subject is administered in the same amount and / or frequency as the dose administered during the treatment period. In some embodiments, the maintenance dose for a subject is 50% of the dose administered during the treatment period. In some embodiments, the maintenance dose comprises two or more administrations, wherein the first administration is selected from the maintenance doses exemplified above, and the second and / or subsequent administrations comprise a lower amount and / or administration frequency than the first or previous administration, respectively. In some embodiments, the second or subsequent administration is determined based on one or more biomarkers exemplified above, and the level of the biomarker is different (e.g., more improved) from the level used when switching from the initial dose to the first administration in the maintenance dose.

[0130] [000185] In some embodiments, treatment of a patient is discontinued when the patient no longer has early stage AD, as assessed, for example, by cognitive assessment, PET SUVr, and / or blood, CSF, or plasma biomarkers.

[0131] [000186] In some embodiments, a patient's amyloid levels may be monitored for regression after cessation of treatment by measuring one or more biomarkers, such as tau PET levels and volumetric MRI (vMRI) including whole brain volume, cortical thickness, total hippocampal volume, and / or lateral ventricle volume. In some embodiments, a patient's amyloid levels may be monitored for regression after cessation of treatment by measuring one or more biomarkers, such as tau PET levels and PET levels, including amyloid PET levels and / or fluorodeoxyglucose (FDG) PET levels. In some embodiments, a patient's amyloid levels may be monitored for regression after cessation of treatment by measuring one or more biomarkers, such as tau PET levels and cerebrospinal fluid levels of biomarkers including CSF levels of Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, neurogranin, neurofilament light chain (NfL), and / or microtubule binding region (MTBR)-tau. In some embodiments, a patient's amyloid levels may be monitored for regression after cessation of treatment by measuring tau PET levels and one or more biomarkers, such as serum or plasma levels of biomarkers including Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and tau phosphorylated at 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0132] [000187] In some embodiments, a patient's biomarkers may be monitored at least once after treatment has stopped. In some embodiments, a patient's biomarkers are monitored at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment has stopped. In some embodiments, treatment is resumed when the patient's biomarker levels are no longer favorable, for example, when tau PET levels increase at the same rate as untreated controls.

[0133] [000188] In some embodiments, the subject has been diagnosed with early AD. In some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - intermediate probability and / or mild Alzheimer's disease dementia.

[0134] [000189] Methods of treatment using anti-Aβ protofibril antibodies, including therapeutically effective doses, are disclosed in PCT / US2022 / 073576; PCT / US2022 / 079571; and PCT / US2022 / 041926, which are incorporated herein by reference. In some embodiments, the methods of treatment include using biomarker levels, e.g., tau PET levels or rates of change in tau PET levels, to enable monitoring and treatment decisions. In some embodiments, the methods of treatment include using biomarker levels, e.g., tau PET levels or rates of change in tau PET levels, to determine switching from a therapeutic dose to a maintenance dose. In some embodiments, the first therapeutically effective dose includes, for example, administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) followed by switching to an intravenous maintenance dose (e.g., at 10 mg / kg, e.g., every other week or every 4, 6, 8, 10, or 12 weeks) until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level is improved compared to an untreated control subject. In some embodiments, the first therapeutically effective dose includes, for example, administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, followed by a switch to a biweekly intravenous maintenance dose (e.g., after administering BAN2401 at 10 mg / kg), until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level has improved compared to an untreated control subject.In some embodiments, the first therapeutically effective dose includes, for example, administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, followed by a monthly intravenous maintenance dose (e.g., after administering BAN2401 at 10 mg / kg), until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level has improved compared to an untreated control subject. In some embodiments, the first therapeutically effective dose includes, for example, administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, followed by a switch to a quarterly intravenous maintenance dose (e.g., after administering BAN2401 at 10 mg / kg), until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level has improved compared to an untreated control subject.

[0135] [000190] In some embodiments, the first therapeutically effective dose includes subcutaneous administration of an anti-Aβ protofibril antibody at 720 mg weekly (e.g., after administering BAN2401 at 720 mg), followed by switching to a subcutaneous maintenance dose (e.g., at 720 mg, e.g., weekly, biweekly, or every 4, 6, 8, 10, or 12 weeks), e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., the tau PET level has improved compared to an untreated control subject. In some embodiments, the first therapeutically effective dose includes, for example, administering an anti-Aβ protofibril antibody subcutaneously at 720 mg weekly (e.g., after administering BAN2401 at 720 mg) followed by switching to a biweekly subcutaneous maintenance dose (e.g., at 720 mg) until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level has improved compared to an untreated control subject.

[0136] [000191] In some embodiments, the first therapeutically effective dose comprises intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg), followed by a switch to a weekly subcutaneous maintenance dose (e.g., at a dose of 720 mg), e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., the tau PET level has improved compared to an untreated control subject. In some embodiments, the first therapeutically effective dose includes, for example, administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week (e.g., after administering BAN2401 at 10 mg / kg) followed by switching to a biweekly subcutaneous maintenance dose (e.g., at a 720 mg dose or a 360 mg dose) until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, for example, the tau PET level is improved compared to an untreated control subject.

[0137] [000192] In some embodiments, the first therapeutically effective dose comprises, e.g., administering an anti-Aβ protofibril antibody subcutaneously weekly, followed by a 720 mg subcutaneous injection comprising, e.g., two simultaneous, sequential injections in a given week of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation, followed by a switch to a weekly 720 mg subcutaneous maintenance dose, e.g., until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., tau PET levels have improved compared to untreated control subjects. In some embodiments, the first therapeutically effective dose comprises, for example, weekly administration of an anti-Aβ protofibril antibody followed by a subcutaneous injection of a 720 mg subcutaneous formulation followed by a switch to a biweekly subcutaneous maintenance dose (e.g., at a dose of 720 mg) until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects. In some embodiments, the first therapeutically effective dose comprises, for example, weekly administration of an anti-Aβ protofibril antibody followed by a subcutaneous injection of a 720 mg subcutaneous formulation followed by a switch to a biweekly subcutaneous maintenance dose (e.g., at a dose of 720 mg) until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until the tau PET level has improved compared to untreated control subjects. In some embodiments, the first therapeutically effective dose includes, for example, weekly subcutaneous administration of an anti-Aβ protofibril antibody followed by a switch to a monthly subcutaneous maintenance dose of 720 mg, e.g., subcutaneous injection of a 720 mg subcutaneous formulation, until the patient has a tau PET level that has not increased by more than 0.05-0.1 after 13 or 18 months of treatment as assessed by temporal tau PET SUVR, or until, e.g., tau PET levels have improved compared to untreated control subjects.

[0138] [C. Subjects with low tau PET] [000193] In various embodiments, disclosed herein are methods for selecting, treating, monitoring treatment, and making decisions regarding further treatment, e.g., maintenance dosing, in patients receiving an anti-amyloid beta protofibril antibody (also referred to as an "anti-amyloid beta (Aβ) protofibril antibody" or "anti-Aβ protofibril antibody"), such as BAN2401. In some embodiments, the subject has low tau levels in whole-brain measurements, e.g., as measured by tau PET. A low level of tau PET can refer to a low level of tau aggregation, e.g., a low level of cortical tau aggregation, as imaged by PET scan imaging. In some embodiments, a subject with low tau PET also has tau accumulation in certain brain regions, e.g., one or more early Braak regions or a combination of regions where tau accumulates in early AD. In some embodiments, the presence of tau in these regions (e.g., as measured by PET) may be measured in combination with, or instead of, measuring low tau in whole brain measurements (e.g., as measured by PET) to identify subjects suitable for treatment as disclosed herein. In some embodiments, one or more additional biomarkers (e.g., plasma and / or CSF markers such as amyloid beta 42:40 ratio, phospho-tau, and / or MTBR-tau243) may be measured in combination with, or instead of, measuring low tau in whole brain measurements (e.g., as measured by PET).

[0139] [000194] Without being bound by theory, it is a surprising discovery that anti-amyloid protofibril antibodies such as BAN2401 (i.e., lecanemab) can be particularly effective in subjects with low levels of tau, e.g., low tau PET levels, as measured in whole-brain measurements and / or by any of the surrogate measures for low global tau discussed herein (e.g., serum measures such as amyloid beta 42:40 ratio or phospho-tau, or CSF measures such as MTBR-tau243, or plasma markers such as MTBR-tau243). In previous studies, it was hypothesized that the effect of anti-amyloid antibodies would be greatest in subjects with at least moderate levels of tau, corresponding to early symptomatic AD and tau pathology. For example, the Trailblazer clinical trial enrolled subjects with moderate levels of tau, as defined by a threshold tau PET level defined in the study, and a smaller number of subjects with high levels of tau, representing a later stage of disease progression. However, subjects with tau PET levels below the threshold were not included in the Trailblazer study.

[0140] [000195] In contrast, the results of this study demonstrate the surprising efficacy of anti-Aβ protofibril antibodies, such as lecanemab, in treating subjects with low tau PET. In some embodiments, treatment with anti-amyloid antibodies results in improved outcomes, as determined by measurements of clinical function and / or biomarkers associated with AD, in subjects with low tau PET levels compared to subjects with moderate and / or high tau PET levels.

[0141] [000196] In some embodiments, thresholds for determining low, moderate, and high tau PET levels are determined for a given PET scanning procedure and tau PET tracer. In some embodiments, the thresholds may be determined using the MK6240 radioactive tracer. Equivalent thresholds may be readily identified using other tracers. In some embodiments, the thresholds may be determined using a common scale for tau PET that reflects analytical methods and / or measurements obtained with different tau PET tracers.

[0142] [000197] In some embodiments, low levels of tau are levels of tau as measured by PET, such as the tau-PET standardized uptake value ratio (SUVR), that are below a threshold, e.g., a threshold set in whole brain measurements.

[0143] [000198] In some embodiments, the whole-brain measurement is a tau PET measurement in the entire cortical gray matter (e.g., a tau PET measurement of cortical tau aggregation). In some embodiments, the tau PET level is measured using the MK6240 radiotracer. In some embodiments, the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by an MK6240 PET scan of the entire cortical gray matter.

[0144] [000199] Subjects with low levels of tau in whole-brain measurements (e.g., throughout the cortical gray matter) may have higher levels of tau in regional brain regions (e.g., medial temporal, meta-temporal, and / or temporal regions).

[0145] [000200] In some embodiments, the local brain region is an early Braak region (e.g., Braak region I, II, or III). In some embodiments, the early Braak region includes the transitional entorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, the local brain region is a composite of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, the medial temporal region, and / or the meta-temporal region. In some embodiments, the local brain region is the medial temporal region (e.g., the entorhinal cortex).

[0146] [000201] In some embodiments, treating AD in subjects with low tau PET levels includes, for example, reducing, slowing, and / or reversing the decline in a measure of cognitive function in a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody compared to a control. In some embodiments, the measure of cognitive function in a treated subject is compared to a baseline measure obtained from the same subject before treatment or to a reference control. In some embodiments, the decline occurs between the time cognitive function is first measured (e.g., the baseline measure) and one or more later time points at which cognitive function is measured again. In some embodiments, the later time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measure. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject not receiving treatment or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measure, such as an average measure combining population data from two or more subjects, and is representative of subjects not receiving treatment. In some embodiments, the measure of cognitive function is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL.

[0147] [000202] In some embodiments, patients with low tau PET levels may have less tau accumulation than patients with higher tau PET levels. The disclosure herein surprisingly shows that these patients may respond better to treatment, e.g., treatment with an anti-Aβ protofibril antibody, e.g., BAN2401, compared to patients with more tau PET, as tested in clinical trials with others (e.g., TRAILBLAZER-ALZ3). In some embodiments, a patient may be classified as having low levels of tau if their tau PET level is below a threshold. In some embodiments, the level of tau may be determined, for example, by measuring the level of tau. IQTau IQ (also referred to as "Tau IQ") is calculated from the overall tau burden from the whole-brain signal using an algorithm. In some embodiments, a patient may be classified as having a low level of tau if their tau level, as measured by PET using an MK tracer, is less than about 1.1, e.g., less than about 1.0. In some embodiments, a patient may be classified as having a low level of tau if their tau PET level, as measured by an MK tracer, is less than 1.06. In some embodiments, a patient may be classified as having a moderate level of tau if their tau PET level, as measured by an 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 their tau level, as measured by an MK tracer, is greater than about 3.0, e.g., greater than about 2.91. In some embodiments, a patient may be classified as having a low level of tau based on their percentile ranking relative to other patients selected for treatment with an anti-Aβ protofibril antibody, e.g., BAN2401. In some embodiments, a cutoff value may be used to remove outliers before determining percentile rankings. In some embodiments, patients with low levels of tau, e.g., low tau PET levels, may be classified as having levels of tau that are at least one standard deviation below the mean level of tau for the patient population. As will be appreciated by those skilled in the art, the threshold for classifying patients as having low, moderate, or high tau PET levels may vary based on the methodology used to determine tau levels in the brain, e.g., depending on the tau PET methodology and the tracer used for tau PET imaging. In some embodiments, a patient may be classified as having low levels of tau if their tau PET levels (e.g., a measure of cortical tau aggregation) as measured by the tracer MK6240 in the entire cortical gray matter are below a threshold. In some embodiments, the level of tau may be determined, e.g., by measuring the mean level of tau. IQUsing an algorithm, the overall tau load from the entire cortical gray matter is calculated. In some embodiments, a patient can be classified as having a low level of tau if the level of tau as measured by PET in the entire cortical gray matter as measured by the MK6240 tracer is less than about 1.1, for example, less than about 1.0. In some embodiments, a patient can be classified as having a low level of tau if the tau PET level as measured by PET in the entire cortical gray matter as measured by the MK6240 tracer is less than 1.06. In some embodiments, a patient can be classified as having a moderate level of tau if the tau PET level as measured by the MK6240 tracer in the entire cortical gray matter is between about 1.1 and 3.0, for example, between 1.06 and 2.91. In some embodiments, a patient can be classified as having a high level of tau if the level of tau as measured by the MK6240 tracer in the entire cortical gray matter is greater than about 3.0, for example, greater than about 2.91. In some embodiments, tau PET levels as measured by MK6240 in whole cortical gray matter may be referred to as "total tau" or "total tau aggregation."

[0148] [D. Measurement of Tau PET Levels] [000203] The disclosures and methods discussed herein are based in part on the discovery that treatments including anti-Aβ protofibril antibodies, such as BAN2401, can result in a reduction in the rate of tau accumulation, as measured by tau-PET levels (e.g., as measured by tau PET imaging), in brain regions such as the temporal region, compared to control patients.

[0149] [000204] In some embodiments, treatment is administered to subjects identified as having low tau PET levels in whole-brain measurements (e.g., throughout the cortical gray matter) and / or by any of the surrogate measures for low global tau PET discussed herein. Subjects with low tau PET in whole-brain measurements may have higher levels of tau PET in regional brain regions. In some embodiments, the regional brain region is an early Braak region (e.g., Braak region I, II, or III). For example, the early Braak region may include the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, the regional brain region is a composite of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, the mesial temporal region, and / or the meta-temporal region. In some embodiments, the local brain region is the medial temporal region (e.g., the entorhinal cortex, hippocampus, parahippocampal gyrus, and the temporal pole (medial and / or inferior lateral tip of the temporal lobe). Thus, reducing tau accumulation may refer to reducing, slowing, and / or reversing tau accumulation in a local brain region.

[0150] [000205] In some embodiments, treatment with an Aβ protofibril antibody reduces tau PET levels (e.g., tau aggregation or accumulation) as measured by an adjusted mean change from baseline tau PET SUVr levels of less than about 0.1, e.g., 0.05. In some embodiments, the decrease in tau PET from baseline is greater in subjects receiving lecanemab than in controls.

[0151] [000206] In some embodiments, measures of tau aggregation in treated subjects are compared to baseline measures obtained from the same subjects before treatment, or to a reference control. In some embodiments, the reference control is an untreated control subject (e.g., a subject who receives a placebo). In some embodiments, the reference control is a measurement obtained from a population of control subjects.

[0152] [000207] In some embodiments, this correlates with a reduction in cerebral amyloid burden and improved cognitive outcomes in the subject. Without being bound by theory, tau PET levels (e.g., tau PET standardized uptake value ratio (SUVr)) can, in various embodiments, be used as a minimally invasive and / or additional biomarker to refine measurement of treatment efficacy and / or to enable monitoring and treatment decisions. Such decisions can include whether to increase or decrease the amount of anti-Aβ protofibril antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, and / or whether to discontinue treatment with the anti-Aβ protofibril antibody.

[0153] [000208] As used herein, the term "tau PET" refers to tau positron emission tomography imaging. In some embodiments, tau PET imaging (also referred to as a tau PET scan) is performed to assess for tau pathology. In some embodiments, tau PET is assessed with a PET tracer, and the same tracer is used in follow-up assessments. In a preferred embodiment, PET imaging uses the [F]MK-6240 (also known as "florquini tau") tracer, referred to herein as the "MK tracer." In some embodiments, the PET tracer is an arylquinoline derivative (e.g., [F]THK5317 and [F]THK5351), a pyridoindole derivative (e.g., [F]AV-1451, also known as [F]-flortaucipir), or a phenyl / pyridinyl-butadienyl-benzothiazone / benzothiazolium (PBB) derivative, such as [C]PBB3. In some embodiments, the PET tracers are [18F]-RO-948, [18F]-PI-2620, [18F]-JNJ-311, and [18F]-GTP1.

[0154] [000209] Tau positron emission tomography (PET) imaging can be used to confirm the presence of tau pathology in the brain of early-stage AD subjects during the screening phase of the study and / or to assess the effect of at least one anti-Aβ protofibril antibody on tau levels in the brain by whole-brain analysis (e.g., entire cortical gray matter or an average of 5-6 cortical regions) and / or brain region analysis (e.g., temporal brain regions).

[0155] [000210] In some embodiments, tau PET imaging across different regions of the brain can be used to determine tau PET levels at a global or regional level. Whole-brain measurements may include tau PET imaging analysis of the whole brain, a large portion of the whole brain, the gray matter of the brain, or a large section of the brain that can be considered representative of a whole-brain measurement (e.g., the entire cortical gray matter). In some embodiments, whole-brain measurements are tau PET measurements of 5-6 cortical regions. In some embodiments, whole-brain measurements are tau PET measurements of the entire cortical gray matter. In some embodiments, whole-brain measurements are tau PET measurements of cortical tau aggregation. Regional brain measurements may include tau PET imaging analysis of a regional brain region. In some embodiments, a regional brain region includes one or more brain structures, e.g., brain structures defined by structure or morphology. In some embodiments, a subject may have a first tau PET level in a whole-brain measurement and a second tau PET level in a regional brain region. In some embodiments, the first tau PET level is lower than the second tau PET level. In some embodiments, the first tau PET level is higher than the second tau PET level. In some embodiments, the first tau PET level is equivalent to the second tau PET level.

[0156] [000211] In some embodiments, the PET scan uses a [F]MK-6240 (florquini tau) tracer. In some embodiments, the PET scan uses a tau PET tracer such as an arylquinoline derivative (e.g., [F]THK5317 and [F]THK5351), a pyridoindole derivative (e.g., [F]AV-1451, also known as [F]-flortaucipir), or a phenyl / pyridinyl-butadienyl-benzothiazone / benzothiazolium (PBB) derivative such as [C]PBB3. In some embodiments, the PET tracer is [F]RO-948, [F]PI-2620, [F]JNJ-311, and [F]GTP1. In some embodiments, tau burden can be identified by visual interpretation of the PET imaging uptake, e.g., by a trained radiologist. In embodiments, brain regions (eg, lobes) are assessed for uptake of an imaging agent (eg, a tau PET tracer).

[0157] [000212] A brain region is a section, part, portion, or compartment of the brain. A brain region may be a region defined in a standard neuroanatomical atlas. A region may correspond to a brain lobe or may constitute a larger or smaller portion of the brain. A region may require or be defined by specific anatomical landmarks. A brain region may be defined according to characteristics specific to a particular experiment or study. A brain region may be defined according to its location, function, anatomical morphology, relationship to other brain regions, and / or PET tracer uptake characteristics. In some embodiments, the brain region is the entire cortex.

[0158] [000213] In some embodiments, the brain region is a combination of two or more brain regions, e.g., regions that accumulate tau in early AD. In some embodiments, the brain region is a combination of two or more lobes, subregions, and / or structures in the brain.

[0159] [000214] For example, a cortical composite region may include two or more brain structures derived from the cortex. In some embodiments, a composite region in a PET scan is a region of interest (ROI) that includes two or more brain regions, for example, a volume-weighted average of two or more brain regions.

[0160] [000215] In some embodiments, the brain region is the temporal region. In some embodiments, the brain region is the medial temporal region. In some embodiments, the brain region is primarily the lateral temporal region. In some embodiments, the brain region may be referred to as the meta-temporal region.

[0161] [000216] As used herein, the temporal region includes at least a portion of the temporal lobe. For example, the temporal region may include the superior posterior portion of the temporal lobe, the superior anterior portion of the temporal lobe, the posterior portion of the temporal lobe, the middle inferior portion of the temporal lobe, and the fusiform gyrus. The temporal region may include these structures from both the left and right hemispheres of the brain. In some embodiments, the temporal region includes the lateral temporal region.

[0162] [000217] In some embodiments, the medial temporal region includes the hippocampus, the anterior medial temporal lobe, the anterior inferior lateral temporal lobe, the parahippocampal cortex, and the entorhinal cortex. The medial temporal region can include these structures from both the left and right hemispheres of the brain.

[0163] [000218] In some embodiments, the medial temporal region includes the entorhinal cortex, hippocampus, parahippocampal gyrus, and / or temporal pole (medial and inferior lateral tip of the temporal lobe). The medial temporal region can include these structures from both the left and right hemispheres of the brain.

[0164] [000219] In some embodiments, meta-regions of interest (ROIs) are defined as those regions of the brain with certain characteristics, such as regions with the most abundant deposits in AD patients, or regions in which tau PET imaging differs between groups of patients (e.g., cognitively unimpaired individuals, e.g., those with normal amyloid PET compared with cognitively unimpaired individuals with abnormal amyloid PET). Examples of meta-ROIs in the temporal region can be found in Jack et al., Alzheimer's Dementia 13, 205-216 (2017). In some embodiments, the meta-ROI can include the meta-temporal region (also referred to as the temporal meta-region). In some embodiments, the meta-temporal region includes the amygdala, the parahippocampal cortex, the middle and inferior temporal lobe, the fusiform gyrus, the posterior temporal lobe, and the entorhinal cortex. The meta-temporal region can include these structures from both the left and right hemispheres of the brain.

[0165] [000220] Thus, PET levels may be assessed in any of the brain regions described herein and / or other brain regions; in some embodiments, the temporal region is assessed for tau PET levels. In some embodiments, the frontal region is assessed for tau PET levels. In some embodiments, the parietal region is assessed for tau PET levels. In some embodiments, the occipital region is assessed for tau PET levels. In some embodiments, the cingulate region is assessed for tau PET levels.

[0166] [000221] In some embodiments, the entire cortical gray matter is assessed for tau PET levels. In some embodiments, the region, e.g., the reference region, used to assess tau PET levels is the ventral cerebellum (Cb).

[0167] [000222] As used herein, "tau levels in the brain," "tau levels," and "tau burden" are used interchangeably. Tau levels can be assessed by PET imaging ("tau PET levels"). As used herein, tau PET levels refer to the measurement of the level of tau in a brain region, e.g., the temporal region, by PET. In some embodiments, tau PET levels can be measured, e.g., by measuring the level of tau in a brain region, e.g., the temporal region. IQThe tau IQ is calculated from the overall tau load from the whole-brain signal using an algorithm (also called "tau IQ"). In some embodiments, "tau PET levels" can be identified in tau PET imaging by the standardized uptake value ratio (SUVr or SUVR). SUVr can be a measure of tau PET tracer uptake in a region of a patient's brain compared (e.g., normalized) to a reference region in the same patient. Methods for calculating tau PET SUVr are known in the art and may include those described herein. One exemplary method for quantitative analysis (e.g., computer processing) of SUVr is PMOD PNEURO biomedical image quantification software (PMOD Technologies, Zurich, Switzerland). In some embodiments, PET images are first assessed for subject motion in the X, Y, and Z planes and, if necessary, corrected for motion, before individual images (e.g., 5-minute emission frames) are averaged using, for example, the PMOD averaging function (PET frames averaged to increase signal-to-noise ratio). In some embodiments, a corresponding MRI from the subject is created (e.g., using a matrix size reduction process, cropping the MRI to include only the brain, segmenting the image to separate the image into binary maps of gray matter, white matter, and CSF, and removing the skull image, leaving only the brain mask). In some embodiments, the averaged PET image and the created MRI are matched using a PMOD matching function to ensure the images are co-oriented. In some embodiments, a brain shape normalization function, e.g., as provided by the PMOD software, is used along with the Brain Norm and Rigid Matching transformation matrices to generate the averaged PET. In some embodiments, this averaged PET is normalized to MNI space (Senjem et al., 2005), which is in the same orientation as the subject's segmented MRI, for quantitative analysis. In some embodiments, the brain is masked using a PMOD mask function, and the image outside the mask is zeroed out to create normalized gray matter PET and normalized white matter PET.Standard uptake values ​​(SUV) may be calculated for all gray matter mapping regions and three white matter regions (pons, cerebellar white matter, and subcortical white matter) using PMOD software calculated using normalized PET, subject weight, and tracer injection volume to obtain units of SUV. In some embodiments, SUVr is the ratio of the mean of the entire cortex compared to a reference region of choice. In some embodiments, the entire cerebellum mask is used as the reference region. In some embodiments, the reference region is a composite reference region consisting of subcortical white matter, ventral cerebellum, whole cerebellum derived, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and cerebellar cortex, pons, subcortical white matter, and cerebellar white matter.

[0168] [000223] In some embodiments, tau PET levels are assessed by a PET tracer. In some embodiments, the PET tracer is [18F]MK-6240. In some embodiments, tau PET levels can be used to classify patients as having different levels of tau. For example, in some embodiments, a patient can be classified as having a low level of tau if the tau PET level is below a threshold. The threshold can be identified as the tau level in the entire cortex or specifically in a region of interest. In some embodiments, the threshold can be the tau PET level measured in the entire cortex (e.g., the entire cortical gray matter). In some embodiments, the threshold is a cutoff for classifying patients as having low, moderate, or high tau PET levels. In some embodiments, a patient can be classified as having a low level of tau if the level of tau, as measured in a specific region of interest, e.g., the entire cortical gray matter, by PET using, for example, an MK tracer, is less than about 1.1, e.g., less than about 1.0. In some embodiments, a patient may be classified as having a low level of tau if their tau PET level, as measured using an MK tracer, is less than 1.06. In some embodiments, a patient may be classified as having a moderate level of tau if their tau PET level, as measured by an 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 their tau level, as measured by an MK tracer, is greater than about 3.0, e.g., greater than about 2.91. In some embodiments, the thresholds for tau PET levels are <1.06 (low level), 1.06-2.91 (moderate level), and >2.91 (high level), when tau PET levels are determined throughout the cortex using a PET tracer, e.g., [18F]MK-6240. In some embodiments, the cutoffs may be determined according to tau PET levels in specific brain regions.As will be appreciated by those skilled in the art, the threshold for classifying a patient as having low, moderate, or high tau PET levels can vary based on the methodology used to determine tau levels in the brain, for example, depending on the tau PET methodology and the tracer used for tau PET imaging. In some embodiments, the threshold can be determined using a common scale for tau PET that reflects analytical methods and / or measurements obtained thereby with different tau PET tracers.

[0169] [000224] In some embodiments, the adjusted mean change from baseline is measured before treatment and at least once after initiating treatment, e.g., over a period of at least 6 months after the first dose of treatment. In some embodiments, the adjusted mean change from baseline is measured over a period of at least 12 months after the first dose of treatment. In some embodiments, the adjusted mean change from baseline is measured over a period of at least 13 months after the first dose of treatment. In some embodiments, the adjusted mean change from baseline is measured over a period of at least 18 months after the first dose of treatment. In some embodiments, the adjusted mean change from baseline is measured over a period of at least 24 months after the first dose of treatment.

[0170] [000225] In some embodiments, after administration of the first dose of the composition, the subject's adjusted mean change from baseline in tau PET SUVr values ​​is less than 0.15. In some embodiments, after administration of the first dose of the composition, the subject's adjusted mean change from baseline in tau PET SUVr values ​​is less than 0.10. In some embodiments, after administration of the first dose of the composition, the subject's adjusted mean change from baseline in tau PET SUVr values ​​is less than 0.05. In some embodiments, 13 months after the first dose of treatment, the subject's adjusted mean change from baseline in tau PET SUVr values ​​is less than 0.15. In some embodiments, after administration of the first dose of the composition, the subject's adjusted mean change from baseline in tau PET SUVr values ​​is less than 0.05. In some embodiments, 18 months after the first dose of treatment, the subject's adjusted mean change from baseline in tau PET SUVr values ​​is less than 0.15.

[0171] [000226] In some embodiments, a subject's adjusted mean change from baseline in tau PET SUVr is measured in a regional brain region. For example, tau PET SUVr may be measured in an early Braak region (e.g., Braak region I, II, or III). The early Braak region may include the transitional entorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, the regional brain region is a composite of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, the medial temporal region, and / or the meta-temporal region. In some embodiments, the regional brain region is the medial temporal region (e.g., the entorhinal cortex). In some embodiments, a subject may have low tau PET levels in whole-brain measurements, but higher tau PET levels in a regional brain region. In some embodiments, a subject may have higher tau PET levels in a first regional brain region, but not in a second regional brain region. For example, a first regional brain region with higher tau PET levels may be an early Braak region (e.g., Braak region I, II, or III), while a second regional brain region without higher PET levels may be a late Braak region (e.g., Braak region IV, V, or VI) reflecting the progression of AD.

[0172] [000227] Additional methods for measuring tau by PET are known in the art. IQ It may also include an algorithm (e.g., see Whittington et al., J. Nucl Med. 2021 Sep 1;62(9):1292-1300 for quantitatively measuring tau PET radiotracers).

[0173] [000228] Measurements of tau PET levels may be used alone to assess treatment efficacy or in combination with one or more additional criteria, such as one or more measurements in bodily fluids (e.g., p-tau and / or the ratio of Aβ to Aβ), PET measurements of Aβ (e.g., via radiotracer uptake), signs of AD based on MRI assessment of brain morphology (e.g., MRI-based prediction of Aβ plaque formation), and / or behavioral measures, as discussed herein. Such assays may also be used to diagnose patients eligible for treatment (e.g., by measuring tau PET levels and determining subjects suitable for treatment because of tau PET levels higher than those observed in healthy control subjects, either alone or in combination with measuring one or more additional markers of AD pathology in the subject). In some embodiments, subjects are selected for treatment due to high tau PET levels in regions of the subject's brain, where the tau PET levels are higher than in subjects without AD. In some embodiments, subjects are selected for treatment due to low tau PET levels in the temporal region of the subject's brain. For example, the tau PET level may be less than about 1.1, e.g., less than 1.06, as measured, e.g., using the PET tracer [F]MK-6240. In some embodiments, a subject is selected for treatment due to high tau PET levels in the temporal region of the subject's brain. For example, the tau PET level may be greater than about 1.1. In some embodiments, a subject is selected for treatment due to low tau PET levels in the temporal region of the subject's brain. For example, the tau PET level may be less than about 1.1. In some embodiments, a subject is selected for treatment due to high tau PET levels in the temporal region of the subject's brain. For example, the tau PET level may be greater than about 1.1. In some embodiments, the measurement of tau PET levels may be used in place of another method of measuring brain tau levels and / or in place of another marker of Aβ. In some embodiments, the measurement of tau PET levels may be used in combination with measuring one or more additional markers.In some embodiments, patients may be monitored by one or more additional biomarkers, such as, but not limited to, (a) tau detected by PET scan, either from visual interpretation or semi-quantitative threshold reading (SUVr); (b) cerebrospinal fluid (CSF) total tau (t-tau); and / or (c) blood biomarkers, such as plasma total tau (t-tau) and / or phosphorylated tau (p-tau) (e.g., p-tau181). In some embodiments, a subject's tau PET levels may be monitored by measuring CSF MTBR-tau243 or plasma MTBR-tau243 species, alone or in combination with one or more additional biomarkers. In some embodiments, a patient's tau PET levels may be monitored in combination with one or more of the ratio of Aβ1-42 to Aβ1-40 and / or p-tau181 measurements in a body fluid sample, e.g., a blood sample. In some embodiments, the combination includes serum or plasma GFAP measurements. In some embodiments, measurements of tau PET levels may be used in place of other methods of measuring brain tau levels to determine treatment efficacy and / or make treatment decisions, such as whether to continue treatment or switch to a maintenance dose.

[0174] [000229] In some embodiments, tau PET levels change during disease progression or the course of treatment in a manner that correlates with other biomarkers. Thus, tau PET levels (e.g., low tau PET levels as measured in whole-brain measurements) may be used to select subjects for treatment, and / or the amount (e.g., level) of a biomarker may be used to select subjects. For example, a biomarker such as an amyloid PET level of <60 CL may be used to select subjects. One or more of CSF t-tau; CSF p-tau; CSF MTBR-tau243; CSF NfL; or the ratio of Aβ1-42 to Aβ1-40, NfL, p-tau181, MTBR-tau243, or GFAP in a bodily fluid sample, e.g., a blood sample such as serum or plasma, may be used to select subjects. In some embodiments, one or more of these biomarkers may serve as a surrogate for a tau PET measurement, e.g., low tau PET, to select subjects for treatment.

[0175] [000230] In some embodiments, tau PET measurements can be taken at one or more time points in a subject receiving treatment for AD and compared to a baseline tau PET measurement (e.g., a measurement from the subject before treatment) to monitor treatment effectiveness and / or determine whether changes, if any, should be made to the treatment regimen. In some embodiments, a change in tau PET levels can indicate that the treatment is effective. For example, a decrease in tau PET levels compared to baseline tau PET levels can indicate whether the treatment is effective. In some embodiments, the treatment regimen can be altered so that the treatment is administered at a maintenance dose. In some embodiments, the treatment regimen can be altered to increase the dose or frequency of administration. In some embodiments, measures of one or more biomarkers can be used to monitor treatment effectiveness and / or determine whether changes, if any, should be made to the treatment regimen. In some embodiments, the one or more biomarkers are amyloid PET, CSF t-tau; CSF p-tau; CSF MTBR-tau243; CSF NfL; or the ratio of Aβ1-42 to Aβ1-40, NfL, p-tau181, MTBR-tau243, or GFAP in a bodily fluid sample, e.g., a blood sample such as serum or plasma. For example, a change in one or more of the biomarkers compared to baseline levels can indicate whether a treatment is effective. In some embodiments, a treatment regimen can be altered so that treatment is administered at a maintenance dose. In some embodiments, a treatment regimen can be altered to increase the dose or frequency of administration. In some embodiments, tau PET levels can be used to calculate a relative change from a baseline measurement (e.g., a tau PET level measurement before initiating treatment). In some embodiments, tau PET level measurements can be repeated after initiation of a treatment regimen to monitor treatment effectiveness. In some embodiments, tau PET levels are measured before treatment and at least once after initiation of treatment, e.g., over a period of at least 6 months after the first administration of treatment. In some embodiments, tau PET levels are measured over a period of at least 12 months after the first administration of treatment.In some embodiments, the tau PET levels are measured over a period of at least 13 months after the first administration of the treatment. In some embodiments, the tau PET levels are measured over a period of at least 18 months after the first administration of the treatment. In some embodiments, the rate of change in the tau PET levels is calculated based on measurements from the subject. In some embodiments, the rate of change in the tau PET levels is calculated based on measurements from the subject, where one measurement is taken from the subject before treatment and at least a second measurement is taken after treatment. In some embodiments, the rate of change in the tau PET levels is calculated based on measurements from the subject, where one measurement is taken from the subject before treatment and at least a second measurement is taken after treatment, and the tau PET levels are measured at least 6 months after the first administration of the treatment. In some embodiments, the rate of change in the tau PET levels is calculated based on measurements from the subject, where one measurement is taken from the subject before treatment and at least a second measurement is taken after treatment, and the tau PET levels are measured at least 12 months after the first administration of the treatment. In some embodiments, the percent change in tau PET levels is calculated based on measurements from the subject, where one measurement is taken from the subject before treatment and at least a second measurement is taken after treatment, and the tau PET level is measured at least 13 months after the first administration of treatment. In some embodiments, the percent change in tau PET levels is calculated based on measurements from the subject, where one measurement is taken from the subject before treatment and at least a second measurement is taken after treatment, and the tau PET level is measured at least 18 months after the first administration of treatment. In some embodiments, a tau PET level that does not increase by more than 0.05-0.1 in a region of the brain over a 13-month period indicates therapeutic efficacy. In some embodiments, a tau PET level that does not increase by more than 0.05-0.1 in a region of the brain over an 18-month period indicates therapeutic efficacy. In some embodiments, a tau PET level that does not increase by more than 0.05-0.1 in the temporal region of the brain over a 13-month period indicates therapeutic efficacy.In some embodiments, tau PET levels that do not increase by more than 0.05-0.1 in the temporal region of the brain over an 18-month period indicate treatment efficacy.

[0176] [000231] In some embodiments, the rate of change in tau PET levels is calculated based on two measurements from the subject. In some embodiments, the rate of change in tau PET levels is calculated based on three or more measurements from the subject. In some embodiments, the rate of change in tau PET levels indicates the rate of tau accumulation in the subject's brain.

[0177] [000232] In some embodiments, the rate of change in tau PET levels is calculated based on at least two measurements from the subject, one measurement taken from the subject before treatment and a second measurement taken after initiation of treatment, wherein the treatment continues for at least 13 or 18 months after the first administration of the treatment. In some embodiments, the rate of change in tau PET levels is compared to the rate of change in tau PET levels in untreated control subjects with AD and not receiving treatment. In some embodiments, a lower rate of increase in tau PET compared to untreated control subjects indicates therapeutic efficacy. In some embodiments, a lower rate of increase in tau PET over a 6-month period compared to untreated control subjects indicates therapeutic efficacy. In some embodiments, a lower rate of increase in tau PET over a 12-month period compared to untreated control subjects indicates therapeutic efficacy. In some embodiments, a lower rate of increase in tau PET over a 13-month period compared to untreated control subjects indicates therapeutic efficacy. In some embodiments, a lower rate of increase in tau PET over an 18-month period compared to untreated control subjects indicates therapeutic efficacy.

[0178] [000233] In some embodiments, an increase in tau PET levels and / or rate of change compared to untreated control subjects with AD who have not received treatment can indicate the need to continue treatment or select an increased dosing regimen, for example, beyond the 13- or 18-month period of treatment. In some embodiments, a lower rate of change in tau PET levels (e.g., measured at 13 or 18 months) compared to untreated control subjects can be used to indicate that treatment may be terminated (e.g., terminated in favor of a maintenance regimen) and / or to otherwise determine a reduction in the dosing regimen or discontinuation of treatment. In some embodiments, an increased rate of change in tau PET values ​​compared to untreated control subjects can be used to determine whether to discontinue a maintenance dosing regimen, e.g., revert to a previous treatment regimen.

[0179] [000234] In some embodiments, a reduced rate of change in tau PET compared to untreated control subjects may indicate effective treatment. In some embodiments, a reduced rate of change in tau PET compared to untreated control subjects may be used to determine whether to switch maintenance dosing regimens. In some embodiments, a tau PET level in a brain region (e.g., temporal region) that does not increase by more than 0.05-0.1 over a 13-month period may indicate effective treatment. In some embodiments, a tau PET level in a brain region (e.g., temporal region) that does not increase by more than 0.05-0.1 over an 18-month period may indicate effective treatment. In some embodiments, a tau PET from a brain region (e.g., temporal region) that is lower than that of untreated control subjects may indicate effective treatment.

[0180] [000235] In some embodiments, the increase in tau PET levels and / or the rate of change of increased tau PET compared to untreated control subjects can be used to determine whether to discontinue a maintenance dosing regimen, e.g., whether to revert to a previous treatment regimen. In some embodiments, an increase in tau PET levels of greater than 0.05-0.1 in a brain region (e.g., temporal region) over a 13-month period can indicate ineffective treatment. In some embodiments, an increase in tau PET levels of greater than 0.05-0.1 in a brain region over an 18-month period can indicate ineffective treatment.

[0181] [000236] Methods for measuring clinical efficacy or monitoring treatment may utilize an established threshold to determine changes in brain tau levels, which may, for example, identify patients suitable for treatment with, for example, an anti-Aβ protofibril antibody, determine whether to continue treatment, switch to a maintenance dose, or conclude that the patient is amyloid-negative. In some embodiments, a tau PET level threshold may be assessed in combination with another measure of brain amyloid burden, such as an amyloid PET scan, CSF, or serum or plasma biomarker, to assist in determining whether a subject is suitable for treatment or continuation of treatment. In some embodiments, a tau PET level higher than a threshold level may be used to determine whether a patient should be treated. In some embodiments, a tau PET level of about 1 (e.g., 1.06) measured in the whole cortex indicates a patient with a low tau PET level who should be treated. In some embodiments, a tau PET level of about 1.06 to 2.91 measured throughout the cortex indicates a patient with moderate tau PET levels who should be treated. In some embodiments, a tau PET level of about 2.91 or greater measured throughout the cortex indicates a patient with high tau PET levels who should be treated. In some embodiments, a subject is selected for treatment with an anti-amyloid beta (Aβ) protofibril antibody, and the subject has a tau PET level in a brain region greater than about 1. In some embodiments, a subject is selected for treatment with an anti-amyloid beta (Aβ) protofibril antibody, and the subject has a tau PET level in a brain region between about 1.06 and 3. In some embodiments, a subject is selected for treatment with an anti-amyloid beta (Aβ) protofibril antibody, and the subject has a tau PET level in a brain region greater than about 3. In some embodiments, the brain region is the entire cortex. In some embodiments, the brain region is the temporal lobe, or a portion (e.g., a subdivision) of the temporal lobe. In some embodiments, the brain region includes the temporal lobe and additional brain compartments outside the temporal lobe.In some embodiments, the brain region is the temporal region. In some embodiments, the brain region is the meta-temporal region. In some embodiments, the brain region is the medial temporal region.

[0182] [000237] In some embodiments, methods of selecting patients for treatment and methods of treating may include selecting patients and / or administering treatment to patients with tau brain levels below a threshold, e.g., below a tau PET threshold, where the treatment may include any of the treatments disclosed herein, including, for example, an anti-Aβ protofibril antibody, e.g., BAN-2401. In some embodiments, methods of determining whether to continue treatment or switch to a maintenance dose include identifying a tau PET level, e.g., a tau level below a threshold. In some embodiments, patients with low tau PET levels may be selected for treatment. In some embodiments, patients with low tau PET levels are provided with a treatment discussed herein, e.g., an anti-Aβ protofibril antibody, e.g., BAN2401.

[0183] [E. Measurement of Aβ42 / 40 ratio] [000238] The disclosures and methods discussed herein rely in part on the discovery that tau PET levels or the rate of change in tau PET levels can be used to select patients for treatment, monitor and enable treatment decisions such as whether to increase or decrease the amount of antibody being administered, determine whether to increase or decrease the frequency of administration, determine whether to introduce additional therapeutic agents, determine whether to switch to a maintenance dose, and / or determine whether to discontinue treatment with an anti-Aβ protofibril antibody, as well as to use tau PET levels in combination with other biomarkers, such as the Aβ42 / 40 ratio. Aβ42 and Aβ40 can be measured and the ratio calculated in blood samples, as disclosed in PCT / US2022 / 073576, incorporated herein by reference. Treatments involving anti-Aβ protofibril antibodies, such as BAN2401, can result in an increase in the Aβ42 / 40 ratio, which correlates with a decrease in cerebral amyloid burden and improved cognitive outcomes in subjects.

[0184] [000239] In some embodiments, treatment with an anti-Aβ protofibril antibody, such as BAN2401, can result in an increase in the Aβ42 / 40 ratio, which correlates with a reduction in cerebral amyloid burden and improved cognitive outcomes in subjects with low tau PET levels in whole-brain measurements. In some embodiments, the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio as measured by an adjusted mean change from baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.009. In some embodiments, the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or greater. In some embodiments, measures of the Aβ42 / 40 ratio in treated subjects are compared to baseline measures obtained from the same subjects before treatment or to a reference control. In some embodiments, the change in the Aβ42 / 40 ratio occurs between the time the Aβ42 / 40 ratio is first measured (e.g., a baseline measurement) and one or more subsequent time points at which the Aβ42 / 40 ratio is measured again. In some embodiments, the subsequent time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measurement. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a treatment-naïve subject or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measurement, such as a mean measurement that combines population data from two or more subjects, and is representative of treatment-naïve subjects.

[0185] [000240] Methods for measuring the Aβ42 / 40 ratio are known in the art, such as assays using LC MS / MS. Methods can include the PrecivityAD™ assay (see, e.g., Kirmess et al., J. Clinica Chimica Acta 519:267-275 (2021)) to measure Aβ42 and Aβ40 in a sample for use in calculating the ratio.

[0186] [000241] Measurements of the Aβ42 / 40 ratio may be used alone to assess treatment efficacy or may be combined with one or more additional criteria, such as tau PET levels, updated PET measurements of Aβ radiotracers, MRI assessment of Aβ plaques, and / or behavioral measures, as discussed herein. Such assays may also be used to diagnose patients eligible for treatment (e.g., by measuring the Aβ42 / 40 ratio and determining subjects suitable for treatment because of a ratio lower than that observed in healthy control subjects, either alone or in combination with measuring one or more additional markers of AD pathology in the subject). In some embodiments, measurements of the Aβ42 / 40 ratio may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine subjects suitable for treatment. In some embodiments, measurements of the Aβ42 / 40 ratio may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine treatment efficacy and / or make treatment decisions, such as whether to continue treatment or switch to a maintenance dose.

[0187] [000242] In some embodiments, the Aβ42 / 40 ratio measurement may utilize a relative change from a baseline measurement. In some embodiments, the Aβ42 / 40 ratio measurement may utilize a set threshold to determine a change in brain amyloid levels, and may, for example, identify patients suitable for treatment with, for example, an anti-Aβ protofibril antibody, determine whether to continue treatment, switch to a maintenance dose, or conclude that the patient is amyloid-negative. In some embodiments, the threshold may be assessed in combination with another measure of brain amyloid burden, such as a PET scan, to assist in determining whether a subject is suitable for treatment or continuation of treatment. In some embodiments, the Aβ42 / 40 ratio threshold may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine amyloid positivity. In some embodiments, the Aβ42 / 40 ratio threshold is 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.099, 0.1 or about 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.099, 0.1. In some embodiments, the threshold is about 0.092. In some embodiments, the threshold is 0.092. In some embodiments, the threshold is about 0.094. In some embodiments, a decrease in the Aβ42 / 40 ratio below the threshold may indicate the need to continue treatment or select an increase in the dosing regimen. In some embodiments, an increase in the Aβ42 / 40 ratio above a threshold can be used to indicate that treatment may be terminated (e.g., terminated in favor of a maintenance regimen) and / or to otherwise determine a reduction in the dosing regimen or discontinuation of treatment. In some embodiments, a decrease in the Aβ42 / 40 ratio below a threshold can be used to determine whether to discontinue the maintenance dosing regimen, e.g., revert to a previous treatment regimen.

[0188] [000243] In some embodiments, tau PET levels or the rate of change in tau PET levels and additional biomarkers, e.g., the level of the Aβ42 / 40 ratio, may be used to select patients for treatment to enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce an additional therapeutic agent, whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, tau PET levels, e.g., an Aβ42 / 40 ratio, e.g., a tau PET level greater than 1.4 as measured by amyloid PET SUVr in the temporal region of the brain in combination with an Aβ42 / 40 ratio greater than 0.092, may be used to select patients for treatment. In some embodiments, tau PET levels, e.g., tau PET levels greater than 1.5 as measured by amyloid PET SUVr in the temporal region of the brain in combination with an Aβ42 / 40 ratio, e.g., an Aβ42 / 40 ratio of 0.092 or greater, may be used to select patients for treatment. Thresholds for determining amyloid positivity by Aβ42 / 40 ratio are disclosed in PCT / US2022 / 073576, incorporated herein by reference. In some embodiments, tau PET levels that did not increase by more than 0.05-0.1 over a 13-month or 18-month period in a region of the brain (e.g., the temporal region) in combination with an Aβ42 / 40 ratio, e.g., an Aβ42 / 40 ratio of 0.092 or greater, may indicate effective treatment. In some embodiments, tau PET levels that increase at a lower rate than untreated control subjects in a region of the brain (e.g., the temporal region) over a 13-month or 18-month period, combined with an Aβ42 / 40 ratio, e.g., an Aβ42 / 40 ratio of 0.092 or greater, may indicate effective treatment. In some embodiments, tau PET levels from a region of the brain (e.g., the temporal region) that are lower than untreated control subjects, combined with an Aβ42 / 40 ratio, e.g., an Aβ42 / 40 ratio of 0.092 or greater, may indicate effective treatment.In some embodiments, indicators of therapeutic efficacy may be used to reduce the amount of antibody being administered, reduce the frequency of administration, or switch to a maintenance dose. In some embodiments, tau PET levels increasing by more than 0.05-0.1 in a brain region (e.g., temporal region) over a 13-month or 18-month period, combined with an Aβ42 / 40 ratio, e.g., an Aβ42 / 40 ratio of 0.092 or less, may indicate ineffective treatment. In some embodiments, tau PET levels increasing at a rate greater than untreated control subjects over a 13-month or 18-month period, combined with an Aβ42 / 40 ratio, e.g., an Aβ42 / 40 ratio of 0.092 or less, may indicate ineffective treatment. In some embodiments, tau PET from a region of the brain (e.g., the temporal region) higher than untreated control subjects, combined with an Aβ42 / 40 ratio, for example, of 0.092 or less, may indicate ineffective treatment. In some embodiments, indicators of treatment efficacy may be used to increase the amount of antibody being administered, increase the frequency of administration, or discontinue treatment.

[0189] [Measurement of Fp-tau levels] [000244] The disclosures and methods discussed herein rely in part on the discovery that tau PET levels or the rate of change of tau PET levels can be used to select patients for treatment, to enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, to determine whether to increase or decrease the frequency of administration, to determine whether to introduce additional therapeutic agents, to determine whether to switch to a maintenance dose, and / or to determine whether to discontinue treatment with an anti-Aβ protofibril antibody, as well as to use tau PET levels in combination with other biomarkers, such as phosphorylated tau (p-tau) levels, including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and / or tau phosphorylated at 231 (P-tau231). p-tau levels can be measured in CSF, serum, or plasma, as disclosed in PCT / US2022 / 079571, which is incorporated herein by reference. Treatments including anti-Aβ protofibril antibodies, such as BAN2401, can result in reduced p-tau181 levels in subjects, which correlates with reduced cerebral amyloid burden and improved cognitive outcomes.

[0190] [000245] In some embodiments, treatment with an anti-Aβ protofibril antibody, such as BAN2401, can result in a reduction in p-tau181 levels in subjects with low tau PET levels in whole-brain measurements compared to controls, e.g., subjects receiving a therapeutically effective dose of an anti-Aβ protofibril antibody. In some embodiments, p-tau181 measurements in treated subjects are compared to baseline measurements obtained from the same subjects before treatment or to a reference control. In some embodiments, the Aβ protofibril antibody reduces plasma p-tau181 by at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml, as measured by an adjusted mean change from baseline p-tau181 levels. In some embodiments, the reduction in p-tau181 occurs between the time the marker is first measured (e.g., baseline measurements) and one or more subsequent time points at which p-tau181 is measured again. In some embodiments, the later time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measure. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject not receiving treatment, or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measurement, such as a mean measurement that combines population data from two or more subjects, and is representative of subjects not receiving treatment.

[0191] [000246] Methods for measuring p-tau ratios are known in the art, such as immunoassay (e.g., Quanterix™ Simoa® p-tau assay) and / or mass spectrometry (IP / LC-MS / MS)-based techniques. Plasma p-tau181 is elevated in early stages of AD as determined by the Braak staging system (I-II) and continues to increase as the disease progresses to Braak stages V-VI (Janelidze et al., "Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology, and longitudinal progression to Alzheimer's dementia," Nat. Med., 26(3):379-386 (2020)). This biomarker is highly correlated with amyloid PET and tau PET, showing a 3.5-fold increase in AD compared to controls, a moderate increase in MCI, and appears to distinguish patients with clinically diagnosed AD from those with other tauopathies (Thijssen et al., “Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration,” Nat. Med., 26(3):387-397 (2020); Janelidze et al.).

[0192] [000247] Measurements of p-tau levels (e.g., p-tau 181 levels, p-tau 217 levels, and / or p-tau 231 levels) may be used alone to assess treatment efficacy or in combination with one or more additional criteria, such as tau PET levels, updated PET measurements of Aβ radiotracers, MRI assessment of Aβ plaques, and / or behavioral measures as discussed herein. Such assays may also be used to diagnose patients eligible for treatment (e.g., by measuring p-tau levels (e.g., p-tau 181 levels, p-tau 217 levels, and / or p-tau 231 levels) and determining subjects suitable for treatment due to tau levels higher than those observed in healthy control subjects, either alone or in combination with measuring one or more additional markers of AD pathology in the subjects). In some embodiments, measurements of p-tau levels (e.g., p-tau 181 levels, p-tau 217 levels, and / or p-tau 231 levels) may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine subjects suitable for treatment. In some embodiments, measurements of p-tau levels (e.g., p-tau 181 levels, p-tau 217 levels, and / or p-tau 231 levels) may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine treatment efficacy and / or make treatment decisions, such as whether to continue treatment or switch to a maintenance dose.

[0193] [000248] In some embodiments, plasma or serum p-tau181 level measurements may utilize relative changes from baseline measurements. In some embodiments, changes in p-tau181 levels may be used to assess treatment efficacy. In some embodiments, a decrease in p-tau181 levels indicates treatment efficacy, e.g., a decrease in brain amyloid levels. In some embodiments, p-tau181 level measurements may utilize an established threshold to determine changes in brain amyloid levels, e.g., to identify and / or select patients suitable for treatment with an anti-Aβ protofibril antibody, determine whether to continue treatment, switch to a maintenance dose, or conclude that the patient is amyloid-negative. In some embodiments, the threshold may be assessed in combination with another measure of brain amyloid burden, such as a PET scan, to assist in determining whether a subject is suitable for treatment or continuation of treatment. In some embodiments, a p-tau181 level threshold may be used in place of another method of measuring brain amyloid levels, such as a PET scan. In some embodiments, a p-tau 181 level threshold of about 2.2-2.3 pg / mL or greater is used to identify and / or select patients suitable for treatment with, for example, an anti-Aβ protofibril antibody. In some embodiments, a p-tau 181 level threshold of about 2.2 pg / mL or greater is used to identify and / or select patients suitable for treatment with, for example, an anti-Aβ protofibril antibody. In some embodiments, a p-tau 181 level threshold of about 2.3 pg / mL or greater is used to identify and / or select patients suitable for treatment with, for example, an anti-Aβ protofibril antibody. In certain such embodiments, p-tau 181 levels are measured using the Quanterix™ Simoa® p-tau assay. In some embodiments, the threshold is about 2.3 pg / mL. In some embodiments, the threshold is about 2.2 pg / mL. In some embodiments, an increase in p-tau181 levels above a threshold may indicate the need to continue treatment or select an increase in the dosing regimen.In some embodiments, a decrease in p-tau181 levels above a threshold may be used to indicate that treatment may be terminated (e.g., terminated in favor of a maintenance regimen) and / or to otherwise determine a reduction in the dosing regimen or discontinuation of treatment. In some embodiments, an increase in tau PET levels compared to a control subject may be used to determine whether to discontinue a maintenance dosing regimen, e.g., revert to a previous treatment regimen.

[0194] [000249] In some embodiments, tau PET levels or the rate of change in tau PET levels and levels of additional biomarkers, e.g., plasma p-tau 181 levels, may be used to select patients for treatment to enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce an additional therapeutic agent, whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, tau PET levels, e.g., plasma p-tau 181 levels, e.g., tau PET levels greater than 1.4 as measured by amyloid PET SUVr in the temporal region of the brain in combination with plasma p-tau 181 levels greater than 2.2 pg / mL, may be used to select patients for treatment. In some embodiments, tau PET levels, e.g., Aβ42 / 40 ratios, e.g., tau PET levels greater than 1.5 as measured by amyloid PET SUVr in the temporal region of the brain in combination with plasma p-tau 181 greater than 2.2 pg / mL, may be used to select patients for treatment. Thresholds for determining amyloid positivity via p-tau 181 are disclosed in PCT / US2022 / 079571, incorporated herein by reference. In some embodiments, p-tau 181 levels, e.g., tau PET levels that did not increase by more than 0.05-0.1 over a 13- or 18-month period in a region of the brain (e.g., the temporal region) in combination with p-tau 181 levels below a threshold, may indicate effective treatment. In some embodiments, tau PET levels that increased at a rate lower than untreated control subjects over a 13- or 18-month period in a region of the brain (e.g., the temporal region) in combination with p-tau 181 levels below a threshold may indicate effective treatment. In some embodiments, tau PET from certain regions of the brain (eg, temporal regions) that are lower than untreated control subjects, combined with subthreshold p-tau181 levels, may indicate effective treatment.In some embodiments, indicators of therapeutic efficacy may be used to decrease the amount of antibody being administered, reduce the frequency of administration, or switch to a maintenance dose. In some embodiments, a tau PET level that increases by more than 0.05-0.1 in a brain region (e.g., temporal region) over a 13-month or 18-month period, combined with a p-tau 181 level at or above a threshold (e.g., a threshold of 2.2 pg / mL), may indicate ineffective treatment. In some embodiments, a tau PET level that increases at a rate higher than untreated control subjects in a brain region (e.g., temporal region) over a 13-month or 18-month period, combined with a p-tau 181 level at or above a threshold (e.g., a threshold of 2.2 pg / mL), may indicate ineffective treatment. In some embodiments, a tau PET from a brain region (e.g., temporal region) higher than untreated control subjects, combined with a p-tau 181 level at or above a threshold (e.g., a threshold of 2.2 pg / mL), may indicate ineffective treatment. In some embodiments, an indicator of the effectiveness of treatment may be used to increase the amount of antibody being administered, increase the frequency of administration, or discontinue treatment.

[0195] [G. Additional Biomarker Changes] 1. Plasma or serum levels of GFAP [000250] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in glial fibrillary acidic protein (GFAP) in the subject's plasma or serum. Without being bound by theory, GFAP levels can be used as a marker of astrocyte activation. GFAP levels can be measured by techniques known in the art, such as immunoassays (e.g., Quanterix™ Simoa® assays) and / or mass spectrometry (IP / LC-MS / MS)-based techniques. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in plasma or serum levels of GFAP in the subject. In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in plasma or serum levels of GFAP of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% compared to baseline.

[0196] [000251] In some embodiments, treatment with an anti-Aβ protofibril antibody, such as BAN2401, can result in a decrease in GFAP plasma or serum levels in subjects with low tau PET levels in whole-brain measurements compared to controls, e.g., subjects receiving a therapeutically effective dose of an anti-Aβ protofibril antibody. In some embodiments, the decrease in GFAP plasma or serum levels occurs between the time the GFAP plasma or serum levels are first measured (e.g., a baseline measurement) and one or more subsequent time points at which the GFAP plasma or serum levels are measured again. In some embodiments, the subsequent time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measurement. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a treatment-naive subject or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measurement, such as an average measurement combining population data from two or more subjects, representative of subjects not receiving treatment. In some embodiments, the Aβ protofibril antibody reduces plasma GFAP by at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml, as measured by an adjusted mean change from baseline GFAP levels.

[0197] [000252] In some embodiments, tau PET levels and plasma or serum GFAP levels may be used to select patients for treatment and enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, tau PET levels that did not increase by more than 0.05-0.1 in a region of the brain (e.g., the temporal region) over a 13- or 18-month period, combined with GFAP levels that decreased over the same period, may indicate effective treatment. In some embodiments, tau PET levels that increased at a rate lower than untreated control subjects over a 13- or 18-month period, combined with GFAP levels that decreased over the same period, may indicate effective treatment. In some embodiments, lower tau PET from certain regions of the brain (e.g., temporal regions) than untreated control subjects, combined with reduced GFAP levels compared to untreated controls, may indicate effective treatment. In some embodiments, indicators of therapeutic effectiveness may be used to reduce the amount of antibody being administered, reduce the frequency of administration, or switch to a maintenance dose.

[0198] [Cerebrospinal fluid levels of neurogranin] In some embodiments, administering to a subject a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in cerebrospinal fluid levels of neurogranin in the subject. In some embodiments, administering to a subject a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in cerebrospinal fluid levels of neurogranin by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% compared to baseline.

[0199] [000254] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject with low tau PET levels results in a decrease in cerebrospinal fluid levels of neurogranin in the subject compared to a control, e.g., a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody. In some embodiments, the measure of neurogranin in the treated subject is compared to a baseline measure obtained from the same subject before treatment or to a reference control. In some embodiments, the decrease in p-tau181 occurs between the time the marker is first measured (e.g., the baseline measure) and one or more subsequent time points at which p-tau181 is measured again. In some embodiments, the subsequent time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measure. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject not receiving treatment or a subject receiving a placebo. In some embodiments, the control is a subject who does not receive lecanemab. In some embodiments, the control is a reference measurement, such as a mean measurement that combines population data from two or more subjects, and is representative of subjects who have not received treatment.

[0200] In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in cerebrospinal fluid levels of neurogranin after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% in cerebrospinal fluid levels of neurogranin after 18 months of administration of the composition compared to baseline.

[0201] [000256] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in cerebrospinal fluid levels of neurogranin of at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL compared to baseline. In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in cerebrospinal fluid levels of neurogranin of at least about 65 pg / mL compared to baseline.

[0202] In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in cerebrospinal fluid levels of neurogranin by at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL compared to baseline after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in cerebrospinal fluid levels of neurogranin by at least 65 pg / mL compared to baseline after 18 months of administration of the composition.

[0203] [000258] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0204] [000259] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered biweekly or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered biweekly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0205] [000260] In some embodiments, tau PET levels and cerebrospinal fluid (CSF) levels of neurogranin may be used to select patients for treatment and enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, tau PET levels that did not increase by more than 0.05-0.1 in a region of the brain (e.g., the temporal region) over a 13- or 18-month period, combined with cerebrospinal fluid (CSF) levels of neurogranin that decreased over the same period, may indicate effective treatment. In some embodiments, tau PET levels that increased at a rate lower than untreated control subjects over a 13- or 18-month period, combined with cerebrospinal fluid (CSF) levels of neurogranin that decreased over the same period, may indicate effective treatment. In some embodiments, tau PET from a region of the brain (e.g., the temporal region) lower than in untreated control subjects, combined with reduced cerebrospinal fluid levels of neurogranin compared to untreated controls, may indicate effective treatment. In some embodiments, indicators of therapeutic effectiveness may be used to reduce the amount of antibody being administered, reduce the frequency of administration, or switch to a maintenance dose.

[0206] 2. Neurofilament Light Chain Levels [000261] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chain compared to placebo. In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chain by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% compared to placebo.

[0207] [000262] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject with low tau PET levels results in a decrease in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chain compared to placebo. In some embodiments, administration of an anti-Aβ protofibril antibody results in a smaller increase in plasma neurofilament light chain over time compared to placebo. In some embodiments, measures of neurofilament light chain in a treated subject are compared to baseline measures obtained from the same subject before treatment or to a reference control. In some embodiments, the change in neurofilament light chain occurs between the time the marker is first measured (e.g., baseline measures) and one or more subsequent time points at which the marker is measured again. In some embodiments, the subsequent time points are at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measures. In some embodiments, the control is a subject not receiving a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject not receiving treatment, or a subject receiving a placebo. In some embodiments, the control is a subject not receiving lecanemab. In some embodiments, the control is a reference measurement, such as a measurement that combines population data from two or more subjects, and is representative of subjects not receiving treatment.

[0208] [000263] In some embodiments, administering to a subject a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chain after 18 months of administration of the composition, compared to placebo. In some embodiments, administering to a subject a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chain after 18 months of administration of the composition, compared to baseline, of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% relative to placebo.

[0209] [000264] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in an increase in cerebrospinal fluid levels of neurofilament light chains of greater than about 35 pg / mL, greater than about 40 pg / mL, greater than about 45 pg / mL, greater than about 50 pg / mL, greater than about 55 pg / mL, greater than about 60 pg / mL, greater than about 65 pg / mL, greater than about 70 pg / mL, or greater than about 75 pg / mL compared to baseline. In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in an increase in cerebrospinal fluid levels of neurofilament light chains of less than about 75 pg / mL compared to baseline.

[0210] [000265] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in an increase in cerebrospinal fluid levels of neurofilament light chains of greater than about 35 pg / mL, greater than about 40 pg / mL, greater than about 45 pg / mL, greater than about 50 pg / mL, greater than about 55 pg / mL, greater than about 60 pg / mL, greater than about 65 pg / mL, greater than about 70 pg / mL, or greater than about 75 pg / mL after 18 months of administration of the composition compared to baseline. In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in an increase in cerebrospinal fluid levels of neurofilament light chains of less than about 75 pg / mL after 18 months of administration of the composition compared to baseline.

[0211] [000266] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0212] [000267] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is 10 mg / kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered biweekly or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered biweekly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0213] [000268] In some embodiments, tau PET levels and plasma or serum levels of neurofilament light chain may be used to select patients for treatment and to enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, tau PET levels that did not increase by more than 0.05-0.1 in a region of the brain (e.g., the temporal region) over a 13- or 18-month period, combined with plasma or serum levels of neurofilament light chain that are decreasing over the same period, may indicate effective treatment. In some embodiments, tau PET levels that increased at a rate lower than untreated control subjects over a 13- or 18-month period, combined with plasma or serum levels of neurofilament light chain that are decreasing over the same period, may indicate effective treatment. In some embodiments, tau PET from a region of the brain (e.g., the temporal region) lower than in untreated control subjects, combined with reduced plasma or serum levels of neurofilament light chains compared to untreated controls, may indicate effective treatment. In some embodiments, indicators of therapeutic effectiveness may be used to reduce the amount of antibody being administered, reduce the frequency of administration, or switch to a maintenance dose.

[0214] 3. Cerebrospinal fluid levels of phospho-tau [000269] In some embodiments, administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a decrease in cerebrospinal fluid levels of phospho-tau (CSF p-tau) in the subject, e.g., compared to a control. In some embodiments, the decrease in CSF p-tau occurs between the time CSF p-tau is first measured (e.g., a baseline measurement) and one or more later time points at which CSF p-tau is again measured. In some embodiments, the later time point is at least 6 months, 12 months, 18 months, 21 months, or 24 months after the baseline measurement. In some embodiments, the control is a subject who does not receive a therapeutically effective dose of an Aβ protofibril antibody, e.g., a treatment-naïve subject or a subject who receives a placebo. In some embodiments, the control is a subject who does not receive lecanemab. In some embodiments, the control is a reference measurement, such as a measurement that combines population data from two or more subjects, and is representative of treatment-naïve subjects.

[0215] [000270] In some embodiments, administering to a subject a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in cerebrospinal fluid levels of phospho-tau (p-tau). In some embodiments, administering to a subject a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein results in a decrease in cerebrospinal fluid levels of phospho-tau by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline.

[0216] [000271] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject with low tau PET levels results in a decrease in cerebrospinal fluid levels of phospho-tau (p-tau). In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject with low tau PET levels results in a decrease in cerebrospinal fluid levels of phospho-tau by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline. In some embodiments, measures of CSF p-tau in treated subjects are compared to baseline measures obtained from the same subjects before treatment or to a reference control. In some embodiments, the reference control is an untreated control subject (e.g., a subject who received a placebo). In some embodiments, the reference control is a measurement obtained from a population of control subjects.

[0217] [000272] In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid levels of phospho-tau after 18 months of administration of the composition. In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in at least a 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% reduction in cerebrospinal fluid levels of phospho-tau after 18 months of administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody compared to baseline.

[0218] [000273] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid levels of phospho-tau of at least about 65 pg / mL, at least about 70 pg / mL, at least about 75 pg / mL, at least about 80 pg / mL, at least about 85 pg / mL, at least about 90 pg / mL, or at least about 95 pg / mL compared to baseline. In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid levels of phospho-tau of at least about 95 pg / mL compared to baseline.

[0219] [000274] In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid levels of phospho-tau of at least about 65 pg / mL, at least about 70 pg / mL, at least about 75 pg / mL, at least about 80 pg / mL, at least about 85 pg / mL, at least about 90 pg / mL, or at least about 95 pg / mL compared to baseline after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid levels of phospho-tau of at least 95 pg / mL compared to baseline after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0220] [000275] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0221] [000276] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered biweekly or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered biweekly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0222] [000277] In some embodiments, tau PET levels and cerebrospinal fluid (CSF) levels of phospho-tau may be used to select patients for treatment and to enable monitoring and treatment decisions such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, tau PET levels that did not increase by more than 0.05-0.1 in a region of the brain (e.g., the temporal region) over a 13- or 18-month period, combined with CSF levels of phospho-tau that are decreasing over the same period, may indicate effective treatment. In some embodiments, tau PET levels that increased at a rate lower than untreated control subjects over a 13- or 18-month period, combined with CSF levels of phospho-tau that are decreasing over the same period, may indicate effective treatment. In some embodiments, tau PET from a region of the brain (e.g., the temporal region) lower than in untreated control subjects, combined with reduced cerebrospinal fluid levels of phospho-tau compared to untreated controls, may indicate effective treatment. In some embodiments, indicators of therapeutic effectiveness may be used to reduce the amount of antibody being administered, reduce the frequency of administration, or switch to a maintenance dose.

[0223] [H. Brain Volume and Brain Areas] [000278] In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in an improvement in global hippocampal atrophy as measured by volumetric MRI (vMRI) compared to placebo. In some embodiments, the subject's brain volume (e.g., total ventricular volume, left and / or right ventricular volume, total brain volume, right and / or left hippocampal volume, cortical thickness) is measured before treatment. In some embodiments, the subject's brain volume (e.g., total ventricular volume, left and / or right ventricular volume, total brain volume, right and / or left hippocampal volume, cortical thickness) is measured 6, 12, and / or 18 months after treatment. In some embodiments, administering a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject results in an improvement in brain volume atrophy as measured by vMRI compared to placebo.

[0224] [000279] In some embodiments, brain regions affected by Alzheimer's disease may include the transitional entorhinal region, limbic regions (e.g., hippocampus), and neocortical regions of the brain. Brain regions may correspond to the Braak staging system, criteria based on the anatomical localization of tau neurofibrillary tangles or phospho-tau, or PET-based Braak staging system, as described, for example, by Therriault et al., Nature Aging volume 2, pages 526-535 (2022). Thus, Braak regions may refer to areas typically affected by tau aggregation at Braak stages. For example, early Braak regions may refer to the entorhinal cortex and / or hippocampus.

[0225] [000280] Generally, early Braak stages can be characterized as follows: Braak stage I can be characterized by tau aggregation in the entorhinal cortex; Braak stage II can be characterized by tau aggregation in the hippocampus; and Braak stage III can be characterized by tau aggregation in the amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus. Late Braak stages, e.g., Braak stages IV and V, can be characterized by tau aggregation in the association cortex; and Braak stage VI can be characterized by tau aggregation in the primary sensory cortex. In some embodiments, tau PET staging uses these Braak classifications: Braak I (entorhinal cortex); Braak II (hippocampus); and Braak III (amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus).

[0226] [000281] In some embodiments, alternative tau-PET staging according to Therriault et al., Nature Aging volume 2, pages 526-535 (2022) may be used to classify disease stages and brain regions as follows: Braak stage I (transient entorhinal), Braak stage II (entorhinal and hippocampal), Braak stage III (amygdala, parahippocampal, fusiform and lingual gyrus), Braak stage IV (insula, inferior temporal, lateral temporal, posterior cingulate and inferior parietal), Braak stage V (orbitofrontal, superior temporal, inferior frontal, cuneus, anterior cingulate, supramarginal, lateral occipital, precuneus, superior parietal, superior frontal and rostromedial), and Braak stage VI (paracentral, postcentral, precentral and pericalvarial).

[0227] [000282] In Braak staging (e.g., tau PET Braak staging), stage and structural classification may vary slightly between methods due to natural patient-to-patient variability and / or staging method variability (e.g., different tau PET tracers and analytical methods). Tau Braak staging results may differ from staging determined during autopsy.

[0228] [000283] In some embodiments, tau aggregation, as measured by tau-PET and staged according to the tau-PET-based Braak staging system, can be associated with other indicators of AD disease progression, e.g., the expression of AD biomarkers such as CSF p-tau, CSF Aβ, and / or amyloid PET, the presence of neurodegeneration, and impaired cognitive function. In some embodiments, tau aggregation in early Braak regions (e.g., stage I, II, or III regions), with or without cognitive impairment, can be detected even in the absence of other AD biomarkers or evidence of neurodegeneration. Thus, tau-PET observed only in early Braak regions, such as the medial temporal region of the brain, can provide an early indicator of tau aggregation even in subjects with few or no other signs or symptoms of AD. In some embodiments, disease progression can be monitored by measuring tau-PET levels as they appear in Braak regions over time, starting with subjects who may exhibit tau-PET in early Braak regions but who have few or no other signs or symptoms of AD. In some embodiments, such subjects may be selected for AD treatment with, for example, at least one anti-Aβ protofibril antibody disclosed herein.

[0229] [000284] In some embodiments, subjects with tau-PET in early Braak zones (e.g., Stage I, II, or III zones) may be treated according to the methods disclosed herein. In some embodiments, the subject is amyloid-negative and / or at risk for amyloid accumulation. In some embodiments, subjects with tau-PET in early Braak zones (e.g., Stage I, II, or III zones) and detectable amyloid PET at moderate levels (e.g., 20-40 centiloids) or high levels (>40 centiloids) may be selected for AD treatment.

[0230] [000285] In some embodiments, the subject may have low levels of tau in a whole brain measurement, preferably as measured by tau PET. In some embodiments, the whole brain measurement is a measurement of tau PET in the entire cortical gray matter (e.g., a measure of cortical tau aggregation). In some embodiments, the low level of tau is a subthreshold tau PET level in the whole brain measurement (e.g., a tau-PET normalized uptake value ratio (SUVR)). In some embodiments, the whole brain measurement is a measurement of tau PET in the entire cortical gray matter (e.g., a measure of cortical tau aggregation). In some embodiments, the tau PET level is measured using the MK6240 radiotracer. In some embodiments, the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, as measured, for example, by an MK6240 PET scan of the entire cortical gray matter.

[0231] [000286] In some embodiments, the subject has low levels of tau in whole-brain measurements (e.g., throughout the cortical gray matter) and higher levels of tau in a local brain region. In some embodiments, the local brain region is an early Braak region (e.g., Braak region I, II, or III). In some embodiments, the early Braak region includes the transitional entorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, the local brain region is a composite of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, the medial temporal region, and / or the meta-temporal region. In some embodiments, the local brain region is the medial temporal region (e.g., the entorhinal cortex).

[0232] [000287] In some embodiments, the whole brain measure is a measure of tau aggregation throughout the cortical gray matter, e.g., "cortical tau aggregation." In some embodiments, the whole brain measure is a measure of tau aggregation in a selection of cortical regions (e.g., about 5-6 cortical regions, or cortical and subcortical regions).

[0233] [000288] In some embodiments, a subject may have low levels of cortical tau aggregation as measured by low tau-PET levels (e.g., SUVr<1.06 in the whole cortical gray matter on an MK6240 PET scan), but higher levels of tau aggregation in localized regions. For example, a subject classified as having low tau-PET according to measurements in the whole cortical gray matter may have tau aggregation in Braak regions I, II, and III. The subject may not have tau aggregation in Braak regions IV, V, and VI.

[0234] [000289] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject with low levels of cortical tau aggregation as defined by low tau-PET levels (e.g., SUVr<1.06 throughout the cortical gray matter in an MK6240 PET scan) results in an improvement in the progression of tau pathology in the brain compared to placebo. For example, the improvement can be a delayed increase, stabilized levels, or decrease in tau-PET in early Braak regions (e.g., the temporal lobe), such as the medial temporal, metatemporal, and temporal regions. The improvement can also be a delayed increase, stabilized levels, or decrease in tau-PET in the medial temporal region, which is often the earliest region where tau aggregation can be observed. In contrast, for subjects with tau levels defined as moderate and / or high (e.g., moderate levels are SUVr between 1.06 and 2.91, and high levels are SUVr above 2.91, as determined in whole cortical gray matter with an MK6240 PET scan), improvement may be a delayed increase, stabilized levels, or decrease in tau-PET across more brain regions, consistent with a higher degree of tau aggregation in these subjects.

[0235] [000290] In some embodiments, administration of a therapeutically effective amount of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein to a subject with low levels of cortical tau aggregation as determined by low tau-PET levels (e.g., SUVr<1.06 in total cortical gray matter on an MK6240 PET scan) results in an improvement in at least one measure of cognitive function, e.g., a slower decline in cognitive function, a stabilized level of cognitive function, or an improvement in cognitive function, compared to placebo. In some embodiments, cognitive function can be measured by CDR-SB, ADAS-Cogl4, or ADCS MCI-ADL. In some embodiments, the measure of "no decline" or the measure of "improvement" can be higher in subjects with low tau-PET levels than in patients with moderate or higher tau-PET levels.

[0236] [000291] For example, a patient treated according to any of the methods disclosed herein may have low tau-PET levels observed in early Braak regions (e.g., SUVr<1.06 in whole cortical gray matter on an MK6240 PET scan), but low levels of cortical tau aggregation as determined by higher levels of tau-PET. Such patients may also have lower levels of CSF p-tau and CSF Aβ, less neurodegeneration, and higher cognitive function than patients with moderate or moderate+high cortical tau aggregation levels, as measured by whole cortical gray matter tau PET. In some embodiments, a patient may have tau-PET indicative of early tau aggregation (e.g., Braak stage I, II, or III), but may not have other AD biomarkers and / or may not have cognitive impairment.

[0237] [I. Anti-Aβ protofibril antibody] [000292] In some embodiments, any anti-Aβ protofibril antibody can be used in the methods disclosed herein. In some embodiments, the antibody comprises one or more of the sequences listed in Tables 1-4, including, for example, the complete set of six complementarity-determining regions (CDRs) and / or the complete set of variable regions and / or the complete set of heavy and light chain sequences. In some embodiments, the anti-Aβ protofibril antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) 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 the 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-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-Aβ protofibril antibody comprises human heavy and light chain variable region frameworks. In some embodiments, the anti-Aβ protofibril antibody comprises a human IgG1 heavy chain constant region and a human Ig kappa light chain constant region. In some embodiments, the anti-Aβ protofibril antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. As used herein in the context of an antibody sequence or structure, "CDR" refers to a complementarity-determining region that provides the primary determinant of antigen binding. Generally, an antigen-binding site has six CDRs: three VH (HCDR1, HCDR2, HCDR3) and three VL (LCDR1, LCDR2, LCDR3). CDRs may be determined according to the Kabat numbering scheme. This can be determined 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, hereinafter referred to as the "Kabat Report").

[0238] [000293] In some embodiments, at least one anti-Aβ protofibril antibody comprises a human constant region. In some embodiments, the human constant region of at least one anti-Aβ protofibril antibody comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variants 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 selected from IgG1 and allelic variants thereof. The amino acid sequence of a human IgG1 constant region is known in the art and is set forth in SEQ ID NO: 11.

[0239] [000294] In some embodiments, the human constant region of at least one anti-Aβ protofibril antibody comprises a light chain constant region selected from the κ-λ-chain constant regions and any allelic variants 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 light chain constant region is selected from κ and its allelic variants. The amino acid sequence of the human κ chain constant region is known in the art and is set forth in SEQ ID NO: 12.

[0240] [000295] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401, also known as lecanemab. The terms "BAN2401" and "lecanemab" are used interchangeably and refer to a humanized IgG1 monoclonal version of mAb158, a murine monoclonal antibody produced to target protofibrils, and disclosed in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3), as described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 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. The full-length sequences of the heavy and light chains of BAN2401 are set forth in SEQ ID NOs: 9 and 10, and are described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015).

[0241] [000296] In some embodiments, the isolated anti-Aβ protofibril antibody to be used in the treatment is present at a concentration of at least 80 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 100 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 200 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration ranging from 80 mg / mL to 300 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 85 mg / mL to 275 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 90 mg / mL to 250 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 95 mg / mL to 225 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 100 mg / mL to 200 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at 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 isolated antibody or fragment thereof is present at a concentration of 100 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 200 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 300 mg / mL. In some embodiments, the isolated antibody or fragment thereof is BAN2401.

[0242] [000297] As used herein, a "fragment" of an antibody includes, for example, a portion of an antibody comprising the antigen-binding or variable region thereof. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and single-chain antibody molecules.

[0243] [000298] In some embodiments, anti-Aβ protofibril antibodies (e.g., BAN2401, or fragments thereof) reduce cerebral amyloid angiopathy (CAA), which is the deposition of amyloid beta peptide in the walls of small to medium-sized blood vessels in the central nervous system and meninges.

[0244] J. A therapeutically effective amount of at least one anti-Aβ protofibril antibody [000299] In various embodiments, the methods of the present disclosure include administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. As used herein, the term "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition sufficient to produce a desired therapeutic effect.

[0245] [000300] Those skilled in the art will understand that the therapeutically effective amount of at least one anti-Aβ protofibril antibody administered to a subject may depend on several factors, including pharmacodynamic characteristics, route of administration, frequency of treatment, and the health, age, and weight of the subject to be treated, and will be able to determine the appropriate amount for each subject using the information disclosed herein.

[0246] [000301] In some embodiments, a therapeutically effective amount is a dose selected to improve efficacy and / or maintain efficacy, and improve at least one of safety and tolerability. In some embodiments, a therapeutically effective amount is selected to reduce at least one side effect while simultaneously improving efficacy and / or maintaining efficacy. Methods for determining therapeutically effective doses and therapeutic efficacy of anti-Aβ protofibril antibodies are disclosed in PCT / US2022 / 073576; PCT / US2022 / 079571; and PCT / US2022 / 041926, which are incorporated herein by reference.

[0247] [000302] In some embodiments, 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg of at least one anti-Aβ protofibril antibody is administered to a subject at a dose of the subject's body weight.

[0248] [000303] In some embodiments, 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg of at least one anti-Aβ protofibril antibody is administered to a subject based on the subject's body weight.

[0249] [000304] In some embodiments, 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg of at least one anti-Aβ protofibril antibody is administered to a subject based on the subject's body weight.

[0250] [000305] In some embodiments, 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg of at least one anti-Aβ protofibril antibody is administered to a subject based on the subject's body weight.

[0251] [000306] In some embodiments, 0.5 mg / kg to 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to the subject. In some embodiments, up to 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to the subject.

[0252] [000307] In some embodiments, the subject is administered 0.5 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 1 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 2 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 2.5 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some emb...

Claims

1. 1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: c. Selecting subjects with low levels of tau in whole brain measurements, preferably as measured by tau PET (low tau PET levels); and d. administering to said subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. A method comprising:

2. 10. The method of claim 1, wherein treating AD comprises reducing, slowing, and / or reversing the decline in a measure of cognitive function.

3. 3. The method of claim 2, wherein the measure of cognitive function is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL.

4. 10. The method of claim 1, wherein treating AD comprises causing a change (e.g., slowing, delaying, or reducing) in at least one marker of AD pathology.

5. 5. The method of claim 4, wherein the marker is plasma Aβ42 / 40 ratio, plasma p-tau181 level, plasma GFAP level, and / or plasma NfL level.

6. 6. The method of claim 5, wherein the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio as measured by an adjusted mean change from baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.

009.

7. 7. The method of claim 5 or claim 6, wherein the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or greater.

8. 6. The method of claim 5, wherein the Aβ protofibril antibody reduces plasma p-tau181 by at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml, as measured by adjusted mean change from baseline p-tau181 levels.

9. 6. The method of claim 5, wherein the Aβ protofibril antibody reduces plasma GFAP by at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml, as measured by adjusted mean change from baseline GFAP levels.

10. 6. The method of claim 5, wherein the Aβ protofibril antibody increases plasma NfL by less than about 2 pg / ml or less than about 3 pg / ml, as measured by adjusted mean change from baseline NfL levels.

11. 5. The method of claim 4, wherein the marker is a tau PET level or an amyloid PET level.

12. 12. The method of claim 11, wherein the Aβ protofibril antibody reduces the tau PET level as measured by an adjusted mean change from baseline tau PET SUVr level of less than about 0.1, e.g., 0.

05.

13. 12. The method of claim 11, wherein the Aβ protofibril antibody reduces the amyloid PET level by about 55, 40, 25, or 20 centiloids.

14. 12. The method of claim 11, wherein the Aβ protofibril antibody reduces the tau PET and / or the amyloid PET levels in a local brain region.

15. 15. The method of claim 14, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III).

16. 16. The method of claim 15, wherein the early Braak region comprises the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus.

17. 15. The method of claim 14, wherein the local brain region is a complex of regions that accumulate tau in early AD.

18. 18. The method of claim 17, wherein the complex region comprises the temporal region, the medial temporal region, and / or the meta-temporal region.

19. 15. The method of claim 14, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex, hippocampus, parahippocampal gyrus, and temporal pole (medial and / or inferior lateral tip of the temporal lobe)).

20. 10. The method of claim 1, wherein the subject has mild cognitive impairment or mild dementia.

21. 10. The method of claim 1, wherein the subject is at risk of developing AD.

22. 10. The method of claim 1, wherein the subject has or is suspected of having pre-AD.

23. 10. The method of claim 1, wherein the subject has or is suspected of having early stage AD.

24. 10. The method of claim 1, wherein the subject has an amyloid PET level of <20 CL, <40 CL, or <60 CL.

25. 10. The method of claim 1, wherein the subject has an amyloid PET level of >20 CL, >40 CL, or >60 CL.

26. 10. The method of claim 1, wherein the subject has elevated amyloid (e.g., is amyloid positive) as measured by amyloid PET.

27. The method of claim 1, wherein the subject is an ApoE4 carrier.

28. 2. The method of claim 1, wherein the low level of tau is a sub-threshold tau PET level (e.g., tau-PET standardized uptake value ratio (SUVR)) in the whole brain measurement.

29. 29. The method of claim 28, wherein the whole-brain measure is a measure of Tau PET in the entire cortical gray matter.

30. 30. The method of claim 28 or 29, wherein the tau PET levels are measured using the MK6240 radiotracer.

31. 31. The method of any one of claims 28 to 30, wherein the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, e.g., as measured on a MK6240 PET scan of whole cortical grey matter.

32. 32. The method of any one of claims 1-31, wherein the subject has low levels of tau in the whole brain measurements (e.g., throughout the cortical gray matter) and higher levels of tau in regional brain regions (e.g., medial temporal, meta-temporal, and / or temporal regions).

33. 33. The method of any one of claims 1-32, wherein the subject further exhibits tau in a regional brain region, e.g., an early Braak region (e.g., Braak region I, II, or III), as measured by tau PET.

34. 1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: c. Selecting subjects with tau in regional brain regions, preferably as measured by PET; and d. administering to said subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. A method comprising:

35. 35. The method of claim 34, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III).

36. 36. The method of claim 35, wherein the early Braak region comprises the transitional entorhinal cortex, the entorhinal cortex, the hippocampus, the amygdala, the parahippocampal gyrus, the fusiform gyrus, and / or the lingual gyrus.

37. 35. The method of claim 34, wherein the local brain region is a complex of regions that accumulate tau in early AD.

38. 38. The method of claim 37, wherein the complex region comprises the temporal region, the medial temporal region, and / or the meta-temporal region.

39. 35. The method of claim 34, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex).

40. The method of any one of claims 1 to 39, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) 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 the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

41. The method of any one of claims 1 to 40, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

42. The method of any one of claims 1 to 41, wherein the anti-Aβ protofibril antibody comprises lecanemab.

43. 43. The method of any one of claims 1 to 42, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg of the subject's weight.

44. 43. The method of any one of claims 1 to 42, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250 to 720 mg.

45. 44. The method of any one of claims 1 to 43, wherein the therapeutically effective dose is administered weekly.

46. 44. The method of any one of claims 1 to 43, wherein the therapeutically effective dose is administered every two weeks.

47. 47. The method of any one of claims 1 to 46, wherein the therapeutically effective dose is administered for at least 13 months, at least 18 months, or at least 24 months.

48. 48. The method of claim 47, wherein the frequency of administration is reduced after 13 months of treatment, e.g., to every 4, 6, 8, 10, or 12 weeks.

49. 48. The method of claim 47, wherein the frequency of administration is reduced after 18 months of treatment, e.g., to every 4, 6, 8, 10, or 12 weeks.

50. 48. The method of claim 47, wherein the frequency of administration is reduced after 24 months of treatment, e.g., to every 4, 6, 8, 10, or 12 weeks.

51. 51. The method of any one of claims 1 to 50, wherein the treatment further comprises administering at least one additional therapy for AD (e.g., an anti-tau antibody such as E2814).

52. The method of any one of claims 1 to 51, wherein the treatment further comprises administering an anti-tau antibody, preferably E2814.

53. 1. A method for selecting a subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody, comprising: a. obtaining tau PET levels from whole brain measurements in said subject; b. Selecting the subject for treatment if the tau PET level is below a threshold level. A method comprising:

54. 54. The method of claim 53, wherein the whole brain measure is tau PET levels in the entire cortical gray matter.

55. 55. The method of claim 53 or 54, wherein the tau PET levels are measured using the MK6240 radiotracer.

56. 55. The method of claim 54, wherein the threshold tau PET level is a tau PET SUVR of about 1.1, preferably about 1.06, e.g., as measured on a MK6240 PET scan of whole cortical gray matter.

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