Methods of treatment using tau PET levels

Abstract

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

Description

[0001] This application claims the benefit and priority of the following U.S. Provisional Patent Application Nos.: 63 / 385,188, filed Nov. 28, 2022; 63 / 506,576, filed Jun. 6, 2023; 63 / 513,797, filed Jul. 14, 2023; and 63 / 592,515, filed Oct. 23, 2023. TECHNICAL FIELD

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

[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 - 59.4 million) (Brookmeyer, R. et al., Forecasting the global burden of Alzheimer’s Disease. Alzheimer Dement. 2007; 3:186 - 91), and it was reported that over 5 million people in the United States had AD (Alzheimer’s Association, Alzheimer’s Association report, 2010 Alzheimer’s disease facts and figures. Alzheimer Dement. 2010; 6:158 - 94). By 2050, the prevalence of AD is predicted to increase to 106.8 million worldwide (range: 47.2 million to 221.2 million), and the prevalence in the United States alone is estimated to be 11 million to 16 million. (Brookmeyer, supra, and 2010 Alzheimer's disease facts and figures, supra).

[0004] The disease typically involves an overall decline in cognitive function, which progresses slowly and renders end-stage subjects bedridden. AD subjects typically survive only 3 to 10 years after symptom onset, although survival extremes of 2 years and 20 years are known. (Hebert, L.E., et al., Alzheimer disease in the U.S. population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122.) Although deaths due to AD are thus greatly underestimated because death certificates rarely attribute the cause of death to AD, AD is still the seventh leading cause of all deaths in the United States and the fifth leading cause of death among Americans aged 65 and older. (Alzheimer’s Association. Alzheimer’s Association report. 2010 Alzheimer’s disease facts and figures. Alzheimer Dement. 2010;6:158-94).

[0005] AD represents a heavy economic burden in industrialized countries, with significant implications for the healthcare system and the treasury, as well as for subjects 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] Histologically, the disease is characterized by neuritic plaques, which are mainly found in the association cortex, limbic system, and basal ganglia. The main component of these plaques is amyloid-β peptide (Aβ). Aβ exists in various conformational states: monomers, oligomers, protofibrils, and insoluble fibrils. The details of the mechanistic relationship between the onset of Alzheimer's disease and Aβ production are not yet clear. However, some anti-amyloid-β antibodies (also known as “anti-Aβ antibodies”) are currently being clinically investigated as potential therapeutic agents for Alzheimer's disease.

[0007] Despite the recent development of AD treatments, including those targeting Aβ, there is still a need for better monitoring of treatments, including more precise measurement of markers that predict treatment responsiveness or measure the response to treatment. Such markers may include combinations of different measurements.

[0008] Accordingly, the present disclosure provides improved methods of selecting, monitoring, and treating patients (also referred to as "subjects") with AD. In some embodiments, treatment with an anti-Aβ protofibril antibody such as BAN2401 can reduce, for example, the rate of tau accumulation in brain regions such as the temporal region, as 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 is associated with a reduction in brain amyloid burden and improvement in cognitive outcomes in the subject. 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 less invasive and / or additional biomarker to improve the measurement of treatment efficacy and / or can be used to permit monitoring and making treatment decisions. Such decisions can include whether to increase or decrease the amount of anti-Aβ protofibril antibody 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] One aspect of the present disclosure relates to a method of treating AD in a subject having or suspected of having Alzheimer's disease (AD), the method comprising (a) selecting a subject having low levels of tau in a whole brain measurement, preferably as measured by tau PET (low tau PET levels), and (b) administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody.

[0010] In some embodiments, treating AD, compared to a control, includes reducing, slowing, and / or reversing the decline of a measure of cognitive function in a subject, such as a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody. In some embodiments, a measure of the cognitive function of a treated subject is compared to a baseline measure obtained from the same subject prior to treatment or to a reference control. In some embodiments, the decline occurs between a time point at which cognitive function is first measured (e.g., the baseline measure) and one or more subsequent time points at which cognitive function 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 measure. In some embodiments, the control is a subject who has not received a therapeutically effective dose of an anti-Aβ protofibril antibody, such as an untreated subject or a subject receiving a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a pooled population data from more than one subject and representing the average measurement of untreated subjects. In some embodiments, the baseline measurement is taken before initiating treatment of 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, compared to a control, includes achieving a change (e.g., slowing, delaying, or reducing) in at least one biomarker of AD pathology in a subject, such as a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody. In some embodiments, the change in the biomarker occurs between a time point at which the biomarker is first measured (e.g., the baseline measure) and one or more subsequent time points at which the biomarker 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 measure. In some embodiments, the control is a subject who has not received a therapeutically effective dose of an anti-Aβ protofibril antibody, such as an untreated subject or a subject receiving a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a pooled population data from more than one subject and representing the average measurement of untreated subjects. In some embodiments, the biomarker is plasma Aβ42 / 40 ratio, plasma p-tau 181 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 relative to the 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 a period of administration of the Aβ protofibril antibody. For example, the plasma Aβ42 / 40 ratio may increase by about 0.003 after treatment with the Aβ protofibril antibody for about 6 months or more, by about 0.006 after treatment with the Aβ protofibril antibody for about 12 months or more, by about 0.007 after treatment with the Aβ protofibril antibody for about 18 months or more, by about 0.008 after treatment with the Aβ protofibril antibody for about 21 months or more, or by about 0.009 after treatment with the Aβ protofibril antibody for about 24 months or more. In some embodiments, the increase in the plasma Aβ42 / 40 ratio in subjects receiving lecanemab is greater relative to baseline than in the control. In some embodiments, the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or higher.

[0013] In some embodiments, the Aβ protofibril antibody decreases plasma p-tau 181, as measured by an adjusted mean change relative to the baseline p-tau 181 level of at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml. In some embodiments, the change is observed after a period of administration of the Aβ protofibril antibody. For example, p-tau 181 may decrease by about 0.2 pg / ml after treatment with the Aβ protofibril antibody for about 6 months or more, by 0.5 pg / ml after treatment with the Aβ protofibril antibody for about 12 months or more, by 0.6 pg / ml after treatment with the Aβ protofibril antibody for about 18 months or more, by about 0.8 pg / ml after treatment with the Aβ protofibril antibody for about 21 months or more, or by about 0.8 pg / ml after treatment with the Aβ protofibril antibody for about 21 months or more. In some embodiments, the decrease in plasma p-tau 181 in subjects receiving lecanemab is greater relative to baseline than in the control. In some embodiments, the Aβ protofibril antibody decreases the p-tau 181 level to about 2.3 pg / mL or less or to about 2.2 pg / mL or less (e.g., as measured using the Quanterix Simoa p-tau assay).

[0014] In some embodiments, the Aβ protofibril antibody reduces plasma GFAP, as measured by an adjusted mean change relative to the baseline GFAP level of at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml. In some embodiments, the change is observed after a period of administration of the Aβ protofibril antibody. For example, plasma GFAP may be reduced by about 20 pg / ml relative to baseline after treatment with the Aβ protofibril antibody for about 6 months or more, by about 30 pg / ml relative to baseline after treatment with the Aβ protofibril antibody for about 12 months or more, by about 50 pg / ml relative to baseline after treatment with the Aβ protofibril antibody for about 18 months or more, by about 80 pg / ml relative to baseline after treatment with the Aβ protofibril antibody for about 21 months or more, or by about 60 mg / ml relative to baseline after treatment with the Aβ protofibril antibody for about 24 months or more. In some embodiments, the reduction in plasma GFAP relative to 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 relative to the baseline NfL level. In some embodiments, the change is observed after a period of administration of the Aβ protofibril antibody. In some embodiments, the increase in plasma NfL relative to baseline is less in subjects receiving lecanemab than in controls. In some embodiments, the plasma NfL in subjects receiving lecanemab does not change relative to baseline or decreases over time.

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

[0017] In some embodiments, the Aβ protofibril antibody reduces the tau PET level, as measured by an adjusted mean change relative to the baseline tau PET SUVr level of less than about 0.1, such as 0.05. In some embodiments, the reduction in tau PET relative to baseline is greater in subjects receiving lecanemab than in controls.

[0018] In some embodiments, the Aβ protofibril antibody reduces the amyloid PET level to about 55, 40, 25, or 20 centiloid (CL). In some embodiments, the reduction in amyloid PET relative to 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 local brain regions. In some embodiments, the reduction of plasma p-tau 181 relative to baseline is greater in subjects receiving lecanemab than in controls.

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

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

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

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

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

[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 AD.

[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 (e.g., amyloid positive) as measured by amyloid PET.

[0032] In some embodiments, the subject has a p-tau 181 level equal to or higher than about 2.2 to 2.3 pg / mL (e.g., as measured using the Quanterix Simoa p-tau assay).

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

[0034] In some embodiments, low levels of tau are tau PET levels below a threshold in a whole-brain measurement (e.g., tau-PET standardized uptake value ratio (SUVR)).

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

[0036] In some embodiments, the tau PET level is measured using the MK6240 radiotracer.

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

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

[0039] In some embodiments, the subject further exhibits tau in local brain regions such as early Braak regions (e.g., Braak regions I, II, or III), as measured by tau PET.

[0040] Another aspect of the present disclosure relates to a method of 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 to the subject a therapeutically effective dose of an anti-amyloid-β (Aβ) protofibril antibody.

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

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

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

[0044] In some embodiments, the composite region includes the temporal region, the medial temporal region, and / or the posterior temporal region.

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

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

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

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

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

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

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

[0052] In some embodiments, the therapeutically effective dose is administered every 2 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 administration frequency is reduced after 13 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

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

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

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

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

[0059] One aspect of the present disclosure relates to a method of 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] In some embodiments, the whole-brain measurement is the tau PET level in the entire cortical gray matter.

[0061] In some embodiments, the tau PET level is measured using the MK6240 radiotracer.

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

[0063] Enumerated embodiments

[0064] 1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising

[0065] a. measuring the tau PET level in a brain region of the subject;

[0066] b. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody;

[0067] c. measuring or having measured a second tau PET level of the subject; and

[0068] d. administering to a subject having a lower tau PET increase rate relative to a control subject a second therapeutically effective dose comprising the same amount or a lower amount of the anti-Aβ protofibril antibody compared to the first dose.

[0069] 2. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising

[0070] a. measuring the tau PET level in a brain region of the subject;

[0071] b. administering to the subject a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody;

[0072] c. measuring or having measured a second tau PET level of the subject; and

[0073] d. Administering to a subject having an equivalent or lower rate of increase in tau PET relative to a control subject a second therapeutically effective dose of the anti-Aβ protofibril antibody comprising the same amount or a higher amount than the first dose and / or administering a second therapeutic agent.

[0074] 3. The method according to Example 2, wherein the second therapeutic agent comprises an anti-tau antibody.

[0075] 4. The method according to any one of Examples 1 to 3, wherein the second tau PET level is measured at 13 months.

[0076] 5. The method according to any one of Examples 1 to 3, wherein the second tau PET level is measured at 18 months.

[0077] 6. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising

[0078] a. Measuring the tau PET level in the temporal region of the brain of the subject;

[0079] b. Administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody;

[0080] c. Measuring or having measured the second tau PET level in the temporal region of the brain of the subject at 13 or 18 months after the first administration; and

[0081] d. Continuing to administer the anti-Aβ protofibril antibody to a subject having a tau PET level that has increased by no more than 0.05 - 0.1 relative to the measurement before administration of the Aβ protofibril antibody as evaluated by tau PET SUVR in the temporal region.

[0082] 7. The method according to Example 6, wherein the temporal region is the medial temporal region, the posterior temporal region, or the temporal region (e.g., the lateral temporal region).

[0083] 8. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising:

[0084] a. Measuring the tau PET level in the temporal region of the brain of the subject; and

[0085] b. Administering to a subject having a higher tau PET level than a subject not having AD a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody.

[0086] 9. The method according to Example 8, the method further comprising:

[0087] a. Measuring a second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0088] b. Administering to a subject having a lower rate of tau PET increase relative to a control subject with AD but not treated with the anti-Aβ protofibril antibody a second therapeutically effective dose comprising the same amount or a lower amount of the anti-Aβ protofibril antibody compared to the first dose.

[0089] 10. The method according to Example 8, the method further comprising:

[0090] a. Measuring a second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0091] b. Administering to a subject having a higher rate of tau PET increase and / or a tau PET level with an increase evaluated by tau PET SUVR in the temporal region of no more than 0.05 - 0.1 relative to a control subject a second therapeutically effective dose comprising the same amount or a higher amount of the anti-Aβ protofibril antibody compared to the first dose.

[0092] 11. The method according to Example 8, the method further comprising:

[0093] a. Measuring a second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0094] b. Administering a second therapeutic agent to a subject having a higher rate of tau PET increase relative to a control subject.

[0095] 12. The method according to Example 1, 2, 6 or 8 to 11, wherein the second tau PET level is measured at least 13 months after the first tau PET level measurement.

[0096] 13. The method according to Example 1, 2, 6 or 8 to 11, wherein the second tau PET level is measured at least 18 months after the first tau PET level measurement.

[0097] 14. A method of treating Alzheimer's disease in a subject, the method comprising

[0098] a. Measuring the tau PET level in a brain region of a subject suspected of having pre-AD; and

[0099] b. Administering a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to a subject having a tau PET level higher than that of a subject not having AD,

[0100] wherein the subject exhibits at least one biomarker of AD (e.g., a reduced Aβ42 / 40 ratio relative to a subject not having AD, e.g., a ratio below a threshold of about 0.092, and / or an elevated p-tau217 level relative to the level in a subject not having AD), and optionally wherein the subject is otherwise cognitively normal.

[0101] 15. A method of reducing brain amyloid beta in a subject having or suspected of having AD, the method comprising

[0102] a. Measuring the tau PET level in a brain region of the subject;

[0103] b. Administering a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to the subject;

[0104] c. Measuring or having measured a second tau PET level of the subject; and

[0105] d. Administering a second therapeutically effective dose comprising the same amount or a lower amount of the anti-Aβ protofibril antibody as the first dose to a subject having a lower tau PET increase rate relative to a control subject.

[0106] 16. A method of reducing brain amyloid beta in a subject having or suspected of having AD, the method comprising

[0107] a. Measuring the tau PET level in a brain region of the subject;

[0108] b. Administering a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to the subject;

[0109] c. Measuring or having measured a second tau PET level of the subject; and

[0110] d. Administering a second therapeutically effective dose comprising the same amount or a higher amount of the anti-Aβ protofibril antibody as the first dose and / or administering a second therapeutic agent to a subject having an equivalent or lower tau PET increase rate relative to a control subject.

[0111] 17. The method according to any one of Examples 10, 11 or 16, wherein the second therapeutic agent comprises an anti-tau antibody.

[0112] 18. The method according to any one of embodiments 15 to 17, wherein the second tauPET level is measured at 13 or 18 months.

[0113] 19. A method of reducing brain amyloid-β in a subject having or suspected of having AD, the method comprising

[0114] a. measuring the tau PET level in the temporal region of the brain of the subject;

[0115] b. administering to the subject a therapeutically effective dose of an anti-amyloid-β (Aβ) protofibril antibody;

[0116] c. measuring or having measured the second tau PET level in the temporal region of the brain of the subject at 13 or 18 months after the first administration; and

[0117] d. continuing to administer the anti-Aβ protofibril antibody to a subject having a tauPET level with an increase of no more than 0.05 - 0.1 as evaluated by tau PET SUVR in the temporal region.

[0118] 20. The method according to embodiment 19, wherein the temporal region is the medial temporal lobe, the posterior temporal lobe, or the temporal lobe.

[0119] 21. A method of reducing brain amyloid-β in a subject having or suspected of having AD, the method comprising:

[0120] a. measuring the tau PET level in the temporal region of the brain of the subject; and

[0121] b. administering to a subject having a tau PET level higher than that of a subject not having AD a treatment comprising a therapeutically effective dose of an anti-amyloid-β (Aβ) protofibril antibody.

[0122] 22. The method according to embodiment 21, the method further comprising:

[0123] a. measuring the second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0124] b. administering to a subject having a lower tau PET increase rate relative to a control subject a second therapeutically effective dose of the anti-Aβ protofibril antibody comprising the same amount or a lower amount than the first dose.

[0125] 23. The method according to embodiment 21, the method further comprising:

[0126] a. Measuring a second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0127] b. Administering to a subject having a lower tau PET increase rate relative to a control subject a second therapeutically effective dose comprising the same amount or a higher amount of the anti-Aβ protofibril antibody compared to the first dose.

[0128] 24. The method according to embodiment 21, the method further comprising:

[0129] a. Measuring a second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0130] b. Administering a second therapeutic agent to a subject having a lower tau PET increase rate relative to a control subject.

[0131] 25. The method according to embodiment 21, the method further comprising:

[0132] a. Measuring a second tau PET level of the subject after the first sampling to determine the second tau PET level; and

[0133] b. Administering a second therapeutic agent to a subject having a higher tau PET increase rate relative to a control subject.

[0134] 26. A method of reducing brain amyloid-β in a subject having or suspected of having AD, the method comprising

[0135] a. Measuring the tau PET level in a brain region of a subject suspected of having pre-AD; and

[0136] b. Administering to a subject having a higher tau PET level than a subject not having AD a treatment comprising a therapeutically effective dose of an anti-amyloid-β (Aβ) protofibril antibody,

[0137] wherein the subject exhibits at least one biomarker of AD (e.g., a reduced Aβ42 / 40 ratio relative to a subject not having AD, e.g., a ratio below a threshold of about 0.092, and / or an elevated p-tau217 level relative to the level of a subject not having AD) but is cognitively normal.

[0138] 27. The method according to any one of embodiments 1-26, the method further comprising co-administering a second therapeutic agent with the anti-Aβ protofibril antibody.

[0139] 28. The method according to embodiment 24, 25 or 27, wherein the second therapeutic agent is an anti-tau antibody.

[0140] 29. The method according to embodiment 28, wherein the anti-tau antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:18 (LCDR1), SEQ ID NO:19 (LCDR2), and SEQ ID NO:20 (LCDR3).

[0141] 30. The method according to 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.

[0142] 31. The method according to any one of embodiments 1-30, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0143] 32. The method according to any one of embodiments 1-31, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:8.

[0144] 33. The method according to any one of embodiments 1-32, wherein the subject has or is suspected of having pre-AD.

[0145] 34. The method according to embodiment 33, wherein the anti-tau antibody is administered to the subject prior to the anti-Aβ protofibril.

[0146] 35. The method according to any one of embodiments 1-32, wherein the subject has or is suspected of having early AD.

[0147] 36. The method according to embodiment 35, wherein the anti-Aβ protofibril is administered to the subject prior to the anti-tau antibody.

[0148] 37. The method according to any one of embodiments 1-36, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg relative to the body weight of the subject.

[0149] 38. The method according to any one of embodiments 1-36, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250 to 720 mg.

[0150] 39. The method according to any one of embodiments 1-36, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of 360 mg.

[0151] 40. The method according to any one of embodiments 1-36, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of 720 mg.

[0152] 41. A method of selecting a subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody, the method comprising:

[0153] a. measuring the tau PET level in a brain region of the subject; and

[0154] b. selecting the subject for treatment if the tau PET level is greater than that of a subject not suffering from AD.

[0155] 42. The method according to embodiment 41, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) having 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) having the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0156] 43. The method according to embodiment 41 or 42, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO:7 and a light chain variable region having the amino acid sequence of SEQ ID NO:8.

[0157] 44. The method according to any one of embodiments 41-43, wherein the tau PET level is about 1.4.

[0158] 45. The method according to any one of embodiments 41-43, wherein the tau PET level is about 1.5.

[0159] 46. A method for monitoring the therapeutic efficacy in a subject having or suspected of having AD, the method comprising:

[0160] a. Administering to the subject a therapeutically effective dose of an anti-Aβ protofibril antibody;

[0161] b. Measuring the tau PET level in a brain region of the subject; and

[0162] c. Comparing the tau PET level with the tau PET level of the subject before treatment, wherein a lower tau PET level relative to a control subject indicates effective treatment.

[0163] 47. A method for monitoring the therapeutic efficacy in a subject having or suspected of having AD, the method comprising

[0164] a. Measuring the tau PET level in the temporal region of the brain of the subject;

[0165] b. Administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody;

[0166] c. Measuring or having measured a second tau PET level in the temporal region of the brain of the subject at 13 or 18 months after the first administration; and

[0167] d. Comparing the tau PET level with the tau PET level of the subject before treatment, wherein an increase in the tau PET level not exceeding 0.05 - 0.1 as evaluated by tau PET SUVR in the temporal region indicates effective treatment.

[0168] 48. The method according to embodiment 46 or 47, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0169] 49. The method according to any one of embodiments 46 to 48, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:8.

[0170] 50. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising:

[0171] a. Measuring the tau PET level in a brain region of the subject;

[0172] b. Administering to the subject a therapeutic dosing regimen comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody;

[0173] c. Measuring a subsequent tau PET level; and

[0174] d. Determining that the subsequent tau PET level is lower than a control level and / or the increase in the tau PET level is not more than 0.05 - 0.1, and switching to a maintenance dosing regimen.

[0175] 51. The method of embodiment 50, wherein the subject has a tau PET level greater than 1.4 as evaluated by tau PET SUVR.

[0176] 52. The method of embodiment 50, wherein the subject has a tau PET level greater than 1.5 as evaluated by tau PET SUVR.

[0177] 53. The method of any one of embodiments 50 - 52, wherein the brain region is the temporal region.

[0178] 54. The method of any one of embodiments 50 - 53, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0179] 55. The method of any one of embodiments 50 - 54, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:8.

[0180] 56. The method according to any one of Examples 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 the start of the therapeutic dosing regimen or after the subject has been converted to an amyloid-negative state (e.g., as determined by amyloid PET).

[0181] 57. The method according to any one of Examples 50-55, wherein the therapeutic dosing regimen comprises administering the anti-Aβ protofibril antibody as an intravenous infusion at a therapeutically effective dose of 10 mg / kg per week relative to the body weight of the subject.

[0182] 58. The method according to any one of Examples 50-55, wherein the therapeutic dosing regimen comprises administering the anti-Aβ protofibril antibody as an intravenous infusion at a therapeutically effective dose of 10 mg / kg every two weeks relative to the body weight of the subject.

[0183] 59. The method according to any one of Examples 50-55, wherein the therapeutic dosing regimen comprises administering the anti-Aβ protofibril antibody subcutaneously at a therapeutically effective dose of 720 mg per week.

[0184] 60. The method according to any one of Examples 50-55, wherein the therapeutic dosing regimen comprises administering the anti-Aβ protofibril antibody subcutaneously at a therapeutically effective dose of 360 mg per week.

[0185] 61. The method according to any one of Examples 50-55, wherein the therapeutic dosing regimen comprises administering the anti-Aβ protofibril antibody subcutaneously at a therapeutically effective dose of 720 mg every two weeks.

[0186] 62. The method according to any one of Examples 50-61, wherein the maintenance dosing regimen comprises intravenous infusion at a therapeutically effective dose of 10 mg / kg every two weeks relative to the body weight of the subject.

[0187] 63. The method according to any one of Examples 50-61, wherein the maintenance dosing regimen comprises intravenous infusion at a therapeutically effective dose of 10 mg / kg per month relative to the body weight of the subject.

[0188] 64. The method according to any one of Examples 50-61, wherein the maintenance dosing regimen comprises intravenous infusion at a therapeutically effective dose of 10 mg / kg every three months relative to the body weight of the subject.

[0189] 65. The method according to any one of Examples 50-61, wherein the maintenance dosing regimen comprises administering the anti-Aβ protofibril antibody subcutaneously at a therapeutically effective dose of 720 mg every two weeks.

[0190] 66. The method according to any one of Examples 50 - 61, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 720 mg per month.

[0191] 67. The method according to any one of Examples 50 - 61, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 360 mg per week.

[0192] 68. The method according to any one of Examples 50 - 67, wherein the maintenance dosing regimen comprises the same dosing regimen as the treatment regimen.

[0193] 69. A method for monitoring the therapeutic efficacy in a subject having or suspected of having AD, the method comprising:

[0194] a. Measuring the tau PET level in a brain region of the subject;

[0195] b. Measuring the level of a second biomarker of the subject;

[0196] c. Administering to the subject a therapeutically effective dose of an anti-Aβ protofibril antibody;

[0197] d. Measuring a second tau PET level in the brain region of the subject after the first sampling;

[0198] e. Measuring a second level of the second biomarker of the subject after the first sampling;

[0199] f. Comparing the tau PET level and the level of the second biomarker of a control subject, wherein a lower tau PET level and / or an improved level of the second biomarker relative to a control patient indicates effective treatment.

[0200] 70. A method for monitoring the therapeutic efficacy in a subject having or suspected of having AD, the method comprising:

[0201] a. Measuring the tau PET level in a brain region of the subject;

[0202] b. Measuring the level of a second biomarker of the subject;

[0203] c. Administering to the subject a therapeutically effective dose of an anti-Aβ protofibril antibody;

[0204] d. Measuring a second tau PET level in the brain region of the subject after the first sampling;

[0205] e. Measure a second level of the second biomarker of the subject after the first sampling;

[0206] f. Compare the tau PET level with the tau PET level of the subject before treatment;

[0207] g. Compare the level of the second biomarker of the subject with the biomarker level of the subject before treatment, wherein a reduced rate of increase in tau PET and / or improvement in the level of the second biomarker relative to a control subject indicates an effective treatment.

[0208] 71. A method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising

[0209] a. Measuring the tau PET level in a brain region of the subject;

[0210] b. Measuring the level of a second biomarker of the subject;

[0211] c. Administering a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to the subject;

[0212] d. Measuring a second tau PET level of the subject after a first sampling;

[0213] e. Measuring the level of the second biomarker of the subject after the first sampling to determine a second level; and

[0214] f. Administering a second therapeutically effective dose of the anti-Aβ protofibril antibody comprising the same amount or a lower amount compared to the first dose to a subject having a lower rate of increase in tau PET and / or improvement in the level of the second biomarker relative to a control subject.

[0215] 72. A method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising

[0216] a. Measuring the tau PET level in a brain region of the subject;

[0217] b. Measuring the level of a second biomarker of the subject;

[0218] c. Administering a first therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody to the subject;

[0219] d. Measuring a second tau PET level of the subject after a first sampling;

[0220] e. Measuring the level of the second biomarker of the subject after the first sampling to determine a second level; and

[0221] f. Administering to a subject having a higher rate of tau PET increase and / or a second biomarker level that does not improve or deteriorate relative to a control subject a second therapeutically effective dose of the anti-Aβ protofibril antibody comprising the same amount or a higher amount of the anti-Aβ protofibril antibody compared to the first dose.

[0222] 73. The method according to any one of embodiments 69-72, wherein the second biomarker comprises one or more of the following:

[0223] Volumetric MRI (vMRI) (including whole brain volume, cortical thickness, total hippocampal volume, lateral ventricle volume), amyloid PET level, fluorodeoxyglucose (FDG) PET level, cerebrospinal fluid levels of Aβ1-42, 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, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), 217 (P-tau217) and / or 231 (P-tau231)), glial fibrillary acidic protein (GFAP) and / or neurofilament light chain (NfL).

[0224] 74. The method according to 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.

[0225] 75. The method according to any one of embodiments 69-73, wherein lower levels of tau PET and lower levels of amyloid PET indicate effective treatment.

[0226] 76. The method according to any one of embodiments 69-73, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0227] 77. The method according to 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.

[0228] 78. The method according to any one of embodiments 1-77, wherein the control subject has Alzheimer's disease, early Alzheimer's disease or preclinical Alzheimer's disease, and wherein the control subject is not treated with the anti-Aβ protofibril antibody.

[0229] 79. The method according to any one of embodiments 1-78, wherein the brain region is the temporal lobe.

[0230] 80. The method according to any one of embodiments 1-78, wherein the brain region is the posterior temporal lobe.

[0231] 81. The method according to any one of embodiments 1-78, wherein the brain region is the medial temporal lobe.

[0232] 82. The method according to any one of embodiments 1-13, 15-25 or 27-88, wherein the subject has Alzheimer's disease.

[0233] 83. The method according to any one of embodiments 1-13, 15-25 or 27-88, wherein the subject has early Alzheimer's disease.

[0234] 84. The method according to any one of embodiments 1-83, wherein the subject has preclinical Alzheimer's disease (pre-AD).

[0235] 85. The method according to any one of embodiments 1-84, wherein the subject has Alzheimer's disease, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, dementia with Lewy bodies or another brain disease or disorder having soluble and / or insoluble Aβ aggregates containing Aβ peptides.

[0236] 86. The method according to any one of embodiments 1-85, wherein the subject has been diagnosed with

[0237] a. mild cognitive impairment due to a moderate likelihood of Alzheimer's disease and / or has been diagnosed with mild Alzheimer's dementia;

[0238] b. mild cognitive impairment due to a moderate likelihood of Alzheimer's disease according to the National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical criteria;

[0239] c. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, based on a total CDR score of 0.5 before treatment and a Memory Box score of 0.5 or higher;

[0240] d. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, based on subjective memory decline in the last 1 year before treatment as confirmed by an informant, for example, and a history of gradual onset and slow progression;

[0241] e. Mild Alzheimer's dementia according to the NIA-AA core clinical criteria for possible Alzheimer's dementia; or

[0242] f. Mild Alzheimer's dementia based on a CDR score of 0.5 to 1.0 before treatment and a Memory Box score of 0.5 or higher.

[0243] 87. The method according to any one of embodiments 1-86, wherein before administration, the subject is amyloid positive, as indicated, for example, by PET assessment, CSF assessment of Aβ(1-42), MRI, retinal amyloid accumulation, and / or specific behavioral / cognitive phenotypes.

[0244] 88. The method according to any one of embodiments 1-87, wherein if the tau PET level has increased by more than 0.05 - 0.1 relative to a control subject, treatment is discontinued.

[0245] 89. The method according to any one of embodiments 1-88, wherein if the treatment does not result in a lower rate of increase in the tau PET level relative to a control subject, treatment is discontinued.

[0246] 90. The method according to 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 relative to the subject's body weight.

[0247] 91. The method according to 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.

[0248] 92. The method according to 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.

[0249] 93. The method according to any one of embodiments 1-57, 59, 60, 62-92, wherein the therapeutically effective dose is administered weekly.

[0250] 94. The method as described in Examples 1 - 56, 58, 61 - 92, wherein the therapeutically effective dose is administered every two weeks.

[0251] 95. The method as described in Examples 1 - 94, wherein the administration frequency is reduced after 13 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0252] 96. The method as described in any one of Examples 90 - 92, wherein the therapeutically effective dose is reduced after 13 months of treatment.

[0253] 97. The method as described in Examples 1 - 96, wherein the administration frequency is reduced after 18 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0254] 98. The method as described in any one of Examples 90 - 92, wherein the therapeutically effective dose is reduced after 18 months of treatment.

[0255] 99. The method as described in any one of Examples 1 - 98, wherein the anti - Aβ protofibril antibody comprises three heavy - chain complementarity - determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0256] 100. The method as described in any one of Examples 1 - 99, wherein the anti - Aβ protofibril antibody comprises a heavy - chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light - chain variable region containing the amino acid sequence of SEQ ID NO:8.

[0257] 101. The method as described in any one of Examples 1 - 100, wherein a second therapeutic agent is administered to the subject sequentially or simultaneously.

[0258] 102. The method as described in Example 101, wherein the second therapeutic agent is an anti - tau antibody.

[0259] 103. The method according to Example 102, wherein the anti-tau antibody comprises three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:18 (LCDR1), SEQ ID NO:19 (LCDR2), and SEQ ID NO:20 (LCDR3).

[0260] 104. The method according to Example 102 or 103, wherein the anti-tau antibody or its antigen-binding fragment comprises a heavy-chain variable region of SEQ ID NO:21 and a light-chain variable region of SEQ ID NO:22.

[0261] 105. The method according to any one of Examples 1-104, wherein the method results in, compared to before treatment and / or compared to untreated control subjects:

[0262] a. Improvement in 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) or slowing of their deterioration; and / or

[0263] b. Reduction in plasma or serum biomarkers (e.g., 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), 217 (P-tau217), and / or 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL)) or slowing of their increase.

[0264] 106. The method according to any one of Examples 1-105, wherein the treatment

[0265] a. Delays clinical decline as determined by ADCOMS;

[0266] b. Delays clinical decline as determined by ADAS MCI-ADL;

[0267] c. Delays clinical decline as determined by the modified iADRS;

[0268] d. Delays clinical decline as determined by CDR-SB; or

[0269] e. Delay clinical decline as determined by ADAS-Cog.

[0270] 107. The method according to any one of embodiments 1-106, wherein the method further comprises monitoring ARIA, such as ARIA-E and / or ARIA-H, such as as observed by MRI.

[0271] 108. The method according to any one of embodiments 1-107, wherein the method does not require a titration step prior to administering the first therapeutically effective dose of the anti-Aβ protofibril antibody to the subject.

[0272] 109. The method according to any one of embodiments 1-108, wherein the method results in at least 24% less (e.g., at least 29% less) cognitive decline compared to an untreated subject, as measured by ADCOMS.

[0273] 110. The method according to any one of embodiments 1-109, wherein the method results in at least 26% less (e.g., at least 27% less) cognitive decline compared to an untreated subject, as measured by CDR-SB.

[0274] 111. The method according to any one of embodiments 1-110, wherein the method results in at least 26% less (e.g., at least 47% less) cognitive decline compared to an untreated subject, as measured by ADAS-Cog14.

[0275] 112. The method according to any one of embodiments 1-111, wherein the method results in at least 37% less cognitive decline compared to an untreated subject, as measured by ADCS MCI-ADL.

[0276] 113. The method according to any one of embodiments 1-112, wherein the method results in at least a 0.2 decrease in PET SUVr relative to baseline compared to an untreated subject, as measured by amyloid-β PET.

[0277] 114. The method according to any one of embodiments 1-113, wherein the method results in at least a 50 decrease in units on a percentile scale relative to baseline compared to an untreated subject, as measured by amyloid-β PET.

[0278] 115. The method according to any one of embodiments 1-114, wherein the method results in at least a 0.005 increase in plasma Aβ42 / 40 relative to baseline compared to an untreated subject.

[0279] 116. The method according to any one of embodiments 1-115, wherein the method results in a reduction of plasma p-tau181 by at least 1 pg / ml relative to baseline compared to an untreated subject.

[0280] 117. The method according to any one of embodiments 1-116, wherein the method results in the subject converting from amyloid positive to amyloid negative.

[0281] 118. The method according to any one of embodiments 1-117, wherein the method reduces the risk of progression to the next stage of AD, as measured by the Clinical Dementia Rating (CDR) total score, for example by at least 10%, at least 20%, at least 30%, at least 31%.

[0282] 119. The method according to any one of embodiments 109-118, wherein the results are measured at least 6 months after the first therapeutically effective dose.

[0283] 120. The method according to any one of embodiments 109-118, wherein the results are measured at least 12 months after the first therapeutically effective dose.

[0284] 121. The method according to any one of embodiments 109-118, wherein the results are measured at least 13 months after the first therapeutically effective dose.

[0285] 122. The method according to any one of embodiments 109-118, wherein the results are measured at least 18 months after the first therapeutically effective dose.

[0286] 123. The method according to any one of embodiments 109-122, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg relative to the body weight of the subject.

[0287] 124. The method according to any one of embodiments 109-123, wherein the therapeutically effective dose is administered every two weeks.

[0288] 125. The method according to any one of embodiments 109-122, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of 720 mg per week.

[0289] 126. A method of treating AD in a subject having or suspected of having Alzheimer's disease (AD), the method comprising

[0290] a. selecting a subject having a low level of tau in a whole brain measurement, preferably as measured by tau PET (low tau PET level), and

[0291] b. Administer to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody.

[0292] 127. The method according to embodiment 126, wherein treating AD comprises reducing, slowing down, and / or reversing the decline in cognitive function measures.

[0293] 128. The method according to embodiment 127, wherein the cognitive function measure is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL.

[0294] 129. The method according to embodiment 126, wherein treating AD comprises achieving a change (e.g., slowing down, delaying, or reducing) in at least one biomarker of AD pathology.

[0295] 130. The method according to embodiment 129, wherein the biomarker is the plasma Aβ42 / 40 ratio, plasma p-tau181 level, plasma GFAP level, and / or plasma NfL level.

[0296] 131. The method according to embodiment 130, wherein the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio, as measured by an adjusted mean change relative to the baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.009.

[0297] 132. The method according to embodiment 130 or embodiment 131, wherein the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or higher.

[0298] 133. The method according to embodiment 130, wherein the Aβ protofibril antibody reduces plasma p-tau 181, as measured by an adjusted mean change relative to the baseline p-tau181 level of at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml.

[0299] 134. The method according to embodiment 130, wherein the Aβ protofibril antibody reduces plasma GFAP, as measured by an adjusted mean change relative to the baseline GFAP level of at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml.

[0300] 135. The method according to 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 an adjusted mean change relative to the baseline NfL level.

[0301] 136. The method according to embodiment 129, wherein the biomarker is a tau PET level or an amyloid PET level.

[0302] 137. The method according to embodiment 136, wherein the Aβ protofibril antibody reduces the tau PET level, as measured by an adjusted mean change relative to the baseline tau PET SUVr level of less than about 0.1, such as 0.05.

[0303] 138. The method according to embodiment 136, wherein the Aβ protofibril antibody reduces the amyloid PET level to about 55, 40, 25, or 20 percentile units.

[0304] 139. The method according to embodiment 136, wherein the Aβ protofibril antibody reduces the tau PET and / or the amyloid PET level in a local brain region.

[0305] 140. The method according to embodiment 139, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III).

[0306] 141. The method according to embodiment 140, wherein the early Braak region includes the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus.

[0307] 142. The method according to embodiment 139, wherein the local brain region is a composite region of regions that accumulate tau in early AD.

[0308] 143. The method according to embodiment 142, wherein the composite region includes the temporal region, the medial temporal region, and / or the posterior temporal region.

[0309] 144. The method according to 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 (the medial and inferolateral tip of the temporal lobe).

[0310] 145. The method according to embodiment 126, wherein the subject has mild cognitive impairment or mild dementia.

[0311] 146. The method according to embodiment 126, wherein the subject is at risk of developing AD.

[0312] 147. The method according to embodiment 126, wherein the subject has or is suspected of having pre-AD.

[0313] 148. The method according to embodiment 126, wherein the subject has or is suspected of having early AD.

[0314] 149. The method according to embodiment 126, wherein the subject has amyloid PET levels of <20CL, <40CL or <60CL.

[0315] 150. The method according to embodiment 126, wherein the subject has amyloid PET levels of >20CL, >40CL or >60CL.

[0316] 151. The method according to embodiment 126, wherein the subject has elevated amyloid (e.g., amyloid positive) as measured by amyloid PET.

[0317] 152. The method according to embodiment 126, wherein the subject is an ApoE4 carrier.

[0318] 153. The method according to embodiment 126, wherein the low level of tau is a tau PET level below a threshold in the whole brain measurement (e.g., tau-PET standardized uptake value ratio (SUVR)).

[0319] 154. The method according to embodiment 153, wherein the whole brain measurement is a measurement of tau PET in the entire cortical gray matter.

[0320] 155. The method according to embodiment 153 or 154, wherein the tau PET level is measured using the MK6240 radiotracer.

[0321] 156. The method according to any one of embodiments 153-155, wherein the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, for the entire cortical gray matter, as measured by MK6240 PET scanning.

[0322] 157. The method according to any one of embodiments 1-156, wherein the subject has a low level of tau in the whole brain measurement (e.g., the entire cortical gray matter) and a higher level of tau in local brain regions (e.g., the medial temporal region, the posterior temporal region, and / or the temporal region), as measured by tau PET.

[0323] 158. The method according to any one of embodiments 1-157, wherein the subject further exhibits tau in local brain regions such as early Braak regions (e.g., Braak regions I, II, or III), as measured by tau PET.

[0324] 159. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising

[0325] a. selecting a subject having tau in a local brain region, preferably as measured by PET, and

[0326] b. administering to the subject a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody.

[0327] 160. The method according to embodiment 159, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III).

[0328] 161. The method according to embodiment 160, wherein the early Braak region includes the entorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus.

[0329] 162. The method according to embodiment 159, wherein the local brain region is a composite region of regions that accumulate tau in early AD.

[0330] 163. The method according to embodiment 162, wherein the composite region includes the temporal region, medial temporal region, and / or posterior temporal region.

[0331] 164. The method according to embodiment 159, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex).

[0332] 165. The method according to any one of embodiments 1-164, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0333] 166. The method according to any one of embodiments 1-165, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:8.

[0334] 167. The method according to any one of embodiments 1-166, wherein the anti-Aβ protofibril antibody comprises lecanemab.

[0335] 168. The method according to any one of Examples 1 - 167, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg relative to the body weight of the subject.

[0336] 169. The method according to any one of Examples 1 - 167, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250 to 720 mg.

[0337] 170. The method according to any one of Examples 1 - 168, wherein the therapeutically effective dose is administered weekly.

[0338] 171. The method according to any one of Examples 1 - 168, wherein the therapeutically effective dose is administered every two weeks.

[0339] 172. The method according to any one of Examples 1 - 171, wherein the therapeutically effective dose is administered for at least 13 months, at least 18 months, or at least 24 months.

[0340] 173. The method according to Example 172, wherein the administration frequency is reduced after 13 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0341] 174. The method according to Example 172, wherein the administration frequency is reduced after 18 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0342] 175. The method according to Example 172, wherein the administration frequency is reduced after 24 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0343] 176. The method according to any one of Examples 1 - 175, wherein the treatment further comprises administering at least one additional AD therapy (e.g., an anti-tau antibody such as E2814).

[0344] 177. The method according to any one of Examples 1 - 176, wherein the treatment further comprises administering an anti-tau antibody, preferably E2814.

[0345] 178. A method of selecting a subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody, the method comprising:

[0346] a. obtaining tau PET levels from whole brain measurements of the subject;

[0347] b. if the tau PET level is below a threshold level, selecting the subject for treatment.

[0348] 179. The method according to embodiment 178, wherein the whole brain measurement is the tau PET level in the entire cortical gray matter.

[0349] 180. The method according to embodiment 178 or 179, wherein the tau PET level is measured using the MK6240 radiotracer.

[0350] 181. The method according to embodiment 179, wherein the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, of the entire cortical gray matter, as measured in an MK6240 PET scan.

[0351] 182. An anti - amyloid - β (Aβ) protofibril antibody for use in a method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the method is the method according to any one of embodiments 126 - 181.

[0352] 183. Use of an anti - amyloid - β (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 according to any one of embodiments 126 - 181.

[0353] 184. A kit for performing the method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD according to any one of embodiments 126 - 181.

[0354] 185. A therapeutically effective dose of an anti - amyloid - β (Aβ) protofibril antibody for use in a method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the subject has a low level of tau in a whole brain measurement, preferably as measured by tau PET (low tau PET level).

[0355] 186. A therapeutically effective dose of an anti - amyloid - β (Aβ) protofibril antibody for use in a method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, wherein the subject has tau in a local brain region, preferably as measured by PET.

[0356] 187. The therapeutically effective dose of an anti - amyloid - β (Aβ) protofibril antibody for use according to any one of embodiments 185 - 186, wherein the treatment of AD includes reducing, slowing down, and / or reversing the decline of cognitive function metrics.

[0357] 188. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 187, wherein the cognitive function measure is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL.

[0358] 189. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-188, wherein treating AD comprises achieving a change (e.g., slowing, delaying, or reducing) in at least one biomarker of AD pathology.

[0359] 190. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 189, wherein the biomarker is the plasma Aβ42 / 40 ratio, plasma p-tau 181 level, plasma GFAP level, and / or plasma NfL level.

[0360] 191. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 190, wherein the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio, as measured by an adjusted mean change relative to the baseline plasma Aβ42 / 40 ratio of at least about 0.003, 0.006, 0.007, 0.008, or 0.009.

[0361] 192. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 190-191, wherein the Aβ protofibril antibody increases the Aβ42 / 40 ratio to about 0.092 or higher.

[0362] 193. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 190-192, wherein the Aβ protofibril antibody decreases plasma p-tau 181, as measured by an adjusted mean change relative to the baseline p-tau 181 level of at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml.

[0363] 194. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 190-193, wherein the Aβ protofibril antibody decreases plasma GFAP, as measured by an adjusted mean change relative to the baseline GFAP level of at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml.

[0364] 195. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one 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 the adjusted mean change relative to the baseline NfL level.

[0365] 196. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of embodiments 189 - 195, wherein the biomarker is the tau PET level or the amyloid PET level.

[0366] 197. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of embodiments 185 - 196, wherein the Aβ protofibril antibody reduces the tau PET level, as measured by an adjusted mean change relative to the baseline tau PET SUVr level of less than about 0.1, such as 0.05.

[0367] 198. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of embodiments 185 - 197, wherein the Aβ protofibril antibody reduces the amyloid PET level to about 55, 40, 25, or 20 percentile units.

[0368] 199. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of embodiments 197 - 198, wherein the Aβ protofibril antibody reduces the tau PET and / or the amyloid PET level in a local brain region.

[0369] 200. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in embodiment 199, wherein the local brain region is an early Braak region (e.g., Braak region I, II, or III).

[0370] 201. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in embodiment 200, wherein the early Braak region includes the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus.

[0371] 202. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in embodiment 199, wherein the local brain region is a composite region of regions that accumulate tau in early AD.

[0372] 203. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 202, wherein the composite region includes the temporal region, the medial temporal region, and / or the posterior temporal region.

[0373] 204. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 199, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex, the hippocampus, the parahippocampal gyrus, and the temporal pole (the medial and inferolateral tip of the temporal lobe)).

[0374] 205. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-204, wherein the subject has mild cognitive impairment or mild dementia.

[0375] 206. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-205, wherein the subject is at risk of developing AD.

[0376] 207. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-206, wherein the subject has or is suspected of having pre-AD.

[0377] 208. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-205, wherein the subject has or is suspected of having early AD.

[0378] 209. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-208, wherein the subject has an amyloid PET level of <20CL, <40CL, or <60CL.

[0379] 210. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-208, wherein the subject has an amyloid PET level of >20CL, >40CL, or >60CL.

[0380] 211. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185-208, wherein the subject has elevated amyloid (e.g., amyloid positive) as measured by amyloid PET.

[0381] 212. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 - 211, wherein the subject is an ApoE4 carrier.

[0382] 213. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 or 187 - 212, wherein the low level of tau is a tau PET level below a threshold in the whole brain measurement (e.g., tau-PET standardized uptake value ratio (SUVR)).

[0383] 214. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 213, wherein the whole brain measurement is a measurement of tau PET in the entire cortical gray matter.

[0384] 215. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 - 214, wherein the tau PET level is measured using the MK6240 radiotracer.

[0385] 216. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 or 187 - 215, wherein the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, in the entire cortical gray matter, as measured by MK6240 PET scan.

[0386] 217. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 or 187 - 216, wherein the subject has a low level of tau in the whole brain measurement (e.g., the entire cortical gray matter) and a higher level of tau in local brain regions (e.g., the medial temporal region, posterior temporal region, and / or temporal region), as measured by tau PET.

[0387] 218. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 or 187 - 217, wherein the subject further exhibits tau in local brain regions such as early Braak regions (e.g., Braak regions I, II, or III), as measured by tau PET.

[0388] 219. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 186 or 218, wherein the local brain region is an early Braak region (e.g., Braak regions I, II, or III).

[0389] 220. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 219, wherein the early Braak regions include the entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus.

[0390] 221. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 186 or 218, wherein the local brain region is a composite region of regions where tau accumulates in early AD.

[0391] 222. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in Example 221, wherein the composite region includes the temporal region, the medial temporal region, and / or the posterior temporal region.

[0392] 223. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 186 or 218, wherein the local brain region is the medial temporal region (e.g., the entorhinal cortex).

[0393] 224. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 - 223, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3).

[0394] 225. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 - 224, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and a light chain variable region containing the amino acid sequence of SEQ ID NO:8.

[0395] 226. A therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody for use as described in any one of Examples 185 - 225, wherein the anti-Aβ protofibril antibody comprises lecanemab.

[0396] 227. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in any one of Examples 185-226, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises an intravenous infusion of 10 mg / kg relative to the body weight of the subject.

[0397] 228. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in any one of Examples 185-227, wherein the therapeutically effective dose of the anti-Aβ protofibril antibody comprises a subcutaneous administration of about 250 to 720 mg.

[0398] 229. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in any one of Examples 185-228, wherein the therapeutically effective dose is administered weekly.

[0399] 230. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in any one of Examples 185-229, wherein the therapeutically effective dose is administered every 2 weeks.

[0400] 231. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in any one of Examples 185-230, wherein the therapeutically effective dose is administered for at least 13 months, at least 18 months, or at least 24 months.

[0401] 232. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in Example 231, wherein the administration frequency is reduced after 13 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0402] 232. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in Example 231, wherein the administration frequency is reduced after 18 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0403] 234. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in Example 231, wherein the administration frequency is reduced after 24 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

[0404] 235. A therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody for use as described in any one of Examples 185-234, wherein the treatment further comprises administering at least one additional AD therapy (e.g., an anti-tau antibody such as E2814).

[0405] 236. A therapeutically effective dose of an anti-amyloid-beta (Aβ) protofibril antibody for use as described in any one of Examples 185-235, wherein the treatment further comprises administering an anti-tau antibody, preferably E2814.

[0406] 237. Use of a therapeutically effective dose of an anti-amyloid-beta (Aβ) protofibril antibody in the manufacture of a medicament for the treatment of Alzheimer's disease (AD) in a subject suffering from or suspected of suffering from AD, wherein the subject has a low level of tau in a whole brain measurement, preferably as measured by tau PET (low tau PET level).

[0407] 238. Use of a therapeutically effective dose of an anti-amyloid-beta (Aβ) protofibril antibody in the manufacture of a medicament for the treatment of Alzheimer's disease (AD) in a subject suffering from or suspected of suffering from AD, wherein the subject has tau in a local brain region, preferably as measured by PET.

[0408] 237. A method for diagnosing early AD in a subject suspected of having Alzheimer's disease (AD) and / or identifying a subject suspected of having Alzheimer's disease suitable for treatment with an anti-amyloid protofibril antibody such as lecanemab, the method comprising:

[0409] a. Obtaining a first tau PET measurement from the whole brain region of the subject and optionally a second tau PET measurement from a local brain region; and

[0410] b. Diagnosing the subject's AD and / or identifying a subject suitable for treatment with an anti-amyloid protofibril antibody such as lecanemab based on the first tau PET level below a threshold level in the whole brain measurement and optionally by the presence of tau PET in the local brain region measurement, preferably wherein the local brain region comprises one or more of early Braak regions (e.g., Braak regions I, II, or III), a composite region of regions that accumulate tau in early AD (e.g., temporal regions, medial temporal regions, and / or posterior temporal regions), or the medial temporal region (e.g., entorhinal cortex, hippocampus, parahippocampal gyrus, and / or temporal pole (medial and inferolateral tip of the temporal lobe)).

[0411] 238. A method for predicting the prognosis of a subject suffering from or suspected of having Alzheimer's disease, the method comprising:

[0412] a. Obtaining a tau PET level from the whole brain measurement of the subject; and

[0413] b. Comparing the tau PET level with a threshold tau PET level,

[0414] Among subjects with tau PET levels equal to or higher than a threshold level, subjects expected to have tau PET levels below the threshold level are expected to have improved AD treatment prognosis compared to those with tau PET levels equal to or higher than the threshold level.

[0415] 239. The method according to any one of embodiments 237 - 238, wherein the whole brain measurement is the tau PET level in the entire cortical gray matter.

[0416] 240. The method according to any one of embodiments 237 - 239, wherein the tau PET level is measured using the MK6240 radiotracer.

[0417] 241. The method according to embodiment 240, wherein the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, of the entire cortical gray matter, as measured in an MK6240 PET scan. BRIEF DESCRIPTION OF THE DRAWINGS

[0418] Figure 1 A graph showing the adjusted mean change (± standard error, SE) relative to baseline tau PET SUVR over time in subjects administered with lecanemab or placebo.

[0419] Figure 2 Shows the effect of administering lecanemab in the entorhinal cortex of subjects.

[0420] Figure 3 A graph showing the functional relationship between the adjusted change relative to baseline tau PET SUVR at 18 months and the baseline tau PET SUVR.

[0421] Figure 4 Shows the effect of lecanemab on tau PET SUVR in selected brain regions.

[0422] Figure 5 Shows the baseline tau PET SURV of the composite region in subjects receiving lecanemab and subjects receiving placebo.

[0423] Figure 6 Shows an increase in baseline tau PET SUVR in subjects in clusters 1 to 4.

[0424] Figure 7 Shows the effect of lecanemab on the adjusted mean change relative to baseline of Tau PET SUVR in subjects with different APOE4 statuses.

[0425] Figure 8Shows the comparison of the effect of lecanemab on the adjusted mean change of Tau PET SUVR relative to baseline in subjects homozygous for the APOE4 allele and heterozygous for the APOE4 allele.

[0426] Figure 9 Compares the effect size of the adjusted mean change relative to baseline of Tau PET SUVR in subjects homozygous for the APOE4 allele with that in subjects who are non-carriers and subjects heterozygous for the APOE4 allele.

[0427] Figure 10 Shows the effect of lecanemab in all brain regions and total tau burden (TauIQ) in subjects homozygous for the APOE4 allele carrier at 18 months.

[0428] Figure 11 Shows the effect of lecanemab in subjects who are non-carriers of the APOE4 allele at 18 months.

[0429] Figure 12 Shows the effect of lecanemab in subjects who are carriers of the APOE4 allele at 18 months.

[0430] Figure 13 Shows the effect of lecanemab in subjects heterozygous for the APOE4 allele at 18 months.

[0431] Figure 14 Shows the effect of lecanemab in brain regions and total tau burden (TauIQ) in subjects below the first quartile (<Q1) at 13 months and 18 months.

[0432] Figure 15 Shows the effect of lecanemab in subjects from the first quartile (Q1) up to the third quartile (<Q3) at Figure 14 the same time points and regions.

[0433] Figure 16 Shows the effect of lecanemab in subjects above the third quartile (>Q3) at Figure 14 and 15 the same time points and regions.

[0434] Figure 17 Shows the change in amyloid PET levels relative to baseline.

[0435] Figure 18 Shows the results obtained from the open-label extension of Study 201.

[0436] Figure 19Shows the results of clinical endpoints (measuring ADCOMS, CDR-SB, ADAS-Cog14) in Study 201.

[0437] Figure 20 Shows the adjusted mean change in CDR-SB relative to baseline in Study 301.

[0438] Figure 21 Shows the adjusted mean change in ADAS-Cog14 relative to baseline in Study 301.

[0439] Figure 22 Shows the adjusted mean change in ADCS MCI-ADL relative to baseline in Study 301.

[0440] Figure 23 Shows that in Study 301, administration of lecanemab reduced brain amyloid-β plaques (adjusted mean change in amyloid-β PET percentage units relative to baseline).

[0441] Figure 24 Shows the health-related quality of life measure - EQ-5D-5L (healthy living subjects).

[0442] Figure 25 Shows the health-related quality of life measure - QOL-AD (total score subjects).

[0443] Figure 26 Shows the health-related quality of life measure - QOL-AD (proxy subjects).

[0444] Figure 27 Shows the health-related quality of life measure - Zarit Burden Interview - study collaborator burden (total score).

[0445] Figure 28 Shows the time to deterioration of the total CDR score.

[0446] Figure 29 Shows the analysis of CDR-SB: observed data and extrapolated slope to 2 years.

[0447] Figure 30 Shows the change in plasma GFAP levels after treatment with lecanemab.

[0448] Figure 31 Shows the average scan results of patients in the Tau PET substudy.

[0449] Figure 32 Shows the tau PET SUVr in Braak staging regions in subjects with low whole-cortex tau aggregation.

[0450] Figure 33 Shows the sorting by decreasing median baseline tau PET SUVr.

[0451] Figure 34 Shows the regional tau PET SUVr in subjects in the low-tau PET subgroups that are amyloid positive or negative based on the 30CL cut-off value.

[0452] Figure 35 Shows the regional tau PET SUVr in subjects in the low-tau PET subgroups who are ApoE4 carriers or non-carriers.

[0453] Figure 36 Shows that compared with placebo, lecanemab slowed down tau pathology in the medial temporal lobe, posterior temporal lobe, and temporal lobe.

[0454] Figure 37 Summarizes the adjusted mean differences in tau pathology as measured by tau-PET SUVr in the brain regions in patients receiving lecanemab compared with those receiving placebo.

[0455] Figure 38 Shows the efficacy of lecanemab on cognitive and functional outcomes in subjects from the overall early AD patients studied in CLARITY (representative tau PET sub-study) and in subjects in the low-tau and medium-high tau subgroups.

[0456] Figure 39 Shows that lecanemab affects different brain regions in the low-tau PET group compared with the medium + high-tau PET group.

[0457] Figure 40 Shows the effects of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in the subjects in the Clarity AD study.

[0458] Figure 41 Shows the effects of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in the subjects from the tau PET sub-study.

[0459] Figure 42 Shows the effects of lecanemab on CDR-SB, ADAS-Cog14, and ADCS MCI-ADL in the subjects with low tau PET levels.

[0460] Figure 43Shows the effect of lecanemab on CDR-SB in subjects with low tau PET levels at 18 months, showing the percentage of subjects who did not show CDR-SB decline and the percentage of subjects who showed CDR-SB improvement.

[0461] Figure 44 Shows amyloid PET levels and amyloid PET clearance rates in subjects from the Tau PET substudy.

[0462] Figure 45 shows fluid biomarkers in patients from the tau PET substudy.

[0463] Figure 46 Shows CDR-SB measurements in subjects in the early-start group and the late-start group.

[0464] Figure 47 Shows the test results of OLE in the context of the observational cohort.

[0465] Figure 48 Shows ADAS-Cog14 measurements in subjects in the early-start group and the late-start group.

[0466] Figure 49 Shows ADCS MCI-ADL measurements in subjects in the early-start group and the late-start group.

[0467] Figure 50 Shows CDR-SB measurements in subjects from the low tau-PET subgroup at 24 months.

[0468] Figure 51 Shows ADAS-Cog14 measurements in subjects from the low tau-PET subgroup at 24 months.

[0469] Figure 52 Shows ADCS MCI-ADL measurements in subjects from the low tau-PET subgroup at 24 months.

[0470] Figure 53 Shows the effect of lecanemab on CDR-SB in subjects with low tau PET levels at 18 - 24 months, showing the percentage of subjects who did not show CDR-SB decline and the percentage of subjects who showed CDR-SB improvement.

[0471] Figure 54 Shows the percentage of patients who showed "no decline" or "improvement" in the CDR-SB, ADAS-Cog 14, and ADCS MCI-ADL analyses using lecanemab up to 24 months.

[0472] Figure 55 It shows that low tau PET levels are associated with lower levels of amyloid PET.

[0473] Figure 56 It shows the clinical outcomes of subjects with baseline amyloid PET <60CL.

[0474] Figure 57 It shows the results of biomarker analysis in patients receiving lecanemab for 24 months. Detailed Description

[0475] The "amyloid hypothesis" proposes that amyloid-β (Aβ) peptides play a central role in the pathogenesis of AD. Specifically, it is hypothesized that neurodegeneration in AD can be caused by the deposition of Aβ plaques in the brain tissue, which is attributed to an imbalance between Aβ production and Aβ clearance, such that neurofibrillary tangles containing tau protein are formed. Aβ peptides generally exist in a dynamic continuum of conformational states, such that the species tend to develop from monomeric Aβ into soluble Aβ aggregates, which include a range of low molecular weight oligomers to higher molecular weight protofibrils, and finally develop into insoluble fibrils (plaques). Targeting these soluble and insoluble Aβ tangles and plaques can provide therapeutic benefits.

[0476] For the purpose of reducing the amount of insoluble Aβ protofibrils deposited in the brain, a variety of immunotherapies have been developed. However, the simple correlation between the amount and progressive accumulation of insoluble amyloid plaques and the clinical course of AD has not been established. Although therapeutic strategies continue to focus on removing insoluble amyloid plaques, an alternative treatment approach may include reducing toxic Aβ aggregates, such as oligomers, which may contribute to the neurodegenerative features 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).

[0477] In various embodiments, when amyloid has been deposited in the brain, but the downstream neurodegenerative cascade that is thought to be triggered by amyloid deposition is still relatively early in its course (i.e., limited brain tissue damage has occurred and the associated clinical deficits are at a minimum), anti-Aβ oligomer antibodies such as BAN2401 and other anti-Aβ oligomer antibodies can be used to treat AD, for example, by slowing the progression of AD in a subject (e.g., those subjects in the early stages of the disease).

[0478] A. Definitions

[0479] The following are definitions of terms used in this application.

[0480] Unless the context clearly indicates otherwise, the singular terms “a / an” and “the” as used herein include plural referents.

[0481] As used herein, the phrase "and / or" means "any one or both" of the elements so joined, i.e., the elements exist conjointly in some cases and separately in other cases. Thus, as a non-limiting example, "A and / or B", when used in conjunction with open-ended language such as "comprising", can in some embodiments refer only to A (optionally including elements other than B); in other embodiments, only to B (optionally including elements other than A); in still other embodiments, to both A and B (optionally including other elements); and so forth.

[0482] As used herein, "at least one" means one or more elements in a list of elements, but necessarily includes at least one of each and every element specifically listed in the list of elements, and does not exclude any combinations of elements in the list. This definition also allows for other elements to optionally occur in addition to the elements specifically identified in the list of elements referred to by the phrase "at least one", whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B", or equivalently "at least one of A and / or B") can in one embodiment refer to at least one, optionally including more than one A, without B (and optionally including elements other than B); in another embodiment, can refer to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, can refer to at least one, optionally including more than one A, and at least one, optionally including more than one B (and optionally including other elements); and so forth.

[0483] As used herein, "about", when used in conjunction with a dose, amount, or ratio, includes values of the specified dose, amount, or ratio or ranges of doses, amounts, or ratios recognized by one of ordinary skill in the art as providing equivalent therapeutic effects to those obtained from the specified dose, amount, or ratio. The term "about" can refer to an acceptable error of a particular value determined by one of ordinary skill in the art, which acceptable error depends in part on how the values are measured or determined. In some embodiments, the term "about" means within 5% of a given value or range.

[0484] When a number is recited alone or as part of a numerical range, it should be understood that the numerical value can vary by up to + / - 10% of the recited value above and below the recited value.

[0485] When ranges of values are listed herein, it is intended that each value and sub-range within the range be covered. For example, "2.5 mg / kg to 10 mg / kg" is intended to cover, 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.

[0486] As used herein, "adjusted mean change relative to baseline" refers to using statistical analysis to calculate the change in biomarker values 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 relative to baseline.

[0487] Amyloid beta 1-42 (Aβ42) refers to the amyloid beta monomer of amino acids 1 to 42 from the full-length protein (Table 5, SEQ ID NO: 13). Amyloid beta 1-40 (Aβ1-40) refers to the amyloid beta monomer of amino acids 1 to 42 from the full-length protein (Table 5, SEQ ID NO: 14).

[0488] 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.

[0489] 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).

[0490] Patients with "preclinical AD" or "prodromal 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 impairment and emerging episodic memory and executive function deficits. Cognitively normal can include individuals with a CDR of 0, or individuals within the normal range of cognitive test scores (MMSE, International Shopping List Task, Logical Memory, etc.). Preclinical AD occurs before significant irreversible neurodegeneration and cognitive impairment and is typically characterized by the presence of in vivo molecular biomarkers of AD without clinical symptoms. Preclinical AD biomarkers that may indicate future development of Alzheimer's disease include, but are not limited to, one or more of the following: moderate or elevated levels of amyloid in the brain determined by amyloid PET (e.g., a measure on a 100-point scale of about 20 - 40, e.g., a measure on a 100-point scale of about 20 - 32), fluorodeoxyglucose (FDG) PET, or tau positron emission tomography (PET); cerebrospinal fluid levels of Aβ1-42 and / or the Aβ1-42 / 1-40 ratio; cerebrospinal fluid levels of total tau; cerebrospinal fluid levels of microtubule-binding region (MTBR)-tau; cerebrospinal fluid levels of neurogranin; cerebrospinal fluid levels of neurofilament light chain (NfL); and blood biomarkers as measured in serum or plasma (e.g., levels of Aβ1-42, the ratio of two forms of amyloid beta peptide (Aβ1-42 / 1-40 ratio, e.g., a ratio between about 0.092 - 0.094 or below about 0.092), plasma levels of plasma total tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (including tau phosphorylated at 181 (P-tau181), 217 (P-tau217), and 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)). For example, it has been found that subjects treated with elenbecestat (E2609), a β-site amyloid precursor protein cleaving enzyme (BACE) inhibitor, with amyloid baseline positron emission tomography (PET) standardized uptake value ratio (SUVr value) of 1.4 to 1.9 showed 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, Illinois, USA. Similarly, subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 have been found not to exhibit detectable sufficient cognitive decline, while subjects with SUVr levels above 1.6 appear to be associated with a plateau effect where amyloid levels have reached a saturation level and treatment has not caused a 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, Illinois, USA.

[0491] "Early AD" or "early Alzheimer's disease" as used herein is a continuum of AD severity from mild cognitive impairment due to a moderate likelihood of AD to mild Alzheimer's dementia. Subjects with early AD include subjects with mild Alzheimer's dementia as defined herein and subjects with mild cognitive impairment (MCI) due to a moderate likelihood of AD as defined herein. In some embodiments, subjects with early AD have an MMSE score of 22 to 30 and a Clinical Dementia Rating (CDR) total range of 0.5 to 1.0. Other methods for detecting early AD disease can employ the tests and assays specified below, including the National Institute on Aging and Alzheimer's Association (NIA-AA) Core Clinical Criteria for probable Alzheimer's dementia in the following reference: McKhann, G.M. 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 CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, modified 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 AD have evidence of elevated amyloid in the brain or a positive amyloid burden. In some embodiments, elevated amyloid in the brain or a positive amyloid burden is indicated and / or confirmed by PET assessment. In some embodiments, elevated amyloid in the brain or a positive amyloid burden 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 in the brain or a positive amyloid burden is indicated and / or confirmed by measuring the level of p-tau181.In some embodiments, an elevated amyloid in the brain or a positive amyloid burden is indicated and / or confirmed by MRI. In some embodiments, an elevated amyloid in the brain or a positive amyloid burden is indicated by retinal amyloid accumulation. In some embodiments, more than one assessment method is used.

[0492] "Amyloid" refers to unbranched, generally extracellular, fibers found in the body; additionally, these fibers bind the dye Congo red and then 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", "brain amyloid", and "amyloid-β peptide (Aβ)" may be used interchangeably.

[0493] In some embodiments, a subject has "elevated amyloid" or "intermediate amyloid". Those of ordinary skill in the art will recognize that amyloid levels from amyloid PET can be reported in "centiloid units" (CL) using a centiloid unit method. (Klunk WE et al. The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer’s Dement. 2015;11:1–15e1–4). The centiloid unit method measures tracers in the range of 0 CL to 100 CL, where 0 is considered the anchor and represents the mean of young healthy controls, and 100 CL represents the mean amyloid burden present in subjects with mild to moderate severity dementia due to AD. (Ibid.). As is known to those of ordinary skill in the art, centiloid unit thresholds can vary, for example, they can be refined based on new or additional scientific information. (See, e.g., http: / / www.gaain.org / centiloid-project). An elevated amyloid level can be set relative to a baseline threshold in healthy controls determined according to methods known to those of ordinary skill in the art (POSA). For example, a centiloid unit value of 32.5 can be used as the threshold for "elevated amyloid", and an "intermediate amyloid" level refers to Aβ amyloid PET in the range of 20 - 32.5 CL (e.g., 30 CL). In another example, a centiloid unit value of 40 can be used as the threshold for "elevated amyloid", and an "intermediate amyloid" level refers to Aβ amyloid PET in the range of 20 - 40 CL.

[0494] As used herein, a subject with "mild Alzheimer's dementia" or "mild AD dementia" is a subject who meets the National Institute on Aging and Alzheimer's Association (NIA-AA) Core Clinical Criteria for probable Alzheimer's dementia in the following reference: McKhann, G.M. 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 who, at screening and baseline, have a Clinical Dementia Rating (CDR) score of 0.5 to 1.0 and a Memory Box score of 0.5 or higher, and subjects who demonstrate a change in score on the Wechsler Memory Scale-Revised Logical Memory II (WMS-R LMII).

[0495] As used herein, a subject with "MCI due to intermediate probability of AD" is a subject so identified according to the NIA-AA Core Clinical Criteria for mild cognitive impairment due to intermediate probability of Alzheimer's disease (see McKhann, supra). For example, the subject may be symptomatic but not demented, and evidence of cerebral amyloid pathology renders them less heterogeneous and more similar to subjects with mild Alzheimer's dementia in terms of cognitive and functional decline, as measured by the ADCOMS composite clinical score as defined herein. Also included are subjects who, at screening and baseline, have a CDR score of 0.5 and a Memory Box score of 0.5 or higher. In addition, subjects with a history of subjective memory decline and gradual onset and slow progression reported by an informant within the most recent 1 year prior to screening are also included herein. Memory decline and / or episodic memory impairment of the subject can be evaluated by a change in score on the WMS-R LM II.

[0496] As used herein, "control subject", "untreated AD subject", or "untreated control subject" is a subject who has not received or has already received treatment 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 preclinical Alzheimer's disease. In some embodiments, the control subject has Alzheimer's disease and has not been treated with an anti-Aβ protofibril antibody.

[0497] The terms "patient" and "subject" are used interchangeably.

[0498] As used herein, "MMSE" refers to the Mini-Mental State Examination, a cognitive tool commonly used for screening purposes and also typically measured longitudinally in AD clinical trials, which has a 30-point scale where a higher score indicates a lower degree of impairment and a lower score indicates a higher degree of impairment, ranging from 0 (highest degree of impairment) to 30 (no impairment). In some embodiments, seven items measuring time and place orientation, registration, recall, attention, language, and drawing can be evaluated 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).

[0499] As used herein, "ADAS-Cog" refers to the Alzheimer's Disease Assessment Scale-Cognitive. ADAS-Cog is a cognitive scale commonly used in Alzheimer's disease trials, which has a structured scale evaluating memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (putting letters in an envelope), and construction praxis (copying geometric designs). (Rosen, W.G. et al., "A new rating scale for Alzheimer’s disease." Am. J. Psychiatry 1984; 141:1356-64). Grades for spoken language, language comprehension, word-finding difficulty, ability to remember test instructions, maze, and digit cancellation can also be obtained. In some embodiments, ADAS-Cog refers to the use of the Alzheimer's Disease Assessment Scale-Cognitive subscale14 (ADAS-Cog14). In some embodiments, modified forms may be used herein and scored from 0 to 90 points, where 0 points indicates no impairment and 90 points indicates the highest degree of impairment. In some embodiments, the ADAS-Cog14 tasks include memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (putting letters in envelopes), constructive praxis (copying geometric designs), speech, language comprehension, word-finding difficulty, ability to remember test instructions, maze, and digit cancellation (Rosen et al., 1984).

[0500] As used herein, "CDR-SB" refers to the Clinical Dementia Rating - Sum of Boxes. CDR is a clinical scale that describes five levels of impairment in the performance aspects of six functional categories including memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal 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 box scores 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 scores for each category, resulting in a total possible score of 0 to 18, where a higher score indicates a higher degree of impairment.

[0501] As used herein, the "CDR total", "total CDR" score, and "total dementia rating CDR" score may be used interchangeably. As used herein, the CDR total score is an assessment of the degree of impairment obtained for each of the six functional categories in the six categories of the CDR scale and is synthesized into one overall assessment of the dementia CDR score (ranging from 0 to 3), where 0 indicates no cognitive impairment, 0.5 indicates mild cognitive impairment, and 1 - 3 indicate mild, moderate, and severe dementia, respectively. The total CDR score can be used as a clinical measure of the severity of dementia. In some embodiments, the total CDR score can be used to determine whether a patient has progressed or maintained the stage of AD, for example, a higher score on a subsequent evaluation indicates AD progression, and for example, no change in the score indicates no AD progression.

[0502] As used herein, "ADCOMS" refers to the Alzheimer's Disease Composite Score, a composite clinical score based on four ADAS-Cog items (delayed word recall, orientation, word recognition, and word finding difficulty), two Mini-Mental State Examination (MMSE) items (time orientation and drawing), and all six CDR-SB items (personal care, community affairs, home and hobbies, memory, orientation, and judgment and problem solving), as discussed in the Examples and in 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 (i.e., prodromal AD or early AD) stages of AD.

[0503] In some embodiments, ADCOMS can be calculated using the following formula:

[0504]

[0505] where A i (t), B i (t), and C i (t) are the item scores at time t corresponding to the items from ADAS-cog, reverse MMSE score, and CDR-SB, respectively (Wang, J. et al., "ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials"). ADCOMS is particularly sensitive to disease progression during the early stages of AD, i.e., prodromal and mild AD.

[0506] As used herein, "ADCS MCI-ADL" refers to the Alzheimer's Disease Cooperative Study - Activities of Daily Living for Mild Cognitive Impairment (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical scale used to assess 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.

[0507] As used herein, "modified iADRS" or "iADRS" refers to a composite tool that combines scores from ADAS Cog14 (all items) and ADCS MCI-ADL (all items). The modified iADRS score can be used to evaluate disease progression:

[0508] Modified iADRS score = [-1(ADAS-cog14)+90]+ADCS MCI-ADL.

[0509] As used herein, "ApoE4 positive" subjects and "ApoE4 carriers" refer to subjects having the ε4 variant of the apolipoprotein (APOE) gene. The ε4 variant is one of several major alleles of the apolipoprotein gene. This gene is generally responsible for fat metabolism. It has been found that carriers of apolipoprotein ε4 show significantly higher amyloid retention rates when compared to non-carriers. (Drzezga, A. et al., "Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease." Neurology. 2009;72:1487-94). In some embodiments, the subjects treated herein are heterozygous carriers of the apolipoprotein E ε4 gene allele. In some embodiments, the subjects are homozygous carriers of the apolipoprotein E ε4 gene allele. The terms "ApoE4 negative" and "ApoE4 non-carrier" are used interchangeably.

[0510] As used herein, whether an early AD subject is "amyloid positive" or "amyloid negative" can be determined based on whether the subject has a positive amyloid burden. In some embodiments, a subject is determined to be amyloid positive or amyloid negative as indicated by longitudinal positron emission tomography (PET) evaluation of the uptake of an imaging agent (e.g., an amyloid imaging agent or a tau imaging agent) into the brain. In some embodiments, evaluation by tau PET imaging determines whether a subject is amyloid positive or amyloid negative. In some embodiments, if the PET SUVr is negative and below a threshold determined for the amyloid PET tracer, the subject is "amyloid negative". In some embodiments, the amyloid PET tracer can be florbetaben (e.g., 18F-Florbetaben )、florbetapir (e.g., 18F-Florbetapir ) and / or flutametamol (e.g., 18F-Flutemetamol ). In some embodiments, the threshold for the PET SUVr of the amyloid PET tracer is about 1.17, and a measurement below this threshold may 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 SUVr threshold is about 1.17. In some embodiments, the level of a biomarker (e.g., the Aβ42 / 40 ratio) in a sample from a subject is evaluated, either alone or in combination with another method (such as PET measurement of brain amyloid), to determine whether the subject is amyloid positive or amyloid negative. In some embodiments, if the Aβ42 / 40 ratio in the sample is equal to or about higher than 0.092 - 0.094, e.g., equal to about 0.092, the subject is "amyloid negative". In some embodiments, if the Aβ42 / 40 ratio in the sample is higher than 0.092, the subject is "amyloid negative". In some embodiments, the presence of amyloid pathology is determined to be amyloid positive or amyloid negative by CSF evaluation using an assessment of a biomarker (such as p-tau181), either alone or in combination with another method (such as PET measurement of brain amyloid). In some embodiments, a qualitative visual reading of a PET scan can be used to determine amyloid positivity and negativity by classifying the subject as having "normal" or "abnormal" uptake based on the PET image pattern. The reader will have been trained and qualified to recognize brain PET images with abnormal or normal uptake patterns, or to detect amyloid by semi-quantitative or quantitative methods. In some embodiments, thresholds will be set for quantitatively determining from a biomarker (e.g., serum or CSF) and / or a PET scan whether the Aβ brain load indicates that the subject is amyloid positive or negative. In some embodiments, a subject is determined to be amyloid positive or negative by an imaging method. The imaging method can be used to determine, calculate, or predict whether the subject is amyloid positive or negative, even when the imaging method is not used to directly visualize amyloid. In some embodiments, the method uses MRI, and / or combines MRI with other imaging modalities such as PET. In some embodiments, a subject is determined to be amyloid positive or negative by retinal amyloid accumulation. In some embodiments, a subject is determined to be amyloid positive or negative by a behavioral / cognitive phenotype.

[0511] As will be understood by one of ordinary skill in the art, numerical, computer, and / or conventional (e.g., pen and paper) cognitive tests can be used to detect early cognitive changes that may indicate a risk of mild cognitive impairment and / or developing dementia, and can thus be used to identify subjects in need of treatment as disclosed herein. For example, such tests can screen for cognitive impairment and can potentially identify individuals with MCI. The tests can use artificial intelligence to analyze the cognitive test results to determine whether cases of mild cognitive impairment will progress to Alzheimer's disease within a year. Early diagnosis of the condition before symptoms begin to appear can be used to help doctors identify earlier subjects in need of treatment as disclosed herein, potentially delaying the onset or reducing the severity of neurodegenerative diseases.

[0512] As used herein, the term "treatment" refers to any administration or application of a therapeutic agent to a subject for a disease or disorder, and includes inhibiting the disease, slowing the progression of the disease, delaying progression, preventing its development, reversing the progression of the disease (e.g., reversing the accumulation of Aβ protofibrils), preventing the onset or development of the disease, alleviating or improving 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, treatment of AD in a subject includes administering (e.g., by intravenous infusion) an anti-amyloid beta (Aβ) protofibril antibody. In some embodiments, treatment of AD in a subject includes administering (e.g., by intravenous infusion) a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody.

[0513] As used herein, the term "infusion" refers to the active administration of one or more agents over a period of time, such as for example about 60 minutes. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibody described herein is administered systemically to a human subject via infusion. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibody is alternatively administered to a human subject, for example, by subcutaneous injection. In some embodiments, the subcutaneous injection is a weekly injection. In some embodiments, the subcutaneous injection is a bi-weekly injection. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibody is administered to a human subject by intravenous infusion.

[0514] In some embodiments, a maintenance dose of a treatment is administered to a subject. As used herein, the term "maintenance dose" refers to the dose administered to a subject to maintain a desired therapeutic effect. In some embodiments, the maintenance dose is administered weekly, bi-weekly, monthly, every two months, every three months (quarterly), or every 24 weeks (every six months or semi-annually). 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 bi-weekly. In some embodiments, the maintenance dose is administered subcutaneously, orally, or nasally. In some embodiments, the maintenance dose is administered subcutaneously.

[0515] 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 bi-weekly 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 at a lower frequency (e.g., every two weeks (bi-weekly), every four weeks, monthly, every six weeks, every eight weeks (2 months), every three months (quarterly), or every six months (semi-annually)). In some embodiments, the maintenance dose is administered as a bi-weekly subcutaneous injection of 720 mg. In some embodiments, the maintenance dose is administered as a bi-weekly subcutaneous injection of 720 mg, comprising two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of a 400 mg / 2 mL) subcutaneous formulation.

[0516] 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 at a lower frequency than during an earlier treatment course.

[0517] In some embodiments, after conversion to the maintenance dose, the biomarker level of the subject may indicate an increase in the level of amyloid in the brain. In some embodiments, after conversion to the maintenance dose, the biomarker level of the subject may begin to deteriorate, e.g., an increase in the plasma Aβ42 / 40 ratio, indicating an increase in the level of amyloid in the brain. In some embodiments, the Aβ42 / 40 ratio of a subject receiving the maintenance dose may decrease. In some embodiments, the subject receives a selected maintenance dose such that the Aβ42 / 40 ratio of the subject may decrease, but the Aβ42 / 40 ratio may remain above the amyloid positive threshold, e.g., for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0518] In some embodiments, after conversion to a maintenance dose, the biomarker level of a subject (e.g., tau PET level) may begin to increase or the rate of increase may increase. In some embodiments, such a subject may be moved back to the treatment regimen. In some embodiments, for example, if the increase remains below the tau PET level or rate of increase observed in control subjects with AD who have not received an anti-Aβ protofibril antibody, the subject may remain on the maintenance dose.

[0519] As used herein, the term “prevent” refers to obtaining a favorable 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 having one or more preclinical symptoms but not clinical symptoms of Alzheimer's disease; or to a subject reporting one or more physical symptoms of Alzheimer's disease, although a clinical diagnosis of having Alzheimer's disease has not been made. As used herein, “prevent” may further include a therapeutic benefit, which means eradicating or ameliorating a latent condition being treated or one or more physical symptoms associated therewith.

[0520] As used herein, the term “ARIA” refers to amyloid-related imaging abnormalities, as evaluated using MRI. In some embodiments, ARIA includes amyloid-related imaging abnormality edema / effusion (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, and these may be used to identify subjects with ARIA or indicate further evaluation of ARIA. In some embodiments, ARIA is evaluated at specified intervals during treatment. In some embodiments, ARIA is evaluated when a subject experiences symptoms of ARIA. In some embodiments, the maximum serum concentration (Cmax) of an anti-Aβ protofibril antibody can be used as a predictor of the risk of ARIA-E. In some embodiments, the risk of ARIA-E can be reduced (e.g., due to a lower Cmax) using a subcutaneous formulation compared to IV administration.

[0521] As used herein, the term "clinical decline" refers to the worsening of one or more clinical symptoms of AD. Methods for measuring clinical decline can employ the tests and assays specified herein. In some embodiments, clinical decline is determined by worsening of ADCOMS. In some embodiments, clinical decline is determined by worsening of MMSE. In some embodiments, clinical decline is determined by worsening of ADAS-Cog. In some embodiments, clinical decline is determined by worsening of FAQ. In some embodiments, clinical decline is determined by worsening of CDR-SB. In some embodiments, clinical decline is determined by worsening of the Wechsler Memory Scale-IV Logical Memory (subscale) I and / or (subscale) II. In some embodiments, clinical decline is determined by worsening of the CDR score. In some embodiments, clinical decline refers to the worsening of one or more biomarkers of AD or brain measurements such as brain atrophy and / or amyloid accumulation (e.g., by PET or MRI).

[0522] 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 is collected from a subject to evaluate potential biomarkers of AD, which may include amyloid fragments and isotypes, tau, and other protein biomarkers associated with AD diagnosis, amyloid or tau load, or disease modification (e.g., neurofilament light chain or NfL). In some embodiments, if possible, the subject is required to fast prior to collection at week 96 and week 216. In other embodiments and / or at other time points, the subject does not need to fast. Levels of pre-AD biomarkers that may indicate the development 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).

[0523] B. Anti-Aβ protofibril antibody and tau PET levels

[0524] In various embodiments, methods are disclosed herein for selecting patients, treating, monitoring treatment, and making decisions regarding maintenance dosing in patients receiving an anti-amyloid-β protofibril antibody (also referred to as an “anti-amyloid-β (Aβ) protofibril antibody” or “anti-Aβ protofibril antibody”) such as BAN2401. 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, for example, a reduced rate of increase or an overall reduction in tau levels in the temporal region of the brain, as measured by PET. In some embodiments, these methods include measuring the tau PET level of a subject. In some embodiments, these methods include measuring the tau PET level of a subject with or suspected of having AD prior to treatment and / or re-measuring the tau PET level in another sample during treatment (it should be understood, however, that additional doses may be administered between sampling time points). In some embodiments, the measurement includes measuring the temporal region of the brain. In some embodiments, an increase in the tau PET level (e.g., in the temporal region) compared to a control subject (e.g., a subject without AD) indicates that the subject is suitable for treatment with an anti-Aβ protofibril antibody such as BAN2401. In some embodiments, a reduction in the tau PET level and / or rate of increase after receiving one or more doses of an anti-Aβ protofibril antibody such as BAN2401 indicates treatment efficacy. In some embodiments, if a reduction in the tau PET level or a reduction in the tau PET rate of increase is detected, a subsequent dose of treatment is administered after a second sampling. In some embodiments, treatment can be titrated based on changes in the tau PET level.

[0525] In some embodiments, additional patient demographics such as age and whether the subject is a carrier of the apolipoprotein E ε4 gene allele can be used in combination with tau PET measurements to select patients for treatment. For example, they can be used 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 can be used in combination with tau PET measurements (e.g., one or more blood biomarkers such as the ratio of Aβ42 to Aβ40 and / or p - tau181). In some embodiments, the age of the subject and / or the standardized measurement of the apolipoprotein E ε4 gene allele of tau PET and / or at least one additional biomarker are used to evaluate whether a sample from the subject (e.g., a plasma sample) indicates that the subject is suitable for treatment with a protofibril antibody such as BAN2401 (e.g., whether 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 can be considered amyloid - positive when the biomarker levels are lower than the levels required to indicate amyloid positivity in a non - carrier subject. Similarly, in another example, an older subject can be considered amyloid - positive when the biomarker levels are lower than the levels required to indicate positivity in a younger subject. In some embodiments, biomarker levels are used to predict amyloid positivity in a receiver operating characteristic (ROC) analysis. In some embodiments, additional patient demographics such as age and whether the subject is a carrier of the apolipoprotein E ε4 gene allele can be used in the ROC analysis in combination with biomarker levels to predict amyloid positivity. In some embodiments, the prediction of a patient's amyloid positivity is used to determine the dose or frequency of treatment.

[0526] In some embodiments, the methods disclosed herein include measuring the tau PET level of a subject with or suspected of having AD prior to treatment with an anti-Aβ protofibril antibody to identify patients suitable for treatment and / or re-measuring the tau PET level in another sample during treatment to monitor treatment efficacy (it should be understood that additional doses may be administered between sampling time points). In some embodiments, if the tau PET level or rate of increase decreases relative 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., decreasing the frequency and / or dose). In some embodiments, further measurements of the tau PET level may be made on the subject after treatment has been stopped or reduced. In some embodiments, if the tau PET level increases relative to the control subject, treatment is restarted, the dose is increased, and / or the frequency of administration is increased. In some embodiments, the dose or frequency of treatment is increased to restore the dose and / or frequency used in a previous treatment (e.g., prior to the start of dose reduction and / or extended dose frequency). In some embodiments, these methods include measuring the tau PET level of a subject during treatment and re-measuring the tau PET level after treatment has been stopped or after the dose 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 the tau PET level or rate of increase is detected, treatment is resumed, or the dose or frequency of treatment is increased compared to the dose or frequency during the period of the level increase. In some embodiments, multiple measurements may be made during treatment prior to deciding to stop treatment and / or reduce treatment based on a decrease in the rate of increase of the tau PET level relative to the control (e.g., based on a trend showing a decrease in the rate of tau accumulation in each subsequent measurement). In some embodiments, multiple measurements may be made after treatment has been stopped or reduced, and a decision to resume treatment and / or increase treatment may be made based on the tau PET level (e.g., based on a trend showing an increase in the rate of tau accumulation relative to the control). In some embodiments, one or more additional measurements of the tau PET level of the subject may be made after treatment is resumed or the treatment regimen is increased. In some embodiments, the tau PET level measurement is performed in conjunction with the measurement of 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, if the tau PET level does not change relative to the control (e.g., relative to an untreated AD subject), treatment may be stopped. In some embodiments, treatment may be stopped due to low treatment efficacy.

[0527] In some embodiments, any method that includes measuring tau PET levels may further include measuring one or more additional biomarkers, or may include measuring one or more additional biomarkers instead of measuring tau PET levels. In some embodiments, any method that includes measuring tau PET levels may further include measuring one or more additional biomarkers. In some embodiments, the additional biomarkers include volumetric MRI (vMRI), such as measuring whole brain volume, cortical thickness, total hippocampal volume, and / or lateral ventricle volume. In some embodiments, one or more additional biomarkers include PET levels, such as amyloid PET levels and / or fluorodeoxyglucose (FDG) PET levels. In some embodiments, one or more additional biomarkers include the 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), 205 (P-tau205), 217 (P-tau217), and 231 (P-tau231)), neurogranin, neurofilament light chain (NfL), and / or microtubule-binding region (MTBR)-tau containing residue 243 (MTBR-tau243). In some embodiments, one or more additional biomarkers include the 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), 205 (P-tau205), 217 (P-tau217), and 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). In some embodiments, one or more additional biomarkers include the microtubule-binding region of tau containing residue 243 (MTBR-tau243). Recent studies have shown that the expression of MTBR-tau243 in CSF and plasma can be correlated 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).

[0528] In some embodiments, provided herein is a method of reducing and / or slowing clinical decline in a subject (e.g., a subject having Alzheimer's disease, pre-AD, or early Alzheimer's disease), the method comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody (e.g., BAN2401) to a patient having a tau PET level that is higher than that of a subject not having AD. In some embodiments, an anti-Aβ protofibril antibody (e.g., BAN2401) is administered to a patient having a tau PET level that is higher than that of a subject not having AD in a therapeutically effective amount. In some embodiments, a decrease in the rate of increase of the tau PET level indicates that cognitive decline in a patient (e.g., a patient having pre-AD or early AD) is slowed relative to decline without treatment. In some embodiments, a decrease in the rate of tau accumulation indicates that cognitive decline in a patient (e.g., a patient having pre-AD or early AD) is slowed relative to decline without treatment. In some embodiments, after detection of a decrease in the rate of increase of tau PET, e.g., as measured 18 months after the start of treatment, the subject may be moved to a maintenance dosing regimen. In some embodiments, after detection of a decrease in the rate of increase of tau PET in combination with a decrease in one or more additional biomarkers of AD progression, e.g., as measured 18 months after the start of treatment, the subject may be moved to a maintenance dosing regimen.

[0529] In some embodiments, provided herein is a method of improving the cognitive outcome of a subject (e.g., a subject having Alzheimer's disease, pre-AD, or early Alzheimer's disease), the method comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody (e.g., BAN2401) to a patient having a tau PET level higher than that of a subject not having 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, modified 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, an anti-Aβ protofibril antibody (e.g., BAN2401) is administered to a patient having a tau PET level higher than that of a subject not having AD in a therapeutically effective amount. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered as a therapeutically effective dose comprising intravenous infusion of 10 mg / kg relative to the body weight of the subject. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered as a therapeutically effective dose comprising subcutaneous administration of 720 mg. In some embodiments, the method results in a reduction in cognitive decline as measured by ADCOMS compared to an untreated subject. In some embodiments, the method results in at least a 24% (e.g., at least a 29%) reduction in cognitive decline as measured by ADCOMS compared to an untreated subject. In some embodiments, the method results in a reduction in cognitive decline as measured by CDR-SB compared to an untreated subject. In some embodiments, the method results in at least a 26% (e.g., at least a 27%) reduction in cognitive decline as measured by CDR-SB compared to an untreated subject. In some embodiments, the method results in a reduction in cognitive decline as measured by ADAS-Cog14 compared to an untreated subject. In some embodiments, the method results in at least a 26% (e.g., at least a 47%) reduction in cognitive decline as measured by ADAS-Cog14 compared to an untreated subject. In some embodiments, the method results in a reduction in cognitive decline as measured by ADCS MCI-ADL compared to an untreated subject. In some embodiments, the method results in at least a 37% reduction in cognitive decline as measured by ADCS MCI-ADL compared to an untreated subject. In some embodiments, the method reduces the risk of progression to a subsequent stage of AD as measured by the CDR total score, e.g., a higher score on a subsequent assessment indicates progression to the next stage of AD, e.g., no change in the score indicates remaining in the same stage of AD.In some embodiments, the measurements are taken at least 6 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the measurements are taken at least 12 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the measurements are taken at least 13 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the measurements are taken at least 18 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0530] In some embodiments, provided herein is a method of treatment using tau PET levels or the rate of change of tau PET levels from a brain region (e.g., the temporal region). For example, in some embodiments, the treatment comprises intravenous or subcutaneous administration of an anti-Aβ protofibril antibody, such as BAN2401. In some embodiments, the method of treatment comprises using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to determine conversion to a maintenance intravenous or subcutaneous dose at a set time point (e.g., after 18 months). In some embodiments, the method of treatment comprises using biomarker levels (e.g., tau PET levels or the 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 fluid sample such as a blood sample). In some embodiments, the combination comprises amyloid PET measurements. In some embodiments, the combination comprises serum or plasma GFAP measurements. In some embodiments, the same biomarker or combination of biomarkers can be used to select patients to be treated with a protofibril antibody (e.g., BAN2401) by comparison to levels in a control subject (e.g., a subject not suffering from AD).

[0531] An anti-Aβ protofibril antibody (such as BAN2401) can be formulated in a pharmaceutical composition as disclosed in PCT / IB2021 / 000155 (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 that comprises 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 that comprises 100 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.

[0532] In some embodiments, BAN2401 is formulated as disclosed in PCT / IB2021 / 000155 (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 that comprises 200 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.

[0533] In some embodiments, provided herein is a method of treatment that includes 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 of tau PET levels) or another therapeutic outcome measure is achieved. In some embodiments, treatment is continued until a desired improvement in one or more biomarkers or other therapeutic outcome measure is achieved, such as when the tau PET level increases by no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment. In some embodiments, treatment is continued until the tau PET level has improved relative to untreated control subjects, and / or treatment is continued until the ratio of Aβ1-42 to Aβ1-40 in a fluid sample (e.g., a blood sample) increases. In some embodiments, treatment is continued until the tau PET level has improved relative to untreated control subjects and / or until the ratio of Aβ1-42 to Aβ1-40 in a fluid sample (e.g., a blood sample) is equal to or higher than 0.092. In some embodiments, treatment is continued until the tau PET level has improved relative to untreated control subjects and / or the level of p-tau181 in a fluid sample (e.g., a blood sample) decreases. In some embodiments, treatment is continued until the tau PET level has improved relative to untreated control subjects and / or the amyloid PET SUVr is negative below a threshold of about 1.17. In some embodiments, the amyloid PET tracer can be florbetaben (e.g., 18F-Florbetaben ), florbetapir (e.g., 18F-Florbetapir ), and / or flutametamol (e.g., 18F-Flutemetamol ). In some embodiments, the threshold for the PET SUVr of 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 SUVr threshold is about 1.17.

[0534] In some embodiments, one or more biomarkers include serum or plasma GFAP measurements. In some embodiments, treatment is continued until the subject is amyloid negative. In some embodiments, after achieving the desired improvement in one or more biomarkers (e.g., tau PET levels or other treatment outcome measures), the subject will be switched to a maintenance dose. In some embodiments, in addition to the anti-Aβ protofibril antibody, the maintenance dosing regimen may further comprise one or more additional therapies, e.g., it may include administration of E2814.

[0535] In some embodiments, provided herein is a method of treatment that includes administering a therapeutically effective dose of an anti-Aβ protofibril antibody until an improvement in cognitive outcomes or other treatment outcome measures of a subject (e.g., a subject having Alzheimer's disease, pre-AD, or early Alzheimer's disease) is achieved in combination with tau PET levels or the rate of change of tau PET. In some embodiments, the method of treatment includes administering a therapeutically effective dose of an anti-Aβ protofibril antibody until the tau PET levels have improved relative to untreated control subjects and an improvement in cognitive outcomes or other treatment outcome measures of the subject is achieved. 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, for example, until the patient has an increase in tau PET levels of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) and an improvement in cognitive outcomes of the subject is achieved. 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, modified 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 method of treatment that includes administering a therapeutically effective dose of an anti-Aβ protofibril antibody continues until cognitive decline is reduced relative to untreated subjects, as measured by ADCOMS. In some embodiments, the efficacy of the method of treatment can be evaluated using the CDR total score, wherein the CDR total score can be used to determine whether a patient has progressed or maintained the stage of AD during treatment, e.g., a higher score on a subsequent evaluation indicates AD progression, e.g., no change in the score indicates no AD progression. In some embodiments, the method of treatment continues until cognitive decline is reduced by at least 24% (e.g., at least 29%) relative to untreated subjects, as measured by ADCOMS. In some embodiments, the method of treatment continues until cognitive decline is reduced relative to untreated subjects, as measured by CDR-SB. In some embodiments, the method of treatment continues until cognitive decline is reduced by at least 26% (e.g., at least 27%) relative to untreated subjects, as measured by CDR-SB. In some embodiments, the method of treatment continues until cognitive decline is reduced relative to untreated subjects, as measured by ADAS-Cog14. In some embodiments, the method of treatment continues until cognitive decline is reduced by at least 26% (e.g., at least 47%) relative to untreated subjects, as measured by ADAS-Cog14.In some embodiments, the method results in a reduction of cognitive decline, as measured by ADCS MCI-ADL, compared to untreated subjects. In some embodiments, the method results in at least a 37% less cognitive decline, as measured by ADCS MCI-ADL, compared to untreated subjects. In some embodiments, the measurements are taken at least 6 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the measurements are taken at least 12 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the measurements are taken at least 13 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the measurements are taken at least 18 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0536] Methods of treatment (including dosing) by intravenous administration of anti-Aβ protofibril antibodies are disclosed in PCT / US2022 / 073576 and PCT / US2022 / 079571 and are incorporated herein by reference. In some embodiments, the treatment comprises intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example for at least 18 months or until the patient is amyloid negative. In some embodiments, the treatment comprises intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example for at least 18 months or until the patient is amyloid negative and then switched to a maintenance dose. In some embodiments, the method of treatment comprises intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example for at least 18 months or until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment, as evaluated by tau PET SUVR in the temporal region, and then switched to a maintenance dose. In some embodiments, the method of treatment comprises intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example for at least 18 months or until the tau PET level has improved relative to untreated control subjects and then switched to a maintenance dose. In some embodiments, the maintenance dose can be the same as the treatment dose or it can involve a reduced dose and / or frequency of administration.

[0537] Methods of treatment (including administration) by subcutaneous administration of anti-Aβ protofibril antibodies are disclosed in PCT / US2022 / 073576, PCT / US2022 / 079571, and PCT / US2022 / 041926 and are incorporated herein by reference. In some embodiments, the treatment comprises subcutaneous administration of an anti-Aβ protofibril antibody (e.g., administration of BAN2401 at 720 mg) weekly, for example for at least 18 months or for example until the patient is amyloid negative. In some embodiments, the treatment comprises subcutaneous administration of BAN2401 weekly, for example by two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation for a weekly subcutaneous injection of 720 mg, for example until the patient is amyloid negative or for example for at least 18 months or for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment, as evaluated by tau PET SUVR in the temporal region. In some embodiments, the treatment comprises subcutaneous administration of BAN2401 weekly, for example by two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation for a weekly subcutaneous injection of 720 mg, for example until the patient is amyloid negative or for example for at least 18 months or for example until the tau PET level has improved relative to untreated control subjects. In some embodiments, the treatment comprises subcutaneous administration of BAN2401 at a dose of 720 mg weekly, for example for at least 18 months or for example until the patient is amyloid negative, then switching to a subcutaneous maintenance dose, for example at a dose of 360 mg. In some embodiments, the treatment comprises subcutaneous administration of BAN2401 at a dose of 720 mg weekly, for example for at least 18 months or for example until the patient is amyloid negative, then switching to a subcutaneous maintenance dose every two weeks, for example at a dose of 720 mg. In some embodiments, the method of treatment comprises subcutaneous administration of BAN2401 weekly, for example by two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation for a weekly subcutaneous injection of 720 mg, for example for at least 18 months or for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment, as evaluated by tau PET SUVR in the temporal region, then switching to a maintenance dose. In some embodiments, the method of treatment comprises subcutaneous administration of BAN2401 weekly, for example by two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation for a weekly subcutaneous injection of 720 mg, for example for at least 18 months or for example until the tau PET level has improved relative to untreated control subjects, then switching to a maintenance dose.In some embodiments, the maintenance dose may be the same as the therapeutic dose, or it may involve a reduced dose and / or frequency of administration.

[0538] In some embodiments, the treatment method includes using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to determine conversion 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, the treatment includes intravenous administration of an anti-Aβ protofibril antibody followed by conversion to an intravenous maintenance dose. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment, as evaluated by tau PET SUVR in the temporal region, and then conversion to an intravenous maintenance dose. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example for at least 18 months or until the tau PET level has improved relative to untreated control subjects, and then conversion to an intravenous maintenance dose. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example for at least 18 months or for example until the patient is amyloid negative, and then conversion to an intravenous maintenance dose every two weeks. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment (as evaluated by tau PET SUVR in the temporal region) or for example until the tau PET level has improved relative to untreated control subjects, and then conversion to a monthly intravenous maintenance dose. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment (as evaluated by tau PET SUVR in the temporal region) or for example until the tau PET level has improved relative to untreated control subjects, and then conversion to a quarterly intravenous maintenance dose. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody followed by conversion to a subcutaneous maintenance dose.In some embodiments, treatment comprises intravenous administration of an anti-Aβ protofibril antibody (e.g., administration of BAN2401 at 10 mg / kg) every two weeks, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then switching to a subcutaneous maintenance dose, e.g., 720 mg administered weekly or every two weeks, 360 mg administered weekly, or 250 mg administered weekly. In some embodiments, an intravenous maintenance dose is administered every two weeks. In some embodiments, an intravenous maintenance dose is administered every four weeks. In some embodiments, an intravenous maintenance dose is administered every six weeks. In some embodiments, an intravenous maintenance dose is administered every eight weeks (2 months). In some embodiments, an intravenous maintenance dose is administered every three months (quarterly). In some embodiments, an intravenous maintenance dose is administered every 24 weeks (every six months or semi-annually). In some embodiments, treatment comprises intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then switching to an intravenous maintenance dose every two weeks.

[0539] In some embodiments, the treatment method includes using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to determine the conversion from subcutaneous treatment 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, the treatment includes subcutaneous administration of an anti-Aβ protofibril antibody followed by conversion to a subcutaneous maintenance dose. In some embodiments, the treatment includes subcutaneous administration of an anti-Aβ protofibril antibody at 720 mg every two weeks (e.g., sequential injection of a 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 after 13 or 18 months of treatment, as evaluated by tau PET SUVR in the temporal region, and then conversion to a subcutaneous injection of 720 mg once a week or every two weeks. In some embodiments, the treatment includes subcutaneous administration of an anti-Aβ protofibril antibody at 720 mg every two weeks (e.g., sequential injection of a 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation), for example for at least 18 months or until the tau PET level has improved relative to untreated control subjects, and then conversion to a subcutaneous injection of 720 mg once a week or every two weeks. In some embodiments, the maintenance dose is administered as a subcutaneous formulation of an anti-Aβ protofibril antibody injected subcutaneously once a week. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 720 mg once a week, including two simultaneous (e.g., sequential) injections of a 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 720 mg once a month, including two simultaneous (e.g., sequential) injections of a 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, the treatment includes subcutaneous administration of an anti-Aβ protofibril antibody at 720 mg once a week (e.g., sequential injection of a 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation), for example for at least 18 months or for example until the patient is amyloid negative, and then conversion to a subcutaneous injection of 720 mg every two weeks.

[0540] In some embodiments, the treatment method includes using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to determine the conversion from intravenous treatment to a maintenance dose. In some embodiments, the maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections). In some embodiments, the treatment includes administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or for example until the tau PET level has improved relative to an untreated control subject, and then converting to a subcutaneous maintenance dose. In some embodiments, the treatment includes administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every two weeks, for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or for example until the tau PET level has improved relative to an untreated control subject, and then converting to a subcutaneous maintenance dose once a week. In some embodiments, the treatment includes administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every two weeks, for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or for example until the tau PET level has improved relative to an untreated control subject, and then converting to a subcutaneous maintenance dose of 720 mg once a week. In some embodiments, the treatment includes administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every two weeks, for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or for example until the tau PET level has improved relative to an untreated control subject, and then converting to a subcutaneous maintenance dose of 720 mg every two weeks.

[0541] In some embodiments, the treatment method includes using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to determine the conversion from subcutaneous treatment to a maintenance dose. In some embodiments, the treatment includes subcutaneous administration of an anti-Aβ protofibril antibody, such as BAN2401, followed by conversion to an intravenous maintenance dose. In some embodiments, the treatment includes weekly subcutaneous administration of BAN2401, such as a subcutaneous injection of 720 mg, including two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL), e.g., until the patient has a tau PET level that has increased by no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then conversion to a maintenance dose. In some embodiments, the treatment includes weekly subcutaneous administration of BAN2401, such as at a dose of 720 mg, e.g., until the patient has a tau PET level that has increased by no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then conversion to a maintenance dose. In some embodiments, the treatment includes weekly subcutaneous administration of BAN2401, such as until the patient has a tau PET level that has increased by no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then conversion to an intravenous maintenance dose of 10 mg / kg every two weeks. In some embodiments, the maintenance dose of the subject is administered in the same amount and / or frequency as the dose during the treatment period. In some embodiments, the maintenance dose of the subject is 50% of the dose during the treatment period.

[0542] In some embodiments, the patient starts with an intravenous maintenance dose, such as administering 10 mg / kg BAN2401 as disclosed above, and then converts to a subcutaneous maintenance dose, such as a subcutaneous injection of 720 mg, including two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, the patient starts with a subcutaneous maintenance dose, such as a subcutaneous injection of 720 mg, including two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of 400 mg / 2 mL) subcutaneous formulation, and then converts to an intravenous maintenance dose, such as administering 10 mg / kg BAN2401 as disclosed above.

[0543] In some embodiments, if it is determined that the patient is no longer amyloid negative, e.g., as assessed by a blood, serum, or CSF biomarker and / or as determined by amyloid PET SUVr, the patient is moved back from the maintenance dose to the initial treatment dose.

[0544] In some embodiments, the maintenance dose of the subject is administered in the same amount and / or frequency as the dose during the treatment period. In some embodiments, the maintenance dose of the subject is 50% of the dose 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 each comprise a lower amount and / or frequency of administration than the first or previous administration. In some embodiments, the conversion to the second or subsequent administration is determined based on one or more of the biomarkers exemplified above, wherein the level of the biomarker is different (e.g., increased compared thereto) from the level used to convert from the initial dose to the first administration of the maintenance dose.

[0545] In some embodiments, if the patient no longer has early AD, e.g., as assessed by cognitive evaluation, PET SUVr, and / or a blood, CSF, or plasma biomarker, treatment of the patient is discontinued.

[0546] In some embodiments, the amyloid levels in a patient can be monitored for regression after treatment discontinuation by measuring tau PET levels and one or more biomarkers such as volumetric MRI (vMRI), including whole brain volume, cortical thickness, total hippocampal volume, and / or lateral ventricle volume. In some embodiments, the amyloid levels in a patient can be monitored for regression after treatment discontinuation by measuring tau PET levels and one or more biomarkers such as PET levels, including amyloid PET levels and / or fluorodeoxyglucose (FDG) PET levels. In some embodiments, the amyloid levels in a patient can be monitored for regression after treatment discontinuation by measuring tau PET levels and one or more biomarkers such as the cerebrospinal fluid levels of the biomarkers, including the 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, the amyloid levels in a patient can be monitored for regression after treatment discontinuation by measuring tau PET levels and one or more biomarkers such as the serum or plasma levels of the 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), 217 (P-tau217), and 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0547] In some embodiments, the biomarkers of a patient can be monitored at least once after treatment discontinuation. In some embodiments, the biomarkers of a patient 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 discontinuation. In some embodiments, if the biomarker levels of the patient become less favorable, such as the tau PET level increasing at the same rate as that of an untreated control, treatment is restarted.

[0548] 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 a moderate likelihood of Alzheimer's disease and / or has been diagnosed with mild Alzheimer's disease dementia.

[0549] Therapeutic methods 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 therapeutic method includes using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to allow monitoring and making treatment decisions. In some embodiments, the therapeutic method includes using biomarker levels (e.g., tau PET levels or the rate of change of tau PET levels) to determine the conversion from a treatment dose to a maintenance dose. In some embodiments, the first therapeutically effective dose includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or until the tau PET level has improved relative to untreated control subjects, and then converting to an intravenous maintenance dose (e.g., at 10 mg / kg, for example every two weeks or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the first therapeutically effective dose includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or until the tau PET level has improved relative to untreated control subjects, and then converting to an intravenous maintenance dose every two weeks. In some embodiments, the first therapeutically effective dose includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or until the tau PET level has improved relative to untreated control subjects, and then converting to an intravenous maintenance dose monthly. In some embodiments, the first therapeutically effective dose includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every two weeks (e.g., administering BAN2401 at 10 mg / kg), for example until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or until the tau PET level has improved relative to untreated control subjects, and then converting to an intravenous maintenance dose quarterly.

[0550] In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody (e.g., administration of BAN2401 at 720 mg) at 720 mg per week, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then converted to a subcutaneous maintenance dose (e.g., at 720 mg, e.g., weekly, bi-weekly, or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody (e.g., administration of BAN2401 at 720 mg) at 720 mg per week, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then converted to a bi-weekly subcutaneous maintenance dose (e.g., at 720 mg).

[0551] In some embodiments, the first therapeutically effective dose comprises intravenous administration of an anti-Aβ protofibril antibody (e.g., administration of BAN2401 at 10 mg / kg) at 10 mg / kg every two weeks, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then converted to a weekly subcutaneous maintenance dose (e.g., at a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises intravenous administration of an anti-Aβ protofibril antibody (e.g., administration of BAN2401 at 10 mg / kg) at 10 mg / kg every two weeks, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as evaluated by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then converted to a bi-weekly subcutaneous maintenance dose (e.g., at a dose of 720 mg or at a dose of 360 mg).

[0552] In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., a subcutaneous injection of 720 mg, comprising two simultaneous (e.g., sequential) injections of 360 mg (2 × 1.8 mL of a 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as assessed by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then switched to a weekly subcutaneous maintenance dose of 720 mg. In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., a 720 mg subcutaneous formulation, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as assessed by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then switched to a weekly subcutaneous maintenance dose of 360 mg. In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., a 720 mg subcutaneous formulation, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as assessed by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then switched to a bi-weekly subcutaneous maintenance dose (e.g., at a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises administration of an anti-Aβ protofibril antibody weekly, e.g., a 720 mg subcutaneous formulation, e.g., until the patient has a tau PET level increase of no more than 0.05 - 0.1 (as assessed by tau PET SUVR in the temporal region) after 13 or 18 months of treatment or e.g., until the tau PET level has improved relative to untreated control subjects, and then switched to a monthly subcutaneous maintenance dose of 720 mg.

[0553] C. Subjects with low tau PET

[0554] In various embodiments, methods are disclosed herein for selecting subjects, 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 a whole-brain measurement, such as as measured by tau PET. Low levels of tau PET may refer to low levels of tau aggregation as imaged by PET scan imaging, such as low levels of cortical tau aggregation. In some embodiments, subjects with low tau PET also have tau accumulation in certain brain regions (e.g., one or more early Braak regions or a composite region 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 a whole-brain measurement (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 biomarkers 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 a whole-brain measurement (e.g., as measured by PET).

[0555] Without being bound by theory, the surprising finding is that anti-amyloid protofibril antibodies such as BAN2401 (i.e., lecanemab) may be particularly effective in subjects with low levels of tau (e.g., low tau PET levels as measured in a whole-brain measurement and / or by any alternative measure of low total 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 biomarker such as MTBR-tau243)). In previous studies, it was hypothesized that the effect of anti-amyloid antibodies was greatest in subjects with at least moderate levels of tau (corresponding to early symptomatic AD and tau pathology). For example, the Trailblazer clinical study included subjects with moderate levels of tau as defined by a threshold tau PET level as 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.

[0556] In contrast, the results of the present study show that anti-Aβ protofibril antibodies (such as lecanemab) have surprising effects in treating subjects with low tau PET. In some embodiments, when compared to subjects with medium and / or high tau PET levels, treating subjects with low tau PET levels with anti-amyloid antibodies results in improved outcomes, as determined by measurement of AD-related clinical functions and / or biomarkers.

[0557] In some embodiments, thresholds for determining low, medium, and high tau PET levels are determined for a given PET scan protocol and tau PET tracer. In some embodiments, the MK6240 radiotracer can be used to determine the thresholds. Other tracers can be used to readily identify comparable thresholds. In some embodiments, a tau PET universal scale that reflects the analytical method and / or measurements obtained with different tau PET tracers can be used to determine the thresholds.

[0558] In some embodiments, a low level of tau is a tau level below a threshold (e.g., a threshold set in a whole-brain measurement) as measured by PET, such as a tau-PET standardized uptake value ratio (SUVR).

[0559] In some embodiments, a whole-brain measurement is a measurement of tau PET in the entire cortical gray matter (e.g., a tau PET measurement of cortical tau aggregation). In some embodiments, the MK6240 radiotracer is used to measure the tau PET level. In some embodiments, the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, in the entire cortical gray matter, as measured with an MK6240 PET scan.

[0560] Subjects with low levels of tau in a whole-brain measurement (e.g., the entire cortical gray matter) may have higher levels of tau in local brain regions (e.g., the medial temporal region, posterior temporal region, and / or temporal region).

[0561] In some embodiments, a local brain region is an early Braak region (e.g., Braak region I, II, or III). In some embodiments, the early Braak regions include the transentorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, a local brain region is a composite region of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, medial temporal region, and / or posterior temporal region. In some embodiments, a local brain region is the medial temporal region (e.g., the entorhinal cortex).

[0562] In some embodiments, treating a subject with low tau PET levels for AD, compared to a control, includes reducing, slowing, and / or reversing decline in measures of cognitive function, such as in a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody. In some embodiments, a measure of cognitive function of a treated subject is compared to a baseline measure obtained from the same subject prior to treatment or to a reference control. In some embodiments, the decline occurs between a time point at which cognitive function is first measured (e.g., the baseline measure) and one or more subsequent time points at which cognitive function 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 measure. In some embodiments, the control is a subject who has not received a therapeutically effective dose of an Aβ protofibril antibody, such as a subject who has not been treated or a subject who has received a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a pooled population data from more than one subject and represents an average measurement of subjects who have not been treated. In some embodiments, the measure of cognitive function is CDR-SB, ADAS-Cog14, and / or ADCS MCI-ADL.

[0563] In some embodiments, a patient with low tau PET levels may have less tau accumulation than a patient with higher tau PET levels. The disclosures herein surprisingly show 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 (such as studied by others in clinical trials (e.g., TRAILBLAZER–ALZ3)). In some embodiments, a patient may be classified as having a low level of tau if the tau PET level is below a threshold. In some embodiments, for example, using Tau IQ(Also referred to as “TauIQ”) The algorithm calculates the level of tau from the total tau burden from the entire brain signal. In some embodiments, if the level of tau as measured by PET using an MK tracer is below about 1.1 (e.g., below about 1.0), the patient may be classified as having a low level of tau. In some embodiments, if the tau PET level as measured using an MK tracer is below 1.06, the patient may be classified as having a low level of tau. In some embodiments, if the 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), the patient may be classified as having a medium level of tau. In some embodiments, if the tau PET level as measured by an MK tracer is above about 3.0 (e.g., above 2.91), the patient may be classified as having a high level of tau. In some embodiments, a patient may be classified as having a low level of tau based on a percentile rank relative to other patients selected to be treated with an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, a cutoff value may be used to remove outliers before determining the percentile rank. In some embodiments, a patient having a low level of tau (e.g., a low tau PET level) may be identified as having a tau level that is at least one standard deviation below the average tau level of the patient population. As will be understood by those of ordinary skill in the art, the thresholds used to classify a patient as having a low, medium, or high tau PET level may vary based on the method used to determine the level of tau in the brain (e.g., depending on the tau PET method and tracer used in tau PET imaging). In some embodiments, if the tau PET level (e.g., a measure of cortical tau aggregation) as measured by tracer MK6240 in the entire cortical gray matter is below a threshold, the patient may be classified as having a low level of tau. In some embodiments, for example, using Tau IQThe algorithm calculates the level of tau from the total tau burden from the entire cortical gray matter. In some embodiments, if the level of tau as measured by PET (as measured by the MK6240 tracer in the entire cortical gray matter) is less than about 1.1 (e.g., less than about 1.0), the patient may be classified as having a low level of tau. In some embodiments, if the tau PET level as measured by PET (as measured by the MK6240 tracer in the entire cortical gray matter) is less than 1.06, the patient may be classified as having a low level of tau. In some embodiments, 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 (e.g., between 1.06 and 2.91), the patient may be classified as having a medium level of tau. In some embodiments, if the tau PET level as measured by the MK6240 tracer in the entire cortical gray matter is greater than about 3.0 (e.g., greater than 2.91), the patient may be classified as having a high level of tau. In some embodiments, the tau PET level as measured by MK6240 in the entire cortical gray matter may be referred to as "total tau" or "total tau aggregation".

[0564] D. Measurement of tau PET level

[0565] The disclosures and methods discussed herein stem in part from the discovery that treatment with an anti-Aβ protofibril antibody such as BAN2401 can result in a reduced rate of tau accumulation, e.g., in brain regions such as the temporal region, as measured by tau PET level (e.g., as measured by tau PET imaging), compared to control patients.

[0566] In some embodiments, the treatment is administered to a subject having a low tau PET level in a whole brain measurement (e.g., the entire cortical gray matter) and / or identified by any alternative measure of low total tau PET discussed herein. A subject having a low tau PET in a whole brain measurement may have a higher level of tau PET 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). 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 local brain region is a composite region of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, medial temporal region, and / or posterior temporal region. In some embodiments, the local brain region is the medial temporal region (e.g., the entorhinal cortex, hippocampus, parahippocampal gyrus, and temporal pole (medial and / or inferolateral tip of the temporal lobe)). Thus, reducing tau accumulation may refer to reducing, slowing, and / or reversing tau accumulation in a local brain region.

[0567] 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 relative to the baseline tau PET SUVr level of less than about 0.1, such as 0.05. In some embodiments, the reduction in tau PET relative to baseline is greater in subjects receiving lecanemab than in controls.

[0568] In some embodiments, the amount of tau aggregation in a treated subject is compared to a baseline measurement obtained from the same subject prior to treatment or to a reference control. In some embodiments, the reference control is an untreated control subject (e.g., a subject receiving a placebo). In some embodiments, the reference control is a measurement obtained from a population of control subjects.

[0569] In some embodiments, this is associated with a reduction in the brain amyloid burden and an improvement in cognitive outcomes in the subject. Without being bound by theory, tau PET levels (e.g., tau PET standardized uptake value ratio (SUVr)) can be used in various embodiments as a less invasive and / or additional biomarker to improve the measurement of treatment efficacy and / or can be used to allow monitoring and making treatment decisions. Such decisions can include whether to increase or decrease the amount of anti-Aβ protofibril antibody 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.

[0570] 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 evaluate tau pathology. In some embodiments, tau PET is evaluated using a PET tracer and the same tracer is used in subsequent evaluations. In a preferred embodiment, the PET imaging uses [18F]MK-6240 (also referred to as the "florquinitau" tracer and referred to herein as the "MK tracer"). In some embodiments, the PET tracer is an arylquinoline derivative (e.g., [18F]THK5317 and [18F]THK5351), a pyridoindole derivative (e.g., [18F]AV-1451, also referred to as [18F]-flortaucipir), or a phenyl / pyridyl-butadienyl-benzothiazolone / benzothiazolium (PBB) derivative (such as [11C]PBB3). In some embodiments, the PET tracer is [18F]-RO-948, [18F]-PI-2620, [18F]-JNJ-311, and [18F]-GTP1.

[0571] Tau positron emission tomography (PET) imaging can be used to confirm the presence of tau pathology in the brains of early AD subjects during the screening phase of a study and / or to evaluate the effect of at least one anti-Aβ protofibril antibody on tau levels in the brain, which is performed by whole-brain analysis (e.g., the entire cortical gray matter, or the average of 5-6 cortical regions) and / or regional brain analysis (e.g., in the temporal brain region).

[0572] In some embodiments, tau PET imaging in different brain regions can be used to determine total or regional levels of tau PET levels. Whole-brain measurements can include tau PET imaging analysis of the whole brain, most of the whole brain, cerebral gray matter, or a large portion of the brain that can be considered representative of whole-brain measurements (e.g., the entire cortical gray matter). In some embodiments, the whole-brain measurement is a tau PET measurement of 5-6 cortical regions. In some embodiments, the whole-brain measurement is a tau PET measurement of the entire cortical gray matter. In some embodiments, the whole-brain measurement is a tau PET measurement of cortical tau aggregation. Regional brain measurements can include tau PET imaging analysis of regional brain regions. In some embodiments, regional brain regions include one or more brain structures, such as brain structures defined by structure or morphology. In some embodiments, a subject can have a first tau PET level in the whole-brain measurement and a second tau PET level in the 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 PET level. In some embodiments, the first tau PET level is equal to the second tau PET level.

[0573] In some embodiments, the PET scan uses the [18F]MK-6240 (florquinitau) tracer. In some embodiments, the PET scan uses a tau PET tracer, such as arylquinoline derivatives (e.g., [18F]THK5317 and [18F]THK5351), pyridoindole derivatives (e.g., [18F]AV-1451, also known as [18F]-flortaucipir), or phenyl / pyridyl-butadienyl-benzothiazolone / benzothiazolium (PBB) derivatives (such as [11C]PBB3). In some embodiments, the PET tracer is [18F]-RO-948, [18F]-PI-2620, [18F]-JNJ-311, and [18F]-GTP1. In some embodiments, the tau load can be determined by visual reading of PET imaging uptake (e.g., by a trained radiologist). In an embodiment, the uptake of an imaging agent (e.g., a tau PET tracer) in a brain region (e.g., a lobe) is evaluated.

[0574] A brain region is a region, part, or subdivision of the brain. A brain region can be a region defined in a standard neuroanatomical atlas. The region can correspond to a lobe of the brain, or it can constitute a larger or smaller part of the brain. The region may require specific anatomical landmarks or be defined by specific anatomical landmarks. A brain region can be defined according to characteristics specific to a particular experiment or study. A brain region can be defined based on its location, function, anatomical structure, connections to other brain regions, and / or properties of PET tracer uptake. In some embodiments, the brain region is the entire cortex.

[0575] In some embodiments, the brain region is a composite region of more than one brain region (e.g., regions that accumulate tau in early AD). In some embodiments, the brain region is a composite region of more than one lobe, subregion, and / or structure in the brain.

[0576] For example, a cortical composite region can include more than one brain structure from the cortex. In some embodiments, a composite region in a PET scan is a region of interest (ROI) that includes more than one brain region, such as a volume-weighted average of more than one brain region.

[0577] 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 predominantly the lateral temporal region. In some embodiments, the brain region can be referred to as the posterior temporal region.

[0578] As used herein, the temporal region includes at least a portion of the temporal lobe. For example, the temporal region can include the posterior superior portion of the temporal lobe, the anterior superior 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 can include these structures from both the left and right hemispheres of the brain. In some embodiments, the temporal region includes the lateral temporal region.

[0579] In some embodiments, the medial temporal region includes the hippocampus, the anterior medial portion of the temporal lobe, the anterior inferior lateral portion of the 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.

[0580] In some embodiments, the medial temporal region includes the entorhinal cortex, the hippocampus, the parahippocampal gyrus, and / or the temporal pole (the 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.

[0581] In some embodiments, the meta-regions of interest (ROI) are defined as those brain regions having certain characteristics, such as the regions with the most tau deposition in AD patients or regions where tau PET imaging differs between groups of patients (e.g., cognitively unimpaired individuals, such as those with normal amyloid PET compared to cognitively unimpaired individuals with abnormal amyloid PET). Examples of posterior ROI in the temporal region can be found in Jack et al., Alzheimer's Dementia 13, 205–216 (2017). In some embodiments, the posterior ROI can include the posterior temporal region (also referred to as the postero-temporal region). In some embodiments, the posterior temporal region includes the amygdala, parahippocampal cortex, middle and inferior portions of the temporal lobe, fusiform gyrus, posterior portion of the temporal lobe, and entorhinal cortex. The posterior temporal region can include these structures from both the left and right hemispheres of the brain.

[0582] Thus, PET levels can be evaluated in any of the brain regions described herein and / or other brain regions. In some embodiments, the tau PET level in the temporal region is evaluated. In some embodiments, the tau PET level in the frontal region is evaluated. In some embodiments, the tau PET level in the parietal region is evaluated. In some embodiments, the tau PET level in the occipital region is evaluated. In some embodiments, the tau PET level in the cingulate gyrus region is evaluated.

[0583] In some embodiments, the tau PET level of the entire cortical gray matter is evaluated. In some embodiments, the region (e.g., reference region) used to evaluate the tau PET level is the ventral cerebellum (Cb).

[0584] As used herein, "tau level in the brain", "tau level", and "tau load" can be used interchangeably. The tau level can be evaluated by PET imaging ("tau PET level"). As used herein, the tau PET level refers to the measurement of the tau level in a brain region (e.g., the temporal region) by PET. In some embodiments, for example, using Tau IQAn algorithm (also referred to as “TauIQ”) calculates tau PET levels from the total tau burden from whole brain signals. In some embodiments, “tau PET levels” can be identified in tau PET imaging by standardized uptake value ratio (SUVr or SUVR). The SUVr can be, for example, a measurement of tau PET tracer uptake in a brain region of the same patient compared to a reference region in the patient (e.g., normalized to the reference region). Methods for calculating tau PET SUVr are known in the art and can include those described herein. An exemplary method for quantitative analysis (e.g., calculation) of SUVr is PMOD PNEURO biomedical image quantification software (PMOD Technologies, Zurich, Switzerland). In some embodiments, object motion in the PET images is first evaluated in the X, Y, and Z planes and, if needed, motion correction is performed prior to averaging individual images (e.g., 5-minute emission frames) using, for example, the PMOD average function (averaging the PET frames to increase signal-to-noise ratio). In some embodiments, corresponding MRIs from the subject are prepared (e.g., using matrix size reduction processing, cropping the MRI to include only the brain, segmentation to separate the image into binary maps of gray matter, white matter, and CSF, and skull stripping to leave only the brain mask). In some embodiments, the averaged PET image and the prepared MRI are matched using the PMOD match function to place the images in the same orientation. In some embodiments, brain normalization functions and brain normalization and rigid matching transformation matrices, such as those provided by the PMOD software, are used to produce the averaged PET. In some embodiments, this averaged PET is normalized to the MNInst space (Senjem et al., 2005), which is in the same orientation as the segmented MRI of the subject, for quantitative analysis. In some embodiments, the PMOD mask function is used to mask the brain and zero out the image outside the mask to create a normalized gray matter PET and a normalized white matter PET. The standardized uptake value (SUV) can be calculated for all gray matter mapped regions and 3 white matter regions (pons, cerebellar white matter, and subcortical white matter) using the normalized PET, subject body weight, and the injected dose of tracer to arrive at the units of SUV. In some embodiments, the SUVr is the ratio of the overall cortical mean compared to a selected reference region. In some embodiments, the whole cerebellum mask is used as the reference region. In some embodiments, the reference region is subcortical white matter, ventral cerebellum, derived whole cerebellum, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and a composite reference region consisting of cerebellar cortex, pontine subcortical white matter, and cerebellar white matter.

[0585] In some embodiments, tau PET levels are evaluated using 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, if the tau PET level is below a threshold, the patient can be classified as having a low level of tau. The threshold can be identified as the tau level in the entire cortex (or alternatively, in a specific 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 cut-off value for classifying patients as having a low tau PET level, a medium tau PET level, or a high tau PET level. In some embodiments, if the level of tau measured using, for example, an MK tracer by PET in a specific region of interest (e.g., the entire cortical gray matter) is below about 1.1 (e.g., below about 1.0), the patient can be classified as having a low level of tau. In some embodiments, if the tau PET level measured using an MK tracer is below 1.06, the patient can be classified as having a low level of tau. In some embodiments, if the tau PET level measured using an MK tracer is between about 1.1 and 3.0 or between 1.06 and 2.91, the patient can be classified as having a medium level of tau. In some embodiments, if the tau PET level measured using an MK tracer is above about 3.0 (e.g., above 2.91), the patient can be classified as having a high level of tau. In some embodiments, when determining the tau PET level in the entire cortex using, for example, the PET tracer [18F]MK-6240, the thresholds for the tau PET level are <1.06 (low level), 1.06 to 2.91 (medium level), and >2.91 (high level). In some embodiments, the cut-off value can be determined based on the tau PET level in a specific brain region. As will be understood by one of ordinary skill in the art, the thresholds for classifying patients as having low, medium, or high tau PET levels can vary based on the method used to determine the tau level in the brain (e.g., depending on the tau PET method and tracer used in tau PET imaging). In some embodiments, a tau PET universal scale that reflects the analytical method and / or the measurements obtained using different tau PET tracers can be used to determine the threshold.

[0586] In some embodiments, the adjusted mean change relative to baseline is measured before treatment and at least once after treatment initiation (e.g., within a time period of at least 6 months after the initial dose of treatment). In some embodiments, the adjusted mean change relative to baseline is measured within a time period of at least 12 months after the initial dose of treatment. In some embodiments, the adjusted mean change relative to baseline is measured within a time period of at least 13 months after the initial dose of treatment. In some embodiments, the adjusted mean change relative to baseline is measured within a time period of at least 18 months after the initial dose of treatment. In some embodiments, the adjusted mean change relative to baseline is measured within a time period of at least 24 months after the initial dose of treatment.

[0587] In some embodiments, after administration of the first dose of the composition, the adjusted mean change in the tau PET SUVr value of the subject relative to baseline is less than 0.15. In some embodiments, after administration of the first dose of the composition, the adjusted mean change in the tau PET SUVr value of the subject relative to baseline is less than 0.10. In some embodiments, after administration of the first dose of the composition, the adjusted mean change in the tau PET SUVr value of the subject relative to baseline is less than 0.05. In some embodiments, 13 months after the initial dose of treatment, the adjusted mean change in the tau PET SUVr value of the subject relative to baseline is less than 0.15. In some embodiments, after administration of the first dose of the composition, the adjusted mean change in the tau PET SUVr value of the subject relative to baseline is less than 0.05. In some embodiments, 18 months after the initial dose of treatment, the adjusted mean change in the tau PET SUVr value of the subject relative to baseline is less than 0.15.

[0588] In some embodiments, the adjusted mean change of the subject's tau PET SUVr relative to baseline is measured in a local brain region. For example, tau PET SUVr can be measured in early Braak regions (e.g., Braak regions I, II, or III). Early Braak regions can include the transentorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, the local brain region is a composite region of regions where tau accumulates in early AD. In some embodiments, the composite region includes the temporal region, medial temporal region, and / or posterior temporal region. In some embodiments, the local brain region is the medial temporal region (e.g., entorhinal cortex). In some embodiments, the subject may have low tau PET levels in a whole-brain measurement but may have higher tau PET levels in a local brain region. In some embodiments, the subject may have higher tau PET levels in a first local brain region but may not have higher tau PET levels in a second local brain region. For example, the first local brain region with higher tau PET levels can be an early Braak region (e.g., Braak regions I, II, or III), while the second local brain region without higher PET levels can be a late Braak region (e.g., Braak regions IV, V, or VI) that reflects the progression of AD.

[0589] Other methods of measuring tau by PET are known in the art. These methods can include Tau IQ algorithms (see, e.g., Whittington et al., J. Nucl Med. [Journal of Nuclear Medicine] September 1, 2021; 62(9):1292-1300 for quantitative measurement of tau PET radiotracers).

[0590] Measurement of tau PET levels can be used alone or in combination with one or more additional criteria, such as one or more measurements in biological fluids (e.g., the ratio of p-tau181 and / or Aβ1-42 to Aβ1-40), PET measurement of Aβ (e.g., via radiotracer uptake), indication of AD based on MRI evaluation of brain anatomy (e.g., MRI-based prediction of Aβ plaque formation), and / or behavioral measurements, as discussed herein, for evaluating treatment efficacy. Such assays can also be used to diagnose patients eligible for treatment (e.g., by measuring tau PET levels and determining that the subject is suitable for treatment alone or in combination with one or more additional markers of AD pathology in the subject due to the tau PET level being higher than that observed in healthy control subjects). In some embodiments, the subject is selected for treatment due to a high tau PET level in a brain region of the subject, where the tau PET level is greater than that of a subject without AD. In some embodiments, the subject is selected for treatment due to a low tau PET level in the temporal region of the subject's brain. For example, where the tau PET level can be less than about 1.1, such as less than 1.06, such as measured using the PET tracer [18F]MK-6240. In some embodiments, the subject is selected for treatment due to a high tau PET level in the temporal region of the subject's brain. For example, where the tau PET level can be greater than about 1.1. In some embodiments, the subject is selected for treatment due to a low tau PET level in the temporal region of the subject's brain. For example, the tau PET level can be less than about 1.1. In some embodiments, the subject is selected for treatment due to a high tau PET level in the temporal region of the subject's brain. For example, the tau PET level can be greater than about 1.1. In some embodiments, the measurement of tau PET levels can be used in place of another method for measuring brain tau levels and / or in place of another marker for Aβ. In some embodiments, the measurement of tau PET levels can be used in combination with the measurement of one or more additional markers. In some embodiments, patients can be monitored by one or more additional biomarkers, such as but not limited to: (a) tau detected by visual reading or semi-quantitative threshold (SUVr) from a PET scan; (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, the tau PET level of a subject can 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, the tau PET level of a patient can be monitored in combination with one or more of the ratio of Aβ1-42 to Aβ1-40 and / or p-tau181 measurements in a fluid sample (e.g., a blood sample). In some embodiments, the combination includes a serum or plasma GFAP measurement. In some embodiments, the measurement of the tau PET level can be used instead of another method for measuring brain tau levels to determine treatment efficacy and / or make treatment decisions, such as whether to continue treatment, switch to a maintenance dose, etc.

[0591] In some embodiments, the tau PET level changes in a manner related to other biomarkers during disease progression or treatment. Thus, the tau PET level (e.g., a low tau PET level as measured in a whole brain measurement) can be used to select subjects for treatment and / or the amount (e.g., level) of a biomarker can be used to select subjects. For example, a biomarker such as the amyloid PET level of <60CL can 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 fluid sample (e.g., a blood sample such as serum or plasma) can be used to select subjects. In some embodiments, one or more of these biomarkers can act as a surrogate for tau PET measurement (e.g., low tau PET) to select subjects for treatment.

[0592] In some embodiments, measurements of tau PET can be made 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 of the subject before treatment) in order to monitor treatment efficacy and / or determine whether the treatment regimen should be changed, if at all. In some embodiments, a change in tau PET level can indicate that the treatment is effective. For example, a decrease in tau PET level compared to the baseline tau PET level can indicate whether the treatment is effective. In some embodiments, the treatment regimen can be changed to administer the treatment at a maintenance dose. In some embodiments, the treatment regimen can be changed to increase the dose or frequency of administration. In some embodiments, a measure of one or more biomarkers can be used to monitor treatment efficacy and / or determine a change in the treatment regimen, if any. In some embodiments, 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 fluid sample (e.g., a blood sample such as serum or plasma). For example, a change in one or more biomarkers compared to the baseline level can indicate whether the treatment is effective. In some embodiments, the treatment regimen can be changed to administer the treatment at a maintenance dose. In some embodiments, the treatment regimen can be changed to increase the dose or frequency of administration. In some embodiments, the tau PET level can be used to calculate the relative change relative to the baseline measurement (e.g., a measurement of the tau PET level before starting treatment). In some embodiments, the tau PET level measurement can be repeated after the start of the treatment regimen to monitor treatment efficacy. In some embodiments, the tau PET level is measured before treatment and at least once after the start of treatment (e.g., within a time period of at least 6 months after the initial dose of treatment). In some embodiments, the tau PET level is measured within a time period of at least 12 months after the initial dose of treatment. In some embodiments, the tau PET level is measured within a time period of at least 13 months after the initial dose of treatment. In some embodiments, the tau PET level is measured within a time period of at least 18 months after the initial dose of treatment. In some embodiments, the rate of change of the tau PET level is calculated based on the measurements of the subject. In some embodiments, the rate of change of the tau PET level is calculated based on the measurements of the subject, where one measurement is made from the subject before treatment and at least a second measurement is made after treatment. In some embodiments, the rate of change of the tau PET level is calculated based on the measurements of the subject, where one measurement is made from the subject before treatment and at least a second measurement is made after treatment, and where the tau PET level is measured at least 6 months after the initial dose of treatment.In some embodiments, the rate of change of tau PET levels is calculated based on measurements of a subject, where one measurement is taken from the subject prior to treatment and at least a second measurement is taken after treatment, and where the tau PET levels are measured at least 12 months after the initial dose of treatment. In some embodiments, the rate of change of tau PET levels is calculated based on measurements of a subject, where one measurement is taken from the subject prior to treatment and at least a second measurement is taken after treatment, and where the tau PET levels are measured at least 13 months after the initial dose of treatment. In some embodiments, the rate of change of tau PET levels is calculated based on measurements of a subject, where one measurement is taken from the subject prior to treatment and at least a second measurement is taken after treatment, and where the tau PET levels are measured at least 18 months after the initial dose of treatment. In some embodiments, an increase in tau PET levels of no more than 0.05 - 0.1 in a brain region over a 13 - month period indicates treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05 - 0.1 in a brain region over an 18 - month period indicates treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05 - 0.1 in the temporal brain region over a 13 - month period indicates treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05 - 0.1 in the temporal brain region over an 18 - month period indicates treatment efficacy.

[0593] In some embodiments, the rate of change of tau PET levels is calculated based on two measurements of the subject. In some embodiments, the rate of change of tau PET levels is calculated based on more than two measurements of the subject. In some embodiments, the rate of change of tau PET levels indicates the rate of tau accumulation in the subject's brain.

[0594] In some embodiments, the rate of change of tau PET levels is calculated based on at least two measurements of a subject, where one measurement is taken from the subject prior to treatment and a second measurement is taken after treatment, where the treatment continues for at least 13 or 18 months after an initial dose of the treatment. In some embodiments, the rate of change of tau PET levels is compared to the rate of change of tau PET levels in untreated control subjects with AD who are not receiving treatment. In some embodiments, a lower rate of increase of tau PET relative to untreated control subjects indicates treatment efficacy. In some embodiments, a lower rate of increase of tau PET over a 6-month time period relative to untreated control subjects indicates treatment efficacy. In some embodiments, a lower rate of increase of tau PET over a 12-month time period relative to untreated control subjects indicates treatment efficacy. In some embodiments, a lower rate of increase of tau PET over a 13-month time period relative to untreated control subjects indicates treatment efficacy. In some embodiments, a lower rate of increase of tau PET over an 18-month time period relative to untreated control subjects indicates treatment efficacy.

[0595] In some embodiments, an increase in tau PET levels and / or rate of change relative to untreated control subjects with AD who are not receiving treatment may indicate a need to continue treatment, such as a treatment duration of more than 13 or 18 months, or to select an increased dosing regimen. In some embodiments, a lower rate of change of tau PET levels (e.g., as measured at 13 or 18 months) relative to untreated control subjects can be used to indicate that treatment can be terminated (e.g., terminated to support a maintenance regimen) and / or otherwise determine a reduced dosing regimen or discontinuation of treatment. In some embodiments, an increase in the rate of change of tauPET values relative to untreated control subjects can be used to determine, for example, whether to discontinue a maintenance dosing regimen and revert to a previous treatment regimen.

[0596] In some embodiments, a decrease in the rate of change of tau PET relative to untreated control subjects may indicate effective treatment. In some embodiments, a decrease in the rate of change of tau PET relative to untreated control subjects can be used to determine whether to switch to a maintenance dosing regimen. In some embodiments, an increase in tau PET levels of less than 0.05 - 0.1 in a brain region (e.g., temporal region) over a 13-month time period may indicate effective treatment. In some embodiments, an increase in tau PET levels of less than 0.05 - 0.1 in a brain region over an 18-month time period may indicate effective treatment. In some embodiments, tau PET in a brain region (e.g., temporal region) being lower than that of untreated control subjects may indicate effective treatment.

[0597] In some embodiments, an increase in tau PET levels and / or an increase in the rate of change of tau PET relative to untreated control subjects can be used to determine, for example, whether to discontinue a maintenance dosing regimen and 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., the temporal region) over a 13-month time 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 time period can indicate ineffective treatment.

[0598] Methods of measuring clinical efficacy or monitoring treatment can employ setting thresholds to determine changes in brain tau levels, for example, to identify patients suitable for treatment, e.g., with an anti-Aβ protofibril antibody, or to determine whether to continue treatment, or to determine whether to switch to a maintenance dose, or to conclude that a patient is amyloid-negative. In some embodiments, tau PET level thresholds can be evaluated in combination with another measurement of brain amyloid burden, such as an amyloid PET scan, CSF, or serum or plasma biomarkers, to assist in determining whether a subject is suitable for treatment or to continue treatment. In some embodiments, tau PET levels can be used in place of another method of measuring brain tau levels. In some embodiments, tau PET levels greater than a threshold level are used to determine whether a patient should be treated. In some embodiments, a tau PET level of approximately 1 (e.g., 1.06) measured across the entire cortex indicates a patient with low tau PET levels who should be treated. In some embodiments, a tau PET level of approximately 1.06 - 2.91 measured across the entire cortex indicates a patient with moderate tau PET levels who should be treated. In some embodiments, a tau PET level of approximately 2.91 or greater measured across the entire 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, wherein the subject has a tau PET level greater than approximately 1 in a brain region. In some embodiments, a subject is selected for treatment with an anti-amyloid beta (Aβ) protofibril antibody, wherein the subject has a tau PET level between approximately 1.06 and 3 in a brain region. In some embodiments, a subject is selected for treatment with an anti-amyloid beta (Aβ) protofibril antibody, wherein the subject has a tau PET level greater than approximately 3 in a brain region. In some embodiments, the brain region is the entire cortex. In some embodiments, the brain region is the temporal lobe or a part (e.g., a subpart) of the temporal lobe. In some embodiments, the brain region includes the temporal lobe and additional brain segments external to the temporal lobe. In some embodiments, the brain region is the temporal region. In some embodiments, the brain region is the posterior temporal region. In some embodiments, the brain region is the medial temporal region.

[0599] In some embodiments, methods of selecting patients for treatment and treatment methods can include selecting patients having a tau brain level below a threshold (e.g., below a tau PET threshold) and / or administering to them a treatment, where the treatment can include any of the treatments disclosed herein, such as including an anti-Aβ protofibril antibody, such as BAN-2401. In some embodiments, methods of determining whether to continue treatment or determining whether to convert to a maintenance dose include identifying a tau level below a threshold, such as a tau PET level. In some embodiments, patients having a low tau PET level can be selected for treatment. In some embodiments, a treatment as discussed herein, such as an anti-Aβ protofibril antibody, such as BAN2401, is provided to patients having a low tau PET level.

[0600] E. Measurement of the Aβ42 / 40 ratio

[0601] The disclosures and methods discussed herein depend in part on the following findings: that not only can tau PET levels or the rate of change of tau PET levels be used to select patients for treatment to allow monitoring and making treatment decisions, such as whether to increase or decrease the amount of antibody administered, determining whether to increase or decrease the dosing frequency, determining whether to introduce additional therapeutic agents, determining whether to convert to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody, but also that tau PET levels can be used in combination with other biomarkers such as the Aβ42 / 40 ratio. Aβ42 and 40 are measured to calculate the ratio in a blood sample, as disclosed in PCT / US2022 / 073576, which is incorporated herein by reference. Treatment comprising an anti-Aβ protofibril antibody such as BAN2401 can result in an increase in the Aβ42 / 40 ratio in a subject associated with a reduction in brain amyloid burden and improvement in cognitive outcomes.

[0602] In some embodiments, treatment with an anti-Aβ protofibril antibody such as BAN2401 can result in an increased Aβ42 / 40 ratio associated with reduced brain amyloid burden and improved cognitive outcomes in subjects with low tau PET levels on whole brain measurement. In some embodiments, the Aβ protofibril antibody increases the plasma Aβ42 / 40 ratio, as measured by an adjusted mean change relative to the 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 higher. In some embodiments, a measure of the Aβ42 / 40 ratio of a treated subject is compared to a baseline measure obtained from the same subject prior to treatment or to a reference control. In some embodiments, the change in the Aβ42 / 40 ratio occurs between the time point at which the Aβ42 / 40 ratio is first measured (e.g., the baseline measure) 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 measure. In some embodiments, the control is a subject who has not received a therapeutically effective dose of the Aβ protofibril antibody, such as an untreated subject or a subject receiving a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a pooled group data from more than one subject and representing the mean measurement of untreated subjects.

[0603] Methods for measuring the Aβ42 / 40 ratio are known in the art, such as assays using LC MS / MS. Methods can include the PrecivityAD TM assay (see, for example, Kirmess et al., J. Clinica Chimica Acta [Clinical Chemistry Acta] 519:267-275 (2021)) and the Sysmex assay (https: / / www.eisai.com / news / 2019 / news201990.html).

[0604] Measurement of the Aβ42 / 40 ratio can be used alone or in combination with one or more additional criteria (such as tau PET levels, PET measurements of Aβ radiotracer uptake, MRI evaluation of Aβ plaques, and / or behavioral measurements) to evaluate treatment efficacy, as discussed herein. Such assays can also be used to diagnose patients eligible for treatment (e.g., by measuring the Aβ42 / 40 ratio and determining that the subject is suitable for treatment either alone or in combination with one or more additional markers of AD pathology in the subject due to the ratio being lower than that observed in healthy control subjects). In some embodiments, measurement of the Aβ42 / 40 ratio can be used in place of another method of measuring brain amyloid levels, such as a PET scan for determining subject eligibility for treatment. In some embodiments, measurement of the Aβ42 / 40 ratio can be used in place of another method of measuring brain amyloid levels, such as a PET scan for determining treatment efficacy and / or making treatment decisions (such as whether to continue treatment, switch to a maintenance dose, etc.).

[0605] In some embodiments, the Aβ42 / 40 ratio measurement can employ a relative change with respect to a baseline measurement. In some embodiments, the Aβ42 / 40 ratio measurement can employ a set threshold to determine a change in brain amyloid levels, for example to identify patients suitable for treatment with, e.g., anti-Aβ protofibril antibodies, or to determine whether to continue treatment, or to determine whether to switch to a maintenance dose, or to conclude that the patient is amyloid negative. In some embodiments, the threshold can be evaluated in combination with another measurement of brain amyloid burden (such as a PET scan) to assist in determining whether a subject is suitable for treatment or to continue treatment. In some embodiments, an Aβ42 / 40 ratio threshold can 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 equal to 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 to below the threshold can indicate a need to continue treatment or select an increased dosing regimen. In some embodiments, an increase in the Aβ42 / 40 ratio to above the threshold can be used to indicate that treatment can be terminated (e.g., to terminate in support of a maintenance regimen) and / or otherwise determine a reduced or discontinued dosing regimen. In some embodiments, a decrease in the Aβ42 / 40 ratio to below the threshold can be used to determine, e.g., whether to discontinue a maintenance dosing regimen and resume a prior treatment regimen.

[0606] In some embodiments, the tau PET level or the rate of change of the tau PET level and the level of an additional biomarker (e.g., the Aβ42 / 40 ratio) can be used to select patients for treatment to allow monitoring and making treatment decisions, such as whether to increase or decrease the amount of antibody administered, determining whether to increase or decrease the dosing frequency, determining whether to introduce additional therapeutic agents, determining whether to switch to a maintenance dose, and / or whether to discontinue treatment with the anti-Aβ protofibril antibody. In some embodiments, the tau PET level can be combined with the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio greater than 0.092) for patient selection for treatment, such as a tau PET level greater than 1.4, as measured by amyloid PET SUVr in the temporal region of the brain. In some embodiments, the tau PET level can be combined with the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or greater than 0.092) for patient selection for treatment, such as a tau PET level greater than 1.5, as measured by amyloid PET SUVr in the temporal region of the brain. The threshold for determining amyloid positivity using the Aβ42 / 40 ratio is disclosed in PCT / US2022 / 073576, which is incorporated herein by reference. In some embodiments, an increase in the tau PET level of less than 0.05 - 0.1 in a brain region (e.g., the temporal region) over a 13-month or 18-month period in combination with the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or greater than 0.092) can indicate effective treatment. In some embodiments, an increase in the tau PET level at a rate lower than that of untreated control subjects in a brain region (e.g., the temporal region) over a 13-month or 18-month period in combination with the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or greater than 0.092) can indicate effective treatment. In some embodiments, a combination of the tau PET in a brain region (e.g., the temporal region) lower than that of untreated control subjects and the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or greater than 0.092) can indicate effective treatment. In some embodiments, an indication of treatment efficacy can be used to decrease the amount of antibody administered, decrease the dosing frequency, or switch to a maintenance dose. In some embodiments, an increase in the tau PET level of more than 0.05 - 0.1 in a brain region (e.g., the temporal region) over a 13-month or 18-month period in combination with the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or less than 0.092) can indicate ineffective treatment. In some embodiments, an increase in the tau PET level at a rate higher than that of untreated control subjects in a brain region (e.g., the temporal region) over a 13-month or 18-month period in combination with the Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or less than 0.092) can indicate ineffective treatment.In some embodiments, a combination of a brain region (e.g., the temporal region) tau PET above that of untreated control subjects and an Aβ42 / 40 ratio (e.g., an Aβ42 / 40 ratio equal to or below 0.092) may indicate ineffective treatment. In some embodiments, an indication of treatment efficacy may be used to increase the amount of antibody administered, increase the frequency of administration, or discontinue treatment.

[0607] Measurement of p-tau levels

[0608] The disclosures and methods discussed herein depend in part on the following findings: that tau PET levels or the rate of change of tau PET levels can be used not only to select patients for treatment to allow monitoring and making treatment decisions such as whether to increase or decrease the amount of antibody 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 whether to discontinue treatment with an anti-Aβ protofibril antibody, but also that tau PET levels can be used in combination with other biomarkers such as phosphorylated tau (p-tau) levels (including tau phosphorylated at 181 (P-tau181), 217 (P-tau217), and / or 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. Treatment with an anti-Aβ protofibril antibody such as BAN2401 can result in a decrease in p-tau181 levels in subjects associated with a reduction in brain amyloid burden and improvement in cognitive outcomes.

[0609] In some embodiments, treatment with an anti-Aβ protofibril antibody such as BAN2401 can result in a decrease in p-tau181 levels in subjects with low tau PET levels in whole brain measurements (e.g., subjects receiving a therapeutically effective dose of an anti-Aβ protofibril antibody) compared to controls. In some embodiments, the measure of p-tau181 in the treated subject is compared to a baseline measure obtained from the same subject prior to treatment or to a reference control. In some embodiments, the Aβ protofibril antibody reduces plasma p-tau181, as measured by an adjusted mean change relative to the baseline p-tau181 level of at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml. In some embodiments, the reduction in p-tau181 occurs between the time point of the first measurement of the biomarker (e.g., the baseline measure) and one or more subsequent time points of re-measurement of p-tau181. In some embodiments, the subsequent time points are 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 who has not received a therapeutically effective dose of an anti-Aβ protofibril antibody, such as a subject who has not been treated or a subject who has received a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a pooled population data from more than one subject and representing the average measurement of subjects who have not been treated.

[0610] Methods for measuring p-tau ratios are known in the art, such as immunoassay-based (e.g., Quanterix TM p-tau assay) and / or mass spectrometry (IP / LC-MS / MS) techniques. As determined by Braak staging (I-II), plasma p-tau181 is elevated in the early stages of AD and continues to increase as the disease progresses to Braak 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 and has been shown to be elevated 3.5-fold in AD compared to controls, with a moderate increase in the MCI group, and also appears to distinguish patients clinically diagnosed with AD from other tauopathies (Thijssen et al., "Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobe degeneration," Nat. Med., 26(3):387-397 (2020); Janelidze et al.).

[0611] Measurement of p-tau levels (e.g., p-tau181 level, p-tau217 level, and / or p-tau231 level) can be used alone or in combination with one or more additional criteria (such as tau PET levels, PET measurements of Aβ radiotracer uptake, MRI evaluation of Aβ plaques, and / or behavioral measurements) to evaluate treatment efficacy, as discussed herein. Such assays can also be used to diagnose patients eligible for treatment (e.g., by measuring the level of p-tau (e.g., p-tau181 level, p-tau217 level, and / or p-tau231 level) and determining that the subject is suitable for treatment alone or in combination with measurement of one or more additional AD pathology markers of the subject due to the level being higher than that observed in healthy control subjects). In some embodiments, measurement of p-tau levels (e.g., p-tau181 level, p-tau217 level, and / or p-tau231 level) can be used in place of another method of measuring brain amyloid levels, such as a PET scan for determining subject eligibility for treatment. In some embodiments, measurement of the level of p-tau (e.g., p-tau181 level, p-tau217 level, and / or p-tau231 level) can be used in place of another method of measuring brain amyloid levels, such as a PET scan for determining treatment efficacy and / or making treatment decisions (such as whether to continue treatment, switch to a maintenance dose, etc.).

[0612] In some embodiments, the measurement of plasma or serum p-tau181 levels can be made as a relative change compared to a baseline measurement. In some embodiments, the change in p-tau181 levels can be used to evaluate treatment efficacy. In some embodiments, a decrease in the level of p-tau181 indicates treatment efficacy, such as a decrease in brain amyloid levels. In some embodiments, the measurement of p-tau181 levels can use a set threshold to determine a change in brain amyloid levels, such as to identify and / or select patients suitable for treatment, for example, with an anti-Aβ protofibril antibody, or to determine whether to continue treatment, or to determine whether to switch to a maintenance dose, or to conclude that a patient is amyloid negative. In some embodiments, the threshold can be evaluated in combination with another measurement of brain amyloid burden, such as a PET scan, to help determine whether a subject is suitable for treatment or continued treatment. In some embodiments, a p-tau181 level threshold can be used instead of another method of measuring brain amyloid levels, such as a PET scan. In some embodiments, a p-tau181 level threshold equal to or higher than about 2.2 to 2.3 pg / mL is used to identify and / or select patients suitable for treatment, for example, with an anti-Aβ protofibril antibody. In some embodiments, a p-tau181 level threshold equal to or higher than about 2.2 pg / mL is used to identify and / or select patients suitable for treatment, for example, with an anti-Aβ protofibril antibody. In some embodiments, a p-tau181 level threshold equal to or higher than about 2.3 pg / mL is used to identify and / or select patients suitable for treatment, for example, with an anti-Aβ protofibril antibody. In certain such embodiments, the p-tau181 levels are measured using a Quanterix TM p-tau assay to measure p-tau181 levels. 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 the p-tau181 level above the threshold can indicate the need to continue treatment or select an increased dosing regimen. In some embodiments, a decrease in the p-tau181 level below the threshold can be used to indicate that treatment can be terminated (e.g., to terminate to support a maintenance regimen) and / or otherwise determine a decrease or discontinuation of the dosing regimen. In some embodiments, an increase in tau PET levels relative to control subjects can be used to determine, for example, whether to discontinue a maintenance dosing regimen and resume a previous treatment regimen.

[0613] In some embodiments, the tau PET level or the rate of change of the tau PET level and the level of an additional biomarker (e.g., plasma p-tau181 level) can be used to select patients for treatment to allow monitoring and making treatment decisions, such as whether to increase or decrease the amount of antibody administered, determining whether to increase or decrease the dosing frequency, determining whether to introduce additional therapeutic agents, determining whether to switch to a maintenance dose, and / or whether to discontinue treatment with the anti-Aβ protofibril antibody. In some embodiments, the tau PET level can be combined with the plasma p-tau181 level (e.g., a plasma p-tau181 level greater than 2.2 pg / mL) for selecting patients for treatment, such as a tau PET level greater than 1.4, as measured by amyloid PET SUVr in the temporal region of the brain. In some embodiments, the tau PET level can be combined with the Aβ42 / 40 ratio (e.g., a plasma p-tau181 level greater than 2.2 pg / mL) for selecting patients for treatment, such as a tau PET level greater than 1.5, as measured by amyloid PET SUVr in the temporal region of the brain. The threshold for determining amyloid positivity with p-tau181 is disclosed in PCT / US2022 / 079571, which is incorporated herein by reference. In some embodiments, an increase in the tau PET level of less than 0.05 - 0.1 in a brain region (e.g., the temporal region) over a 13- or 18-month period in combination with a p-tau181 level (e.g., a p-tau181 level equal to or below the threshold) can indicate effective treatment. In some embodiments, an increase in the tau PET level at a rate lower than that of untreated control subjects in a brain region (e.g., the temporal region) over a 13- or 18-month period in combination with a p-tau181 level equal to or below the threshold can indicate effective treatment. In some embodiments, a brain region (e.g., the temporal region) tau PET lower than that of untreated control subjects in combination with a p-tau181 level equal to or below the threshold can indicate effective treatment. In some embodiments, an indication of treatment efficacy can be used to decrease the amount of antibody administered, decrease the dosing frequency, or switch to a maintenance dose. In some embodiments, an increase in the tau PET level of more than 0.05 - 0.1 in a brain region (e.g., the temporal region) over a 13- or 18-month period in combination with a p-tau181 level equal to or above the threshold (e.g., a threshold of 2.2 pg / mL) can indicate ineffective treatment. In some embodiments, an increase in the tau PET level at a rate higher than that of untreated control subjects in a brain region (e.g., the temporal region) over a 13- or 18-month period in combination with a p-tau181 level equal to or above the threshold (e.g., a threshold of 2.2 pg / mL) can indicate ineffective treatment.In some embodiments, a combination of tau PET in brain regions (e.g., temporal regions) that are higher than those of untreated control subjects and a p-tau181 level that is equal to or higher than a threshold (e.g., a threshold of 2.2 pg / mL) can indicate ineffective treatment. In some embodiments, an indication of treatment efficacy can be used to increase the amount of antibody administered, increase the frequency of administration, or discontinue treatment.

[0614] G. Additional Biomarker Changes

[0615] 1. Plasma or Serum Levels of GFAP

[0616] In some embodiments, administering to a subject a composition disclosed herein that comprises a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the glial fibrillary acidic protein (GFAP) in the plasma or serum of the subject. Without being bound by theory, the GFAP level can be used as a marker of astrocyte activation. The GFAP level can be measured by techniques known in the art, such as techniques based on immunoassays (e.g., Quanterix TM assay) and / or mass spectrometry (IP / LC-MS / MS). In some embodiments, administering to a subject a composition disclosed herein that comprises a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the plasma or serum level of GFAP in the subject. In some embodiments, administering to a subject a composition disclosed herein that comprises a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the plasma or serum level of GFAP 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% relative to baseline.

[0617] In some embodiments, treatment with an anti-Aβ protofibril antibody such as BAN2401 can result in a decrease in the plasma or serum level of GFAP in subjects with low tau PET levels in whole brain measurements (e.g., subjects receiving a therapeutically effective dose of an anti-Aβ protofibril antibody), compared to a control. In some embodiments, the decrease in the plasma or serum level of GFAP occurs between the time point of the first measurement of the plasma or serum level of GFAP (e.g., baseline measurement) and one or more subsequent time points of re-measurement of the plasma or serum level of GFAP. 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, such as an untreated 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 pooled population data from more than one subject and representing the average measurement of untreated subjects. In some embodiments, the Aβ protofibril antibody reduces plasma GFAP, as measured by an adjusted mean change relative to the baseline GFAP level of at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml.

[0618] In some embodiments, tau PET levels and plasma or serum levels of GFAP can be used to select patients for treatment to allow monitoring and making treatment decisions, such as whether to increase or decrease the amount of antibody administered, determine whether to increase or decrease the dosing frequency, determine whether to introduce additional therapeutic agents, determine whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, a combination of an increase in tau PET level of less than 0.05 - 0.1 in a brain region (e.g., temporal region) over a 13-month or 18-month period and a decrease in GFAP level over the same period can indicate effective treatment. In some embodiments, a combination of an increase in tau PET level at a rate lower than that of untreated control subjects in a brain region (e.g., temporal region) over a 13-month or 18-month period and a decrease in GFAP level over the same period can indicate effective treatment. In some embodiments, a combination of a brain region (e.g., temporal region) tau PET lower than that of untreated control subjects and a GFAP level decreased relative to untreated controls can indicate effective treatment. In some embodiments, an indication of treatment efficacy can be used to decrease the amount of antibody administered, decrease the dosing frequency, or switch to a maintenance dose.

[0619] Cerebrospinal fluid level of neurogranin

[0620] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of neurogranin in the subject. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level 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% relative to baseline.

[0621] In some embodiments, compared to a control, administering to a subject having low tau PET levels (e.g., a subject receiving a therapeutically effective dose of an anti-Aβ protofibril antibody) a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of neurogranin in the subject. In some embodiments, the measure of neurogranin in the treated subject is compared to a baseline measure obtained from the same subject prior to treatment or to a reference control. In some embodiments, the decrease in p-tau 181 occurs between the time point at which the marker is first measured (e.g., the baseline measure) and one or more subsequent time points at which p-tau 181 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 measure. In some embodiments, the control is a subject who has not received a therapeutically effective dose of the Aβ protofibril antibody, such as a subject who has not been treated or a subject who has received a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a pooled population data from more than one subject and representing the average measurement of untreated subjects.

[0622] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of neurogranin 18 months after administering the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level 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% relative to baseline 18 months after administering the composition.

[0623] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level 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 relative to baseline. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of neurogranin of at least about 65 pg / mL relative to baseline.

[0624] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level 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 relative to baseline 18 months after administering the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of neurogranin of at least 65 pg / mL relative to baseline 18 months after administering the composition.

[0625] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0626] In some embodiments, the therapeutically effective amount of the at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, the composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered every two weeks or monthly. In some embodiments, a composition comprising 10 mg / kg BAN2401 is administered every two weeks. In some embodiments, a composition comprising 10 mg / kg BAN2401 is administered monthly.

[0627] In some embodiments, tau PET levels and cerebrospinal fluid levels of neurogranin can be used to select patients for treatment to allow monitoring and making treatment decisions, such as whether to increase or decrease the amount of antibody administered, determining whether to increase or decrease the dosing frequency, determining whether to introduce additional therapeutic agents, determining whether to switch to a maintenance dose, and / or whether to discontinue treatment with the anti-Aβ protofibril antibody. In some embodiments, a combination of an increase in tau PET levels of less than 0.05 - 0.1 in a brain region (e.g., temporal region) over a 13 - or 18 - month period and a decrease in cerebrospinal fluid levels of neurogranin over the same period can indicate effective treatment. In some embodiments, a combination of an increase in tau PET levels in a brain region (e.g., temporal region) at a rate lower than that of untreated control subjects over a 13 - or 18 - month period and a decrease in cerebrospinal fluid levels of neurogranin over the same period can indicate effective treatment. In some embodiments, a combination of a brain region (e.g., temporal region) tau PET lower than that of untreated control subjects and a cerebrospinal fluid level of neurogranin decreased relative to untreated controls can indicate effective treatment. In some embodiments, an indication of treatment efficacy can be used to decrease the amount of antibody administered, decrease the dosing frequency, or switch to a maintenance dose.

[0628] 2. Level of neurofilament light chain

[0629] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti - Aβ protofibril antibody results in a decrease in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chain relative to placebo. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti - Aβ protofibril antibody results in a decrease in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chain relative to placebo 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%.

[0630] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chain relative to placebo. In some embodiments, administering the anti-Aβ protofibril antibody results in a smaller increase in plasma neurofilament light chain over time relative to placebo. In some embodiments, a measure of neurofilament light chain in a treated subject is compared to a baseline measure obtained from the same subject prior to treatment or to a reference control. In some embodiments, the change in neurofilament light chain occurs between the time point at which the marker is first measured (e.g., the baseline measure) and one or more subsequent time points at which the marker 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 who has not received a therapeutically effective dose of the anti-Aβ protofibril antibody, such as an untreated subject or a subject receiving placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a measurement that combines population data from more than one subject and represents measurements of untreated subjects.

[0631] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chain relative to placebo 18 months after administering the composition. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease 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% in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chain relative to baseline 18 months after administering the composition relative to placebo.

[0632] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a cerebrospinal fluid level of neurofilament light chain that is greater than about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL relative to baseline. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a cerebrospinal fluid level of neurofilament light chain that is no greater than about 75 pg / mL relative to baseline.

[0633] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a cerebrospinal fluid level of neurofilament light chain that is greater than about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, about 75 pg / mL relative to baseline 18 months after administering the composition. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a cerebrospinal fluid level of neurofilament light chain that is no greater than about 75 pg / mL relative to baseline 18 months after administering the composition.

[0634] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0635] In some embodiments, the therapeutically effective amount of the at least one anti-Aβ protofibril antibody disclosed herein is 10 mg / kg. In some embodiments, the composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered every two weeks or monthly. In some embodiments, a composition comprising 10 mg / kg BAN2401 is administered every two weeks. In some embodiments, a composition comprising 10 mg / kg BAN2401 is administered monthly.

[0636] In some embodiments, tau PET levels and plasma or serum levels of neurofilament light chain can be used to select patients for treatment to allow monitoring and making treatment decisions, such as whether to increase or decrease the amount of antibody administered, determine whether to increase or decrease the dosing frequency, determine whether to introduce additional therapeutic agents, determine whether to switch to a maintenance dose, and / or whether to discontinue treatment with the anti-Aβ protofibril antibody. In some embodiments, a combination of an increase in tau PET level of less than 0.05 - 0.1 in a brain region (e.g., temporal region) over a 13 - or 18 - month period and a decrease in plasma or serum level of neurofilament light chain over the same period may indicate effective treatment. In some embodiments, a combination of an increase in tau PET level at a rate lower than that of untreated control subjects in a brain region (e.g., temporal region) over a 13 - or 18 - month period and a decrease in plasma or serum level of neurofilament light chain over the same period may indicate effective treatment. In some embodiments, a combination of a tau PET in a brain region (e.g., temporal region) lower than that of untreated control subjects and a plasma or serum level of neurofilament light chain decreased relative to untreated controls may indicate effective treatment. In some embodiments, an indication of treatment efficacy can be used to decrease the amount of antibody administered, decrease the dosing frequency, or switch to a maintenance dose.

[0637] Cerebrospinal fluid level of 3-phospho-Tau

[0638] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid phosphorylated Tau (CSF p-tau) level in the subject, e.g., compared to a control. In some embodiments, the decrease in CSF p-tau occurs between the time point at which CSF p-tau is first measured (e.g., a baseline measurement) and one or more subsequent time points at which CSF p-tau 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 who has not received a therapeutically effective dose of an Aβ protofibril antibody, e.g., a subject who has not been treated or a subject who has received a placebo. In some embodiments, the control is a subject who has not received lecanemab. In some embodiments, the control is a reference measurement, such as a measurement that combines data from a group of more than one subject and represents the measurement of a subject who has not been treated.

[0639] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phosphorylated-Tau (p-tau) in the subject. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phosphorylated-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% relative to baseline.

[0640] In some embodiments, administering to a subject having a low tau PET level a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phosphorylated-Tau (p-tau) in the subject. In some embodiments, administering to a subject having a low tau PET level a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phosphorylated-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% relative to baseline. In some embodiments, the measurement of CSF p-tau in the treated subject is compared to a baseline measurement obtained from the same subject prior to treatment or to a reference control. In some embodiments, the reference control is an untreated control subject (e.g., a subject who has received a placebo). In some embodiments, the reference control is a measurement obtained from a group of control subjects.

[0641] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phospho-Tau 18 months after administration of the composition. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phospho-Tau 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%, at least 10%, at least 11%, at least 12%, or at least 13% relative to baseline 18 months after administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0642] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level 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 relative to baseline. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phospho-Tau of at least about 95 pg / mL relative to baseline.

[0643] In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level 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 relative to baseline 18 months after administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in a decrease in the cerebrospinal fluid level of phospho-Tau of at least 95 pg / mL relative to baseline 18 months after administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0644] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0645] In some embodiments, a 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 every two weeks or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered every two weeks. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0646] In some embodiments, tau PET levels and cerebrospinal fluid levels of phosphorylated-Tau can be used to select patients for treatment to allow monitoring and making treatment decisions such as whether to increase or decrease the amount of the antibody administered, determining whether to increase or decrease the frequency of administration, determining whether to introduce additional therapeutic agents, determining whether to switch to a maintenance dose, and / or whether to discontinue treatment with an anti-Aβ protofibril antibody. In some embodiments, an increase in tau PET levels of less than 0.05 - 0.1 in a brain region (e.g., the temporal region) over a 13-month or 18-month period in combination with a decrease in cerebrospinal fluid levels of phosphorylated-Tau over the same period may indicate effective treatment. In some embodiments, an increase in tau PET levels at a rate lower than that of untreated control subjects in a brain region (e.g., the temporal region) over a 13-month or 18-month period in combination with a decrease in cerebrospinal fluid levels of phosphorylated-Tau over the same period may indicate effective treatment. In some embodiments, a combination of a brain region (e.g., the temporal region) tau PET lower than that of untreated control subjects and a cerebrospinal fluid level of phosphorylated-Tau decreased relative to untreated controls may indicate effective treatment. In some embodiments, an indication of treatment efficacy can be used to decrease the amount of the antibody administered, decrease the frequency of administration, or switch to a maintenance dose.

[0647] H. Brain volume and brain regions

[0648] 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 improvement in total hippocampal atrophy relative to placebo, as measured by volumetric MRI (vMRI). In some embodiments, the brain volume of the subject (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 brain volume of the subject (e.g., total ventricular volume, left and / or right ventricular volume, total brain volume, right and / or left hippocampal volume, cortical thickness) is measured at 6, 12, and / or 18 months after treatment. 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 improvement in brain volume atrophy relative to placebo, as measured by vMRI.

[0649] In some embodiments, brain regions affected by Alzheimer's disease may include the transentorhinal region, limbic regions (e.g., the hippocampus), and neocortical regions of the brain. These brain regions may correspond to the Braak staging system (a standard based on the anatomical localization of tau neurofibrillary tangles or phosphorylated-tau) or the PET-based Braak staging system, such as described in Therriault et al., Nature Aging, Volume 2, pages 526–535 (2022). Thus, Braak regions may refer to regions that are typically affected by tau aggregation in the Braak staging. For example, early Braak regions may refer to the entorhinal cortex and / or the hippocampus.

[0650] Generally speaking, early Braak staging may be characterized as follows: Braak stage I may be characterized by tau aggregation in the entorhinal cortex, Braak stage II may be characterized by tau aggregation in the hippocampus, and Braak stage III may be characterized by tau aggregation in the amygdala, parahippocampal gyrus, fusiform gyrus, and lingual gyrus. Later Braak staging (e.g., Braak stages IV and V) may be characterized by tau aggregation in the association cortex, and Braak stage VI may be characterized by tau aggregation in the primary sensory cortex. In some embodiments, tau PET staging uses the following Braak classifications: Braak I (entorhinal cortex); Braak II (hippocampus); Braak III (amygdala, parahippocampal gyrus, fusiform gyrus, lingual gyrus).

[0651] In some embodiments, an alternative tau-PET staging according to Therriault et al., Nature Aging, Volume 2, pages 526–535 (2022) may be used to classify the staging and brain regions as follows: Braak stage I (transentorhinal), Braak stage II (entorhinal and hippocampus), Braak stage III (amygdala, parahippocampal gyrus, fusiform gyrus, lingual gyrus), Braak stage IV (insula, inferior temporal, lateral temporal, posterior cingulate, and inferior parietal), Braak stage V (orbital frontal, superior temporal, inferior frontal, cuneus, anterior cingulate cuneus, supramarginal gyrus, lateral occipital, precuneus, superior parietal, superior frontal, and rostral medial frontal), and Braak stage VI (paracentral, postcentral, precentral, and pericalcarine).

[0652] In Braak staging (e.g., tau PET Braak staging), due to natural differences between patients and / or variations in the staging methods (e.g., different tau PET tracers and analysis methods), the classification of staging and structures may vary slightly between various methods. The results of tau PET Braak staging may differ from the staging determined during autopsy.

[0653] In some embodiments, tau aggregation, as measured by tau-PET and staged according to tau-PET-based Braak staging, may be correlated with other markers of AD disease progression (e.g., AD biomarkers such as CSF p-tau, CSF Aβ, and / or amyloid PET expression, presence of neurodegeneration, and impaired cognitive function). In some embodiments, tau aggregation in early Braak regions (e.g., stage I, II, or III regions) can be detected even in the absence of other AD biomarkers or evidence of neurodegeneration (with or without cognitive impairment). Thus, tau-PET observed only in early Braak regions such as the medial temporal region of the brain can provide an early marker 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 the tau-PET levels that appear over time in Braak regions, starting with subjects who may show tau-PET in early Braak regions but have few or no other signs or symptoms of AD. In some embodiments, such subjects can be selected for AD treatment, for example, with at least one anti-Aβ protofibril antibody disclosed herein.

[0654] In some embodiments, subjects with tau-PET in early Braak regions (e.g., stage I, II, or III regions) can be treated according to the methods disclosed herein. In some embodiments, the subjects are amyloid negative and / or at risk of amyloid accumulation. In some embodiments, subjects with tau-PET in early Braak regions (e.g., stage I, II, or III regions) and detectable amyloid PET at moderate levels (e.g., 20 - 40 percentile units) or elevated levels (> 40 percentile units) can be selected for AD treatment.

[0655] In some embodiments, the subject may have low levels of tau in a whole-brain measurement, preferably as measured by tauPET. 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 levels of tau are tau PET levels below a threshold in a whole-brain measurement (e.g., tau-PET standardized 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 tauPET level is measured using the MK6240 radiotracer. In some embodiments, the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, of the entire cortical gray matter, as measured by MK6240 PET scan.

[0656] In some embodiments, the subject has low levels of tau in a whole brain measurement (e.g., whole cortical gray matter) and higher levels of tau in local brain regions. 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 transentorhinal cortex, entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus, fusiform gyrus, and / or lingual gyrus. In some embodiments, the local brain region is a composite region of regions that accumulate tau in early AD. In some embodiments, the composite region includes the temporal region, medial temporal region, and / or posterior temporal region. In some embodiments, the local brain region is the medial temporal region (e.g., entorhinal cortex).

[0657] In some embodiments, the whole brain measurement is a measure of tau aggregation (e.g., "cortical tau aggregation") in the whole cortical gray matter. In some embodiments, the whole brain measurement is a measure of tau aggregation in selected cortical regions (e.g., about 5 - 6 cortical regions, or cortical and subcortical regions).

[0658] In some embodiments, the 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 in an MK6240 PET scan), but may have higher levels of tau aggregation in local regions. For example, a subject classified as having low tau - PET based on 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.

[0659] In some embodiments, administering to a subject having a low level of cortical tau aggregation, as defined by a low tau-PET level (e.g., SUVr < 1.06 in whole cortical gray matter in a MK6240 PET scan), a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in an improvement in the progression of tau pathology in the brain relative to placebo. For example, the improvement can be a delay in the increase, stabilization of the level, or a decrease in tau-PET in early Braak regions (e.g., the temporal lobe) such as the medial temporal region, posterior temporal region, and temporal region. The improvement can be a delay in the increase, stabilization of the level, or a decrease in tau-Pet in the medial temporal region, which is typically the earliest region where tau aggregation can be observed. In contrast, for subjects having tau levels defined as moderate and / or high (e.g., a moderate level is an SUVr between 1.06 - 2.91 and a high level is an SUVr above 2.91, as determined in whole cortical gray matter in a MK6240 PET scan), the improvement can be a delay in the increase, stabilization of the level, or a decrease in tau-PET in more brain regions, which is consistent with a greater degree of tau aggregation in these subjects.

[0660] In some embodiments, administering to a subject having a low level of cortical tau aggregation, as determined by a low tau-PET level (e.g., SUVr < 1.06 in whole cortical gray matter in a MK6240 PET scan), a composition disclosed herein comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody results in an improvement in at least one measure of cognitive function relative to placebo, e.g., a slowing of the decline of cognitive function, stabilization of the level of cognitive function, or improvement of cognitive function. In some embodiments, cognitive function can be measured by CDR-SB, ADAS-Cog14, or ADCS MCI-ADL. In some embodiments, the measure of "no decline" or "improvement" may be higher in subjects having a low tau-PET level compared to patients having a moderate or higher tau-PET level.

[0661] For example, a patient treated according to any method disclosed herein may have low levels of cortical tau aggregation, as determined by low tau-PET levels (e.g., SUVr < 1.06 in the entire cortical gray matter in an MK6240 PET scan), but higher levels of tau-PET are observed in early Braak regions. Such a patient may also have lower levels of CSF p-tau and CSF Aβ, less neurodegeneration, and higher cognitive function compared to patients with moderate or moderate+high levels of cortical tau aggregation (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.

[0662] I. Anti-Aβ protofibril antibody

[0663] 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, such as comprising the complete set of 6 complementarity determining regions (CDRs) and / or the complete set of variable regions and / or the complete set of heavy and light chain sequences from each table. In some embodiments, the anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) having 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) having 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 having the amino acid sequence of SEQ ID NO:7 and a light chain variable region having 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 Igκ light chain constant region. In some embodiments, the anti-Aβ protofibril antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:9 and a light chain having the amino acid sequence of SEQ ID NO:10. As used herein in the context of antibody sequences or structures, "CDR" refers to the complementarity determining regions that provide the major determinants for antigen binding. Generally, there are six CDRs in the antigen binding site; three in VH (HCDR1, HCDR2, HCDR3), and three in VL (LCDR1, LCDR2, LCDR3). The CDRs can be determined according to the Kabat numbering scheme, which can be determined by reference to the Kabat report (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, Maryland, 1991, hereinafter referred to as the "Kabat report").

[0664] In some embodiments, the at least one anti-Aβ protofibril antibody comprises a human constant region. In some embodiments, the human constant region of the 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 its allelic variants. The amino acid sequence of the human IgG1 constant region is known in the art and is shown in SEQ ID NO:11.

[0665] In some embodiments, the human constant region of the at least one anti-Aβ antibody comprises a light chain constant region selected from κ-λ chain constant regions and any allelic variants thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region is 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 shown in SEQ ID NO:12.

[0666] 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 the humanized IgG1 monoclonal form of mAb158, a murine monoclonal antibody that was generated to target protofibrils and is 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) containing 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) containing the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3), and is described in WO 2007 / 108756 and Journal of Alzheimer’s Disease 43:575-588 (2015). BAN2401 comprises (i) a heavy chain variable region containing the amino acid sequence of SEQ ID NO:7 and (ii) a light chain variable region containing the amino acid sequence of SEQ ID NO:8. The full-length sequences of the heavy and light chains of BAN2401 are listed in SEQ ID NO:9 and 10 and are described in WO 2007 / 108756 and Journal of Alzheimer’s Disease 43:575-588 (2015).

[0667] In some embodiments, the isolated anti-Aβ protofibril antibody to be used for 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.

[0668] As used herein, a "fragment" of an antibody comprises a portion of the antibody, such as comprising an antigen-binding region or its variable region. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and single-chain antibody molecules.

[0669] In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401 or a fragment thereof) reduces cerebral amyloid angiopathy (CAA), i.e., the deposition of amyloid-β peptides in the walls of small to medium-sized blood vessels in the central nervous system and meninges.

[0670] J. A therapeutically effective amount of at least one anti-Aβ protofibril antibody

[0671] In various embodiments, the methods of the invention 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 the desired therapeutic effect.

[0672] One of ordinary skill in the art will understand that the therapeutically effective amount of at least one anti-Aβ protofibril antibody administered to a subject can depend on a variety of factors, including pharmacodynamic characteristics, route of administration, frequency of treatment, and the health, age, and weight of the subject to be treated, and, with the information disclosed herein, will be able to determine the appropriate amount for each subject.

[0673] In some embodiments, the therapeutically effective amount is a dose selected to improve efficacy and / or maintain efficacy and to improve at least one of safety and tolerability. In some embodiments, the therapeutically effective amount is selected to reduce at least one side effect and at the same time improve efficacy and / or maintain efficacy. The therapeutically effective doses of anti-Aβ protofibril antibodies and methods for measuring therapeutic efficacy are disclosed in PCT / US2022 / 073576, PCT / US2022 / 079571, and PCT / US2022 / 041926, and are incorporated herein by reference.

[0674] In some embodiments, relative to the body weight of the subject, administering to the subject from 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.

[0675] In some embodiments, relative to the body weight of the subject, administering to the subject from 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.

[0676] In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject at 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 relative to the subject's body weight.

[0677] In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject at 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 relative to the subject's body weight.

[0678] In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject starting at 0.5 mg / kg, 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 relative to the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject at 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 relative to the subject's body weight.

[0679] In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject at 0.5 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject at 1 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to a subject at 2 mg / kg relative to the subject's body we...

Claims

1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, the method comprising c. selecting a subject having a low level of tau in a whole brain measurement, preferably as measured by tau PET (low tau PET level), and d. administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) protofibril antibody.

2. The method according to claim 1, wherein treating AD comprises reducing, slowing down, and / or reversing the decline in cognitive function measures.

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

4. The method according to claim 1, wherein treating AD comprises achieving a change (e.g., slowing down, delaying, or reducing) in at least one biomarker of AD pathology.

5. The method according to claim 4, wherein the biomarker is plasma Aβ42 / 40 ratio, plasma p-tau 181 level, plasma GFAP level, and / or plasma NfL level.

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

009.

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

8. The method according to claim 5, wherein the Aβ protofibril antibody decreases plasma p-tau 181, as measured by an adjusted mean change relative to the baseline p-tau 181 level of at least about 0.2 pg / ml, 0.5 pg / ml, 0.6 pg / ml, 0.7 pg / ml, or 0.8 pg / ml.

9. The method according to claim 5, wherein the Aβ protofibril antibody decreases plasma GFAP, as measured by an adjusted mean change relative to the baseline GFAP level of at least about 20 pg / ml, 30 pg / ml, 50 pg / ml, 60 pg / ml, or 80 pg / ml.

10. The method according to 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 an adjusted mean change relative to the baseline NfL level.

11. The method according to claim 4, wherein the biomarker is tau PET level or amyloid PET level.

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

05.

13. The method according to claim 11, wherein the Aβ protofibril antibody reduces the amyloid PET level to about 55, 40, 25 or 20 percentage units.

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

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

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

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

18. The method according to claim 17, wherein the composite region includes the temporal region, the medial temporal region and / or the posterior temporal region.

19. The method according to 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 inferolateral tip of the temporal lobe)).

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

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

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

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

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

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

26. The method according to claim 1, wherein the subject has elevated amyloid (e.g., amyloid positive) measured by amyloid PET.

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

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

29. The method according to claim 28, wherein the whole brain measurement is a measurement of tau PET in the entire cortical gray matter.

30. The method according to claim 28 or 29, wherein the tau PET level is measured using the MK6240 radiotracer.

31. The method according to any one of claims 28-30, wherein the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, for the entire cortical gray matter, as measured by MK6240 PET scan.

32. The method according to any one of claims 1-31, wherein the subject has a low level of tau in the whole brain measurement (e.g., whole cortical gray matter) and a higher level of tau in local brain regions (e.g., medial temporal region, posterior temporal region, and / or temporal region).

33. The method according to any one of claims 1-32, wherein the subject further exhibits tau in local brain regions such as early Braak regions (e.g., Braak regions I, II, or III), as measured by tau PET.

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

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

36. The method according to claim 35, wherein the early Braak region includes the entorhinal cortex, the entorhinal cortex, the hippocampus, the amygdala, the parahippocampal gyrus, the fusiform gyrus, and / or the lingual gyrus.

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

38. The method according to claim 37, wherein the composite region includes the temporal region, the medial temporal region, and / or the posterior temporal region.

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

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

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

8.

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

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

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

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

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

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

48. The method according to claim 47, wherein the administration frequency is reduced after 13 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

49. The method according to claim 47, wherein the administration frequency is reduced after 18 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

50. The method according to claim 47, wherein the administration frequency is reduced after 24 months of treatment, for example, reduced to a frequency of once every 4, 6, 8, 10, or 12 weeks.

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

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

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

54. The method according to claim 53, wherein the whole - brain measurement is the tau PET level in the entire cortical gray matter.

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

56. The method according to claim 54, wherein the threshold tau PET level is, for example, a tau PET SUVR of about 1.1, preferably about 1.06, of the entire cortical gray matter, as measured in an MK6240 PET scan.

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