Methods for Treating Alzheimer's Disease

Abstract

Provided is a method for treating Alzheimer's disease in a human subject in need thereof, comprising administering to the subject an anti-beta amyloid antibody (e.g., aducanumab).

Description

[Technical field]

[0001] The present disclosure relates generally to methods for treating Alzheimer's disease. [Background technology]

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by cognitive impairment, behavioral disturbances, psychiatric symptoms, and impairment in activities of daily living. These clinical symptoms constitute AD dementia.

[0003] AD International estimates that the number of people with dementia worldwide will increase from the current 47 million to 131 million by 2050. AD, the most common cause of dementia, accounts for 60-80% of dementia cases. In the United States, it is estimated that 5.2 million Americans suffer from dementia caused by AD, and the prevalence is estimated to double or triple by 2050 unless an effective treatment is found.

[0004] Thus, there is a continuing need for methods of treating Alzheimer's disease patients. Summary of the Invention

[0005] The present disclosure describes, inter alia, a method for treating Alzheimer's disease, comprising administering anti-beta amyloid antibody.The present disclosure encompasses the recognition that, for example, there is a correlation between plasma p-tau levels, amyloid beta plaque levels, and clinical progression of Alzheimer's disease in subjects treated with anti-beta amyloid antibodies, such as aducanumab.Thus, the present disclosure provides the insight that p-tau levels in the plasma of human subjects can be used to evaluate and / or adjust treatment with anti-beta amyloid antibodies.

[0006] Furthermore, the present disclosure provides the recognition that plasma p-tau levels may be useful for identifying subgroups that may experience improved benefits from treatment with anti-beta amyloid antibodies, such as aducanumab. Thus, the present disclosure provides the insight that plasma p-tau levels may be useful for identifying and / or selecting patients for treatment with anti-beta amyloid antibodies, such as aducanumab. The present disclosure also provides that plasma p-tau levels may be useful for monitoring subjects receiving treatment with anti-beta amyloid antibodies, such as aducanumab, and / or for determining whether such subjects should continue to receive treatment including anti-beta amyloid antibodies, such as aducanumab.

[0007] Plasma p-tau measurement can provide advantages over existing techniques that can be invasive, painful, and time-consuming. By allowing subjects (e.g., patients) and physicians access to information regarding how subjects are responding to treatment with anti-beta amyloid antibodies, e.g., aducanumab, the technology described herein can improve subject outcomes and increase subject compliance in a subject population that already experiences difficult signs and symptoms and may be prone to treatment errors.

[0008] Furthermore, the present disclosure provides the insight that plasma p-tau levels in a subject show dose-dependent and time-dependent correlations with aducanumab treatment. These correlations provide subjects and physicians with a meaningful way to determine whether administration of aducanumab is effective in treating Alzheimer's disease in a subject. For example, plasma p-tau levels in a subject's plasma can be useful in determining an aducanumab treatment regimen that results in treating the subject's Alzheimer's disease while minimizing adverse events (e.g., ARIA).

[0009] Furthermore, the present disclosure demonstrates that plasma p-tau levels may be sufficient to perform certain evaluations and / or monitoring. Thus, in some embodiments described herein, the methods may not include evaluations and / or monitoring of other biomarkers, e.g., the methods described herein may not include evaluations and / or monitoring of CSF p-tau levels, amyloid plaques, or αβ42 / 40 ratios.

[0010] In some embodiments, the present disclosure provides evidence suggesting that baseline levels of plasma p-tau may correlate with aducanumab treatment response. The present disclosure demonstrates that patients with higher plasma p-tau levels at baseline (e.g., patients in the fourth quartile of baseline plasma p-tau levels) show improved response to aducanumab treatment. The present disclosure embraces the recognition that baseline levels of plasma p-tau may be useful in determining whether administration of aducanumab is effective in treating Alzheimer's disease in a subject. Thus, in some embodiments, baseline levels of plasma p-tau may be used to select patients or patient populations for treatment with aducanumab. In some embodiments, the methods described herein may include measuring baseline levels of plasma p-tau.

[0011] In some embodiments, the disclosure provides a method comprising: (i) determining p-tau levels in plasma of a human subject; and (ii) administering one or more doses of an anti-beta amyloid antibody to the human subject.

[0012] In some embodiments, the p-tau level in the plasma of the human subject is determined before the human subject receives a dose of the anti-beta amyloid antibody. In some embodiments, a method is provided further comprising determining the p-tau level in the plasma of the human subject at a first and a second time point. In some embodiments, the first time point for determining the p-tau level is before the human subject receives a dose of the anti-beta amyloid antibody. In some embodiments, the second time point for determining the p-tau level is after the human subject receives at least one dose of the anti-beta amyloid antibody. In some embodiments, the second time point for determining the plasma p-tau level is after at least 10 doses of the anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the plasma p-tau level is after at least 14 doses of the anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the plasma p-tau level is after at least 19 doses of the anti-beta amyloid antibody have been administered to the human subject.

[0013] In some embodiments, a human subject is administered an anti-beta amyloid antibody periodically, for example, every four weeks for a period of 56, 78, 104, 128, 134, or more weeks.

[0014] In some embodiments, p-tau levels in the plasma of the human subject are determined at a first and a second time point, the first time point occurring before the second time point, and if the level of plasma p-tau at the first time point is higher than the level of plasma p-tau at the second time point, the method further comprises a second or subsequent administration of an anti-beta amyloid antibody to the human subject. In some embodiments, the second or subsequent administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or greater than the dose of the anti-beta amyloid antibody administered to the human subject in the first administration.

[0015] In some embodiments, the p-tau level in the plasma of the human subject is determined at a first time point and a second time point, the first time point occurring before the second time point, and if the level of plasma p-tau at the first time point is lower than the level of plasma p-tau at the second time point, the method further comprises a second or subsequent administration of an anti-beta amyloid antibody to the human subject. In some embodiments, the second or subsequent administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or less than the dose of the anti-beta amyloid antibody administered to the human subject in the first administration.

[0016] In some embodiments, the plasma p-tau level of the human subject is determined at a first and a second time point, the first time point being a baseline or reference measurement, and the second time point occurring after one or more administrations of an anti-beta amyloid antibody. In some embodiments, the first time point is a baseline occurring before administration of the anti-beta amyloid antibody. In some embodiments, the plasma p-tau level at the first time point is an adjusted baseline. In some embodiments, the plasma p-tau level at the first time point is an unadjusted baseline. In some embodiments, the plasma p-tau level at the second time point is reduced by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% compared to the first time point (e.g., baseline). In some embodiments, the plasma p-tau level at the second time point is reduced by at least 10% compared to the first time point (e.g., baseline).

[0017] In some embodiments, the p-tau level in the plasma of the human subject is compared to a baseline measurement of p-tau in plasma. In some embodiments, the baseline measurement of p-tau in plasma is, for example, from a healthy human subject or a human subject diagnosed with AD who is not receiving treatment.

[0018] In some embodiments, the p-tau level in the plasma of the human subject is compared to the baseline level of p-tau in subjects administered a placebo. In some embodiments, the p-tau level in the plasma of the human subject is reduced by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 24%, or at least 25% compared to the p-tau level of patients in the placebo group at the same time point.

[0019] In some embodiments, the human subject has a plasma p-tau level that is reduced in comparison to the adjusted mean change from baseline of patients in the placebo group at the same time point. In some embodiments, the human subject has a plasma p-tau level that is reduced in comparison to the adjusted mean change from baseline of patients in the placebo group at the same time point. In some embodiments, the human subject has a plasma p-tau level that is reduced in comparison to the adjusted mean change from baseline of patients in the placebo group at the same time point. In some embodiments, the time point is after a period of 56 weeks, 78 weeks, 104 weeks, 128 weeks, 134 weeks, or more.

[0020] In some embodiments, after 56 weeks of administration, human subjects have an adjusted mean change from baseline in p-tau levels in plasma that is reduced within the range of -0.1 to -0.6 compared to the adjusted mean change from baseline of patients in the placebo group at the same time point.

[0021] In some embodiments, after 78 weeks of administration, human subjects have an adjusted mean change from baseline in p-tau levels in plasma that is reduced within the range of -0.2 to -0.7, compared to the adjusted mean change from baseline of patients in the placebo group at the same time point.

[0022] In some embodiments, the disclosure provides a method comprising: (i) determining a p-tau level in plasma of a human subject at baseline; and (ii) administering one or more doses of an anti-beta amyloid antibody to subjects whose plasma p-tau level is above the reference level.

[0023] In some embodiments, plasma p-tau levels comprise tau phosphorylated at one or more sites selected from Y18, S46, T50, S69, T71, S113, T123, T153, T175, T181, S184, S85, S191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414 / S416, S422, T427, S433, and S435. In some embodiments, the p-tau level in plasma is 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0024] In some embodiments, the human subject has or is suspected of having a disease associated with the accumulation and deposition of beta-amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0025] In some embodiments, the human subject is diagnosed with mild cognitive impairment due to Alzheimer's disease. In some embodiments, the subject is diagnosed with mild cognitive impairment due to Alzheimer's disease, with moderate likelihood, by a CDR global score of 0.5 and a memory box score of 0.5 or greater before treatment. In some embodiments, the subject is diagnosed with mild cognitive impairment due to Alzheimer's disease, with moderate likelihood, by a history of subjective memory decline with gradual onset and slow progression over the last year before treatment, as confirmed, for example, by a caregiver. In some embodiments, the subject is diagnosed with mild Alzheimer's dementia by the NIA-AA Core Clinical Criteria for Probable Alzheimer's Disease Dementia. In some embodiments, the subject is diagnosed with mild Alzheimer's dementia, with a CDR score of 0.5-1.0 and a memory box score of 0.5 or greater before treatment.

[0026] In some embodiments, the one or more doses of an anti-beta amyloid antibody administered to a human subject comprises one or more doses of an anti-beta amyloid antibody selected from aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.

[0027] In some embodiments, the anti-beta amyloid antibody comprises a VHCDR1 having the amino acid sequence of SEQ ID NO:3, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5, and a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. In some embodiments, the anti-beta amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:1, and a VL comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the anti-beta amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:10, and a light chain comprising the amino acid sequence of SEQ ID NO:11. In some embodiments, the anti-beta amyloid antibody is aducanumab.

[0028] In some embodiments, administering the anti-beta amyloid antibody is by intravenous administration. In some embodiments, administering the anti-beta amyloid antibody is by subcutaneous administration.

[0029] In some embodiments, the methods provided include administering a dose of an anti-beta amyloid antibody in an amount of 3 mg of antibody per kg of body weight of the human subject. In some embodiments, the methods provided include administering a dose of an anti-beta amyloid antibody in an amount of 6 mg of antibody per kg of body weight of the human subject. In some embodiments, the methods provided include administering a dose of an anti-beta amyloid antibody in an amount of 10 mg of antibody per kg of body weight of the human subject.

[0030] In some embodiments, the methods provided comprise administering the anti-beta amyloid antibody as a multiple dose regimen including multiple doses of 1 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks, multiple doses of 3 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks, multiple doses of 6 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks, and multiple doses of 10 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks.

[0031] In some embodiments, the methods provided include: (a) administering a dose of an anti-beta amyloid antibody to the human subject in an amount of 1 mg of antibody per kg of the human subject's body weight; (b) 4 weeks after step (a), administering a dose of the antibody to the human subject in an amount of 1 mg of antibody per kg of the human subject's body weight; (c) 4 weeks after step (b), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of the human subject's body weight; and (d) 4 weeks after step (c), administering a dose of the antibody to the human subject. (e) 4 weeks after step (d), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of the human subject's body weight; (f) 4 weeks after step (e), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of the human subject's body weight; and (g) after step (f), at consecutive intervals of 4 weeks, administering a dose of the antibody to the human subject in an amount of 10 mg of antibody per kg of the human subject's body weight.

[0032] In some embodiments, the methods provided include administering a dose of the antibody at a cumulative dose of at least 150 mg of antibody per kg of body weight of the human subject. In some embodiments, the methods provided include administering a dose of the antibody at a cumulative dose of at least 200 mg of antibody per kg of body weight of the human subject. In some embodiments, the methods provided include administering a dose of the antibody in an amount of 10 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 52 weeks. In some embodiments, the methods provided include administering a dose of the antibody in an amount of 6 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 112 weeks. In some embodiments, the methods provided include administering the antibody in multiple doses to the human subject, the multiple doses including (a) at least two doses of 3 mg of antibody per kg of body weight of the human subject every 4 weeks, and (b) at least 30 doses of 6 mg of antibody per kg of body weight of the human subject every 4 weeks.

[0033] In some embodiments, the human subject is an ApoE carrier. In some embodiments, the human subject has Down's syndrome. In some embodiments, the human subject is 65 years of age or older. In some embodiments, the human subject is 65-74 years of age. In some embodiments, the human subject is 75 years of age or older.

[0034] In some embodiments, the human subject is 65-74 years old and the human subject has a plasma p-tau level at a second time point that is reduced by at least 5% to at least 20% compared to a first baseline time point. In some embodiments, the human subject is 65-74 years old and the subject has a plasma p-tau level at a second time point that is reduced by at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% compared to a first baseline time point. In some embodiments, the human subject is 65-74 years old and the subject has a plasma p-tau level at a second time point that is reduced by at least 10% to at least 30% compared to a placebo group patient at the same time point. In some embodiments, the human subject is 65-74 years of age and the subject has a plasma p-tau level that is reduced by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, or at least 25% compared to patients in a placebo group at the same time point.

[0035] In some embodiments, the human subjects have an adjusted mean change from baseline in p-tau levels in plasma that is reduced by at least -0.2, -0.25, -0.3, -0.35, -0.4, -0.45, -0.5, -0.55, -0.6, -0.65, -0.7, -0.75, -0.8, -0.85, -0.9, -0.95 compared to the adjusted mean change from baseline of patients in a placebo group at the same time point. In some embodiments, the time point is after a period of 56 weeks, 78 weeks, 104 weeks, 128 weeks, 134 weeks, or more.

[0036] In some embodiments, after 56 weeks of administration, human subjects have an adjusted mean change from baseline in p-tau levels in plasma that is reduced within the range of -0.1 to -0.6 compared to the adjusted mean change from baseline of patients in the placebo group at the same time point.

[0037] In some embodiments, after 78 weeks of administration, human subjects have an adjusted mean change from baseline in plasma p-tau levels that is reduced within the range of -0.2 to -0.7 compared to the adjusted mean change from baseline of patients in the placebo group at the same time point.

[0038] In some embodiments, the human subject is 75 years of age or older and the subject has a plasma p-tau level at the second time point that is reduced by at least 5% to at least 25% compared to the first baseline time point. In some embodiments, the human subject is 75 years of age or older and the subject has a plasma p-tau level at the second time point that is reduced by at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% compared to the first baseline time point. In some embodiments, the human subject is 75 years of age or older and the subject has a plasma p-tau level at the second time point that is reduced by at least 20% to at least 40% compared to patients in a placebo group at the same time point. In some embodiments, the human subject is 75 years of age or older and the subject has plasma p-tau levels that are reduced by at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% compared to patients in a placebo group at the same time point.

[0039] In some embodiments, the human subject is an ApoE non-carrier and the subject has a plasma p-tau level at the second time point that is at least 5% to at least 25% reduced compared to the first baseline time point. In some embodiments, the human subject is an ApoE non-carrier and the subject has a plasma p-tau level at the second time point that is at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% reduced compared to the first baseline time point. In some embodiments, the human subject is an ApoE non-carrier and the subject has a plasma p-tau level at the second time point that is at least 10% to at least 40% reduced compared to patients in the placebo group at the same time point. In some embodiments, the human subject is an ApoE non-carrier and the subject has plasma p-tau levels that are reduced by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% compared to patients in a placebo group at the same time point.

[0040] In some embodiments, the human subject is an ApoE carrier and the subject has a plasma p-tau level at the second time point that is at least 5% to at least 20% reduced compared to the first baseline time point. In some embodiments, the human subject is an ApoE carrier and the subject has a plasma p-tau level at the second time point that is at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% reduced compared to the first baseline time point. In some embodiments, the human subject is an ApoE carrier and the subject has a plasma p-tau level at the second time point that is at least 10% to at least 30% reduced compared to patients in the placebo group at the same time point. In some embodiments, the human subject is an ApoE carrier and the subject has plasma p-tau levels that are reduced by at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, or at least 25% compared to patients in the placebo group at the same time point.

[0041] In some embodiments, the human subject does not develop amyloid-related imaging abnormalities (ARIA) during the course of treatment that require discontinuation of treatment.

[0042] In some embodiments, methods provided include methods of treating Alzheimer's Disease (AD) in a human subject. In some embodiments, methods provided include methods of monitoring a treatment response in a human subject. In some embodiments, methods provided include methods of determining a treatment regimen for a human subject. In some embodiments, methods provided include methods of monitoring a cognitive status of a human subject.

[0043] In some embodiments, methods provided include methods of characterizing or evaluating the effectiveness of an anti-beta amyloid antibody in a human subject.

[0044] In some embodiments, the present disclosure provides a method comprising determining p-tau levels in plasma of a human subject who has received at least one dose of an anti-beta amyloid antibody, and adjusting the amount of a dose of the anti-beta amyloid antibody administered to the human subject based on the determined plasma p-tau level.

[0045] In some embodiments, the present disclosure provides a method for selecting patients for treatment with an anti-beta amyloid antibody comprising determining p-tau levels in the plasma of a human subject.

[0046] In some embodiments, the present disclosure provides a method of determining a dosage of an anti-beta amyloid antibody to be administered to a human subject, comprising determining p-tau levels in the plasma of the human subject.

[0047] In some embodiments, the present disclosure provides a method for selecting patients to receive an anti-beta amyloid antibody for cognitive support services, comprising determining p-tau levels in plasma of a human subject.

[0048] In some embodiments, the present disclosure provides a method comprising determining p-tau levels in the plasma of a human subject who has received at least one dose of an anti-beta amyloid antibody. In some embodiments, the provided method comprises comparing the p-tau level in the plasma of the human subject with a reference plasma p-tau level. In some embodiments, the reference plasma p-tau level is the p-tau level in the plasma of the human subject before receiving a dose of the anti-beta amyloid antibody. In some embodiments, the reference plasma p-tau level is the average p-tau level in the plasma of a plurality of human subjects.

[0049] In some embodiments, the plurality of human subjects is a plurality of healthy human subjects without evidence of AD. In some embodiments, the plurality of human subjects is a plurality of human subjects with known levels of amyloid plaques. In some embodiments, the plurality of human subjects is a plurality of human subjects with known levels of tau tangles. In some embodiments, the plurality of human subjects is a plurality of human subjects with a predetermined level of cognition.

[0050] In some embodiments, if the p-tau level in the plasma of the human subject is higher than the baseline plasma p-tau level, the human subject is classified as susceptible to cognitive deterioration. In some embodiments, if the p-tau level in the plasma of the human subject is higher than the baseline plasma p-tau level, the human subject is classified as susceptible to an increased number of amyloid plaques. In some embodiments, if the p-tau level in the plasma of the human subject is higher than the baseline plasma p-tau level, the human subject is classified as susceptible to an increased number of tau tangles.

[0051] In some embodiments, the methods provided include administering another dose of an anti-beta amyloid antibody to the human subject if the p-tau level in the plasma of the human subject is higher than the baseline plasma p-tau level. In some embodiments, administering another dose of an anti-beta amyloid antibody to the human subject includes administering to the human subject a dose of an anti-beta amyloid antibody that is equal to or greater than a previous dose of an anti-beta amyloid antibody received by the human subject.

[0052] In some embodiments, plasma p-tau levels comprise tau phosphorylated at one or more sites selected from Y18, S46, T50, S69, T71, S113, T123, T153, T175, T181, S184, S85, S191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414 / S416, S422, T427, S433, and S435. In some embodiments, the p-tau level in plasma is 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0053] In some embodiments, the human subject is an ApoE carrier. In some embodiments, the human subject has Down's syndrome. In some embodiments, the human subject is 65 years of age or older. In some embodiments, the human subject is 65-74 years of age. In some embodiments, the human subject is 75 years of age or older.

[0054] In some embodiments, the present disclosure provides a kit comprising a composition comprising an anti-beta amyloid antibody for administration to a human subject and instructions for use. In some embodiments, the instructions direct administration to a human subject having one or more characteristics.

[0055] In some embodiments, the instructions direct administration to a human subject having Down's syndrome. In some embodiments, the instructions direct administration to a human subject who is 65 years of age or older. In some embodiments, the instructions direct administration to a human subject who is 65-74 years of age. In some embodiments, the instructions direct administration to a human subject who is 75 years of age or older.

[0056] In some embodiments, the instructions direct administration to a human subject whose plasma p-tau levels are above a baseline or threshold level. 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0057] In some embodiments, kits for use in accordance with the present disclosure may include instructions for processing samples, running tests on the samples, interpreting the results, etc.

[0058] In some embodiments, the instructions are for determining p-tau levels in the plasma of a human subject at a first and a second time point. In some embodiments, the first time point for determining p-tau levels is before the human subject receives a dose of an anti-beta amyloid antibody. In some embodiments, the second time point for determining p-tau levels is after the human subject receives at least one dose of an anti-beta amyloid antibody. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 10 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 14 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 19 doses of an anti-beta amyloid antibody have been administered to the human subject.

[0059] In some embodiments, the instructions direct continued administration to a human subject whose change in plasma p-tau levels between the first and second time points meets or exceeds a baseline or threshold level. 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0060] These and other features and advantages provided in the present disclosure will be more fully understood from the following detailed description taken in conjunction with the appended claims, which should be noted that the claims are defined by the recitations therein and not by the specific discussion of the features and advantages set forth in this description.

[0061] The drawings contained herein, which consist of the following figures, are for illustration purposes only and not for limitation: [Brief description of the drawings]

[0062] [Figure 1] FIG. 1 shows a schematic of a study design for administering an exemplary anti-Abeta (Aβ) antibody, such as aducanumab. [Diagram 2] Shown are changes from baseline in Aβ PET complex standardized uptake value ratio (SUVR) by MMRM in the 18F-florbetapir amyloid PET analysis population from Study 1. ***p<0.0001 (nominal) compared with placebo. [Diagram 3] Shown are changes from baseline in Aβ PET complex SUVR by MMRM in the 18F-florbetapir Aβ PET analysis population from Study 2. ***p<0.0001 (nominal) compared with placebo. [Figure 4] 1 shows the adjusted mean change in plasma p-tau181 levels for the Study 1 population. [Diagram 5] 1 shows the adjusted mean change in plasma p-tau181 levels for the study 2 population. [Figure 6] Scatter plots of change from baseline plasma p-tau181 vs. baseline florbetapir amyloid PET complex SUVR (reference region = cerebellum) for the Study 1 population at week 78. Circles represent subjects receiving placebo, squares represent subjects receiving the "low dose" exemplary anti-Aβ antibody treatment, and triangles represent subjects receiving the "high dose" exemplary anti-Aβ antibody treatment. [Figure 7]Scatter plots of change from baseline plasma p-tau181 vs. baseline florbetapir amyloid PET complex SUVR (reference region = cerebellum) for the Study 2 population at week 78. Circles represent subjects receiving placebo, squares represent subjects receiving the "low dose" exemplary anti-Aβ antibody treatment, and triangles represent subjects receiving the "high dose" exemplary anti-Aβ antibody treatment. [Figure 8A] For the patient population from Study 1, change from baseline plasma p-tau181 is shown in subjects with baseline florbetapir amyloid PET complex SUVR >1.10 (open circles, dashed line) and in subjects with baseline florbetapir amyloid PET complex SUVR ≤1.10 (filled circles, solid line). [Figure 8B] For the patient population from Study 2, change from baseline plasma p-tau181 is shown in subjects with baseline florbetapir amyloid PET complex SUVR >1.10 (open circles, dashed line) and in subjects with baseline florbetapir amyloid PET complex SUVR ≤1.10 (filled circles, solid line). [Figure 9] 1 shows a forest plot of plasma p-tau181 subgroup analysis for subjects receiving a "low dose" exemplary anti-Aβ antibody treatment. [Figure 10] 1 shows a forest plot of plasma p-tau181 subgroup analysis for subjects receiving a "high dose" exemplary anti-Aβ antibody treatment. [Figure 11] 1 shows a forest plot of plasma p-tau181 subgroup analysis based on baseline amyloid PET SUVR for subjects receiving a "high dose" exemplary anti-Aβ antibody treatment. [Figure 12] 13 shows a forest plot of plasma p-tau181 subgroup analysis based on baseline amyloid PET SUVR for subjects receiving a "low dose" exemplary anti-Aβ antibody treatment. [Figure 13]13 shows a forest plot of plasma p-tau181 subgroup analysis based on baseline plasma p-tau181 for subjects receiving a "high dose" exemplary anti-Aβ antibody treatment. [Figure 14] 13 shows a forest plot of plasma p-tau181 subgroup analysis based on baseline plasma p-tau181 for subjects receiving a "low dose" exemplary anti-Aβ antibody treatment. [Figure 15] 1 shows a line plot of adjusted mean change in plasma p-tau181 from baseline over time for Study 1 subjects over the placebo-controlled long-term extension period. [Figure 16] 1 shows a line plot of adjusted mean change in plasma p-tau181 from baseline over time for placebo-controlled Study 2 subjects over the long-term extension period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] Aducanumab is a human monoclonal antibody that targets Aβ aggregates. In June 2021, the US Food and Drug Administration (FDA) granted accelerated approval of ADUHELM™ (aducanumab-avwa) as the first and only Alzheimer's disease treatment that addresses the disease's hallmark pathology by reducing amyloid beta plaques in the brain. The efficacy of ADUHELM was evaluated in two Phase 3 clinical trials, EMERGE (Study 1) and ENGAGE (Study 2), in patients with early stages of Alzheimer's disease (mild cognitive impairment and mild dementia) with confirmed presence of amyloid pathology. The efficacy of ADUHELM was also evaluated in a double-blind, randomized, placebo-controlled, dose-ranging Phase 1b study, PRIME (Study 3). In these studies, ADUHELM consistently demonstrated dose- and time-dependent effects on reducing amyloid beta plaques (59 percent in ENGAGE [p<0.0001], 71 percent in EMERGE [p<0.0001], and 61 percent in PRIME [p<0.0001]). Using data from the EMERGE and ENGAGE Phase 3 aducanumab trials, the present disclosure provides a novel method for evaluating plasma p-tau in approximately 7,000 plasma samples from 1,815 patients with early Alzheimer's disease. 181 We describe an investigation into the effects of aducanumab treatment on

[0064] Specific Definitions As utilized in accordance with the present disclosure, unless otherwise indicated, the following terms shall be understood to have the following meanings: Unless otherwise required by context, singular terms shall include the plural and plural terms shall include the singular.

[0065] Additionally, the singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. Thus, for example, reference to "a method" includes one or more methods, and / or steps of that type described herein and / or that will become apparent to those skilled in the art upon reading this disclosure.

[0066] The term "about" or "approximately" includes within a meaningful range of values. The permissible variations encompassed by the term "about" or "approximately" will depend on the particular system under study and can be readily appreciated by one of ordinary skill in the art.

[0067] As used herein, the term "administering" or "administration" typically refers to administering a composition (e.g., comprising an anti-Aβ antibody as described herein) to a subject to deliver the composition or an agent contained in the composition to a target site or site to be treated. Those skilled in the art will recognize various routes that may be utilized for administration to a subject, e.g., a human subject, in the appropriate circumstances. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may involve a single dose or multiple doses. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve administration that is intermittent (e.g., multiple doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) administration.

[0068] The term "determining" as used herein may utilize or be accomplished through the use of any of a variety of techniques available to one of skill in the art, including, for example, the specific techniques explicitly mentioned herein. In some embodiments, determining involves the physical manipulation of the sample. In some embodiments, determining involves consideration and / or manipulation of data or information. In some embodiments, determining involves obtaining relevant information and / or materials from a source. In some embodiments, determining involves comparing one or more features of the sample or entity to a comparable reference.

[0069] As used herein, the terms "improve," "increase," "inhibit," "decrease," or their grammatical equivalents, refer to a value relative to a baseline or other reference measurement. In some embodiments, a suitable reference measurement may be or include a measurement in a particular system (e.g., a single individual) under otherwise comparable conditions in the absence of (e.g., before and / or after) a particular agent or treatment, or in the presence of an appropriate comparable reference agent. In some embodiments, a suitable reference measurement may be or include a measurement in a comparable system known or expected to respond in a particular way in the presence of the relevant agent or treatment.

[0070] As used herein, the terms "treat", "treatment", or "treating" refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset, reduce severity, and / or reduce the occurrence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a disease, disorder, and / or condition, for example, to reduce the risk of developing pathologies associated with the disease, disorder, and / or condition.

[0071] Alzheimer's Disease The present disclosure provides methods for treating patients having or suspected of having Alzheimer's disease, abbreviated herein as AD, which is a dementia primarily identified by clinical diagnosis and established by certain markers of the disease.

[0072] AD is a continuum with certain operationally defined stages of disease progression. AD pathology begins before the onset of clinical symptoms. For example, amyloid plaques, one marker of AD pathology, form 10 to 20 years before the onset of AD dementia. Currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages can be further divided into subcategories based on the severity of symptoms and measures of AD progression.

[0073] Since AD ​​does not occur in distinct stages, those skilled in the art will recognize that differences between patient groups may not be clear in certain clinical settings. Nevertheless, clinical disease stages can be characterized by measurements such as Aβ accumulation (CSF / PET), synaptic dysfunction (FDG-PET / fMRI), tau-mediated neuronal damage (CSF), brain structure (volumetric MRI), cognition, and clinical function, and changes in these measurements over time. (Jack CR, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol., 2010; 9(1): 119-28).

[0074] The current core clinical criteria for all cognitive burdens, referred to as the NINCDS-ADRDA criteria (McKhann GM, V. diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Inst. on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7 (2011) 263-269), are known in the art and can be used in practicing the present invention. This includes impaired ability to acquire and remember new information, impaired reasoning and processing of complex tasks, impaired visuospatial abilities, impaired language function (speaking, reading, writing), cognitive or behavioral impairments with changes in personality, behavior, or attitude. Alzheimer's disease is currently diagnosed using the core criteria and is typically characterized by symptoms that have a gradual onset over months to years (insidious onset) rather than sudden over hours or days. Subjects with Alzheimer's disease usually have a clear history of cognitive deterioration by report or observation.

[0075] Other diagnostic classification systems have evolved as new information about AD becomes available. These systems include the International Working Group (IWG) New Research Criteria for the Diagnosis of AD (Dubois B et al., Lancet Neurol., 2007; 6(8): 734-736), the IWG Research Criteria (Dubois et al., Lancet Neurol., 2010; 9(11): 1118-27), the NIA / AA Criteria (Jack CR et al. Alzheimer's Dement., 2011; 7(3): 257-62), and the DSM-5 Criteria (American Psychiatric Association, DSM-5, 2013). These classification systems can also be used in diagnosing AD subjects for treatment according to the methods of the present disclosure.

[0076] In some embodiments, the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, mild cognitive impairment due to Alzheimer's disease, intermediate stage Alzheimer's disease, or late stage Alzheimer's disease.

[0077] patient As used herein, the term "patient" includes any human subject who may benefit from treatment with an anti-beta amyloid antibody. In some embodiments, the patient has or is suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0078] In some embodiments, the patient is one for whom diagnosis, prognosis, prevention, or therapy of Alzheimer's disease is desired, including human subjects in need of treatment. Patients in need of treatment include those already with AD, as well as those prone to having AD, or those in whom the symptoms of AD are to be prevented. A typical patient will be male or female between the ages of 40-90 (e.g., 45-90, 50-90, 55-90, 60-90). In some embodiments, the patient is 65 years of age or older. In some embodiments, the patient is 65-74 years of age. In some embodiments, the patient is 75 years of age or older.

[0079] In some embodiments, the disclosure provides a method of treating a patient with AD (including, but not limited to, a patient with preclinical, prodromal, mild, moderate, or severe AD). In certain instances, the disclosure provides a method of treating a patient with prodromal Alzheimer's disease. In some cases, the disclosure provides a method of treating a patient with early Alzheimer's disease. In some cases, the disclosure provides a method of treating a patient to reduce clinical decline of Alzheimer's disease. In some embodiments, the patient with Alzheimer's disease also has Down's syndrome.

[0080] In some cases, the disclosure provides a method of treating a patient with mild cognitive impairment due to Alzheimer's disease. In other cases, the disclosure provides a method of treating a patient with mild Alzheimer's disease dementia. In some embodiments, the patient has amyloid pathology, as identified, for example, by positron emission tomography (PET) imaging. In some cases, the amyloid beta pathology is [ 18 In some cases, amyloid-β pathology is confirmed by [F]-florbetapir PET imaging. 18 F]-flutemetomole PET imaging. In some cases, amyloid-β pathology is 18 F]-florbetaben PET imaging. In some cases, amyloid-beta pathology is confirmed by CSF amyloid-beta analysis. In some cases, amyloid-beta pathology is confirmed by blood amyloid-beta analysis. In some cases, amyloid-beta pathology is confirmed by Congo red staining and birefringence under polarized light microscopy. In some cases, amyloid-beta pathology is confirmed by immunohistochemistry (IHC), electron microscopy, or mass spectrometry. In some cases, amyloid-beta pathology is confirmed by any method that assesses amyloid-beta levels.

[0081] In some cases, the present disclosure provides a method of treating a patient with Down's syndrome who has or is suspected of having an accumulation of beta amyloid deposits. In some embodiments, the patient with Down's syndrome has confirmed amyloid pathology. In some embodiments, the patient with Down's syndrome has been diagnosed with AD.

[0082] In certain cases, the treated patient has a Mini-Mental State Examination (MMSE) score of 24-30 (including borderline). In some cases, the treated patient has a CDR global score of 0.5. In some cases, the treated patient has an RBANS score of 85 or less (based on delayed memory index score). In some cases, the treated patient has at least 6 years of work experience. In some cases, the treated patient has an MMSE score of 24-30 (including borderline), a CDR global score of 0.5, and an RBANS score of 85 or less (based on delayed memory index score). In certain cases, the patient is an ApoE carrier (e.g., ApoE4 positive). In certain cases, the patient is an ApoE non-carrier (e.g., ApoE4 negative).

[0083] In some embodiments, the patient being treated has mid-stage Alzheimer's disease, characterized by an MMSE score of about 10 to 20, or an equivalent score on another scale. In some embodiments, late stage Alzheimer's disease is characterized by an MMSE score of about 9 or less, or an equivalent score on another scale.

[0084] In some embodiments, the patient has p-tau tangles, p-tau threads, and / or p-tau neuritic plaques. In some embodiments, the patient has neocortical p-tau tangles, neocortical p-tau threads, and / or neocortical p-tau neuritic plaques. In some embodiments, the p-tau tangles, p-tau threads, and / or p-tau neuritic plaques are detected in the patient by a positron emission tomography (PET) scan of the human subject's brain. In some embodiments, the p-tau tangles, p-tau threads, and / or p-tau neuritic plaques are detected in the patient by analysis of the amount of p-tau and / or t-tau in the CSF and / or plasma of the human subject.

[0085] AD patients in need of treatment range from subjects with amyloid pathology and early neurodegeneration, to subjects with widespread neurodegeneration and irreversible neuronal loss accompanied by progressive cognitive and functional impairment, to subjects with dementia.

[0086] Patients with preclinical AD can be identified by an asymptomatic stage with or without memory complaints, as well as emerging episodic memory and executive dysfunction, which is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence of clinical symptoms.

[0087] Prodromal AD patients are in a pre-dementia stage characterized primarily by cognitive impairment and newly emerging functional impairment with disease progression. Prodromal AD patients typically have a Mini-Mental State Examination (MMSE) score of 24-30 (including borderline), spontaneous memory complaints, objective memory loss defined as a free recall score of less than 27 on the Free and Cued Choice Recall Test (FCSRT), a global Clinical Dementia Scale (CDR) score of 0.5, the absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living, as well as the absence of dementia.

[0088] Patients with mild AD typically have an MMSE score of 20-26 (inclusive), an overall CDR of 0.5 or 1.0, and meet the National Institute on Aging-Alzheimer's Association core clinical criteria for probable AD (see section 22).

[0089] The diagnosis of AD is based on clinical symptoms, and patients with mild AD will exhibit significant behavior at work, forgetfulness, mood swings, and attention disorders. Patients with moderate AD will exhibit cognitive impairment, restricted daily activities, impaired orientation, asthenia, agnosia, aphasia, and behavioral abnormalities. Patients with severe AD will be characterized by loss of independence, memory and language decline, and incontinence.

[0090] In certain embodiments, the treatment comprises18 In certain embodiments, the treatment is for patients with early stage amyloid positive disease as assessed by F-florbetapir PET scan. 18 The treatment is for early stage patients who are amyloid positive as assessed by F-flutemetmol PET scan. In certain embodiments, the treatment is for early stage patients who are amyloid positive as assessed by F-florbetaben PET scan. In certain cases, the human subject is confirmed to have brain amyloid beta lesions before the start of treatment. The patient may be asymptomatic or only exhibit transient symptoms of headache, confusion, difficulty walking, or visual impairment. The patient may or may not be an ApoE carrier (e.g., ApoE4 carrier), as determined by ApoE genotyping.

[0091] In other embodiments, the treatment is of patients with any medical or neurological condition (other than AD) that may contribute to the subject's cognitive impairment, such as stroke or other cerebrovascular disease, other neurodegenerative disease, a history of clinically significant psychiatric illness, acute or subacute micro- or macro-bleeds, previous macro-bleeds, or superficial cerebral hemosiderosis. These patients can be treated after screening and selection by a qualified clinician.

[0092] Anti-Aβ antibody There are numerous anti-beta amyloid antibodies known in the art, including, for example, aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.

[0093] In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises lecanemab. In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises gantenerumab. In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises donanemab. In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises LY3002813. In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises bapineuzumab. In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises crenezumab. In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure is or comprises MEDI-1814. In some embodiments, the anti-beta amyloid antibody used in the methods of the disclosure is or comprises solanezumab.

[0094] In some embodiments, the anti-beta amyloid antibody used in the methods of the present disclosure comprises aducanumab (also known as BIIB037). Aducanumab is an anti-Aβ antibody that recognizes aggregated forms of Aβ, including plaques. BIIB037 contains a human kappa light chain. BIIB037 consists of two heavy chains and two human kappa light chains connected by interchain disulfide bonds. By "BIIB037" or "aducanumab" is meant an anti-Aβ antibody comprising the amino acid sequences set forth in SEQ ID NOs: 10 and 11.

[0095] In vitro characterization studies have confirmed that the antibody BIIB037 recognizes a conformational epitope present in Aβ aggregates, the accumulation of which is thought to underlie the development and progression of AD.

[0096] In vivo pharmacology studies show that a murine IgG2a chimeric version of the antibody (ch12F6A) with similar properties significantly reduces amyloid plaque burden in the brain of aged Tg2576 mice, a mouse model of AD. The reduction in parenchymal amyloid was not accompanied by changes in vascular amyloid, as has been reported for certain anti-Aβ antibodies (Wilcock OM, Colton CA. Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets, 2009 Mar;8(1):50-64).

[0097] The VH and VL of antibody BIIB037 have amino acid sequences that are identical to the amino acid sequences of the VH and VL of antibody NI-101.12F6A described in U.S. Patent No. 8,906,367 (see Tables 2-4, which are incorporated by reference in their entirety). Specifically, antibody BIIB037 has an antigen-binding domain comprising the VH and VL variable regions shown in Table A (VH) and Table B (VL), corresponding complementarity determining regions (CDRs) shown in Table C, and heavy and light chains shown in Table D(H) and Table E(L).

[0098] [Table A]

[0099] [Table B]

[0100] [Table C]

[0101] The amino acid sequence of the mature heavy chain of BIIB037 is provided in Table D below.

[0102] [Table D]

[0103] The amino acid sequence of the mature light chain of BIIB037 is provided in Table E below.

[0104] [Table E]

[0105] In addition to antibody BIIB037, the present disclosure contemplates the use of other anti-A beta amyloid antibodies, such as antibodies comprising either a VH region comprising or consisting of SEQ ID NO:1, or a VL region comprising or consisting of SEQ ID NO:2, or antibodies comprising a VH region comprising or consisting of SEQ ID NO:1 and a VL region comprising or consisting of SEQ ID NO:2, where the VH and / or VL regions have one or more substitutions, deletions, and / or insertions. In some embodiments, these VH and VL regions have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still be able to bind to beta-amyloid. In certain embodiments, these amino acid substitutions occur only in the framework regions. In some embodiments, the amino acid substitution(s) are conservative amino acid substitutions. In certain embodiments, the VH and VL regions contain 1-5 (1, 2, 3, 4, 5) amino acid deletions and / or additions and can still bind beta-amyloid. In certain embodiments, these deletions and / or additions are made at the N-terminus and / or C-terminus of the VH and / or VL regions. In some embodiments, one amino acid is deleted and / or added at the N-terminus and / or C-terminus of the VH region. In some embodiments, one amino acid is deleted and / or added at the N-terminus and / or C-terminus of the VL region.

[0106] Other antibodies contemplated for use in the present disclosure include antibodies comprising the variable heavy (VH) and variable light (VL) CDRs of Table C. Thus, the anti-beta amyloid antibodies comprise CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs: 3-8. In some embodiments, the anti-beta amyloid antibodies comprise CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs: 4-8 and comprise an amino acid sequence comprising or consisting of GFAFSSYGMH (SEQ ID NO: 9) as the VH CDR1. In some cases, the present disclosure encompasses anti-A beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on any CDR definition (e.g., Kabat, Chothia, enhanced Chothia, AbM, or contact definition). See, e.g., http: / / www.bioinf.org.uk / abs / index.html. In some embodiments, the present disclosure encompasses anti-A beta amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the Chothia definition. In some embodiments, the disclosure encompasses anti-A beta amyloid antibodies that comprise the VH and VL CDRs of BIIB037 based on the enhanced Chothia definition. In some embodiments, the disclosure encompasses anti-A beta amyloid antibodies that comprise the VH and VL CDRs of BIIB037 based on the AbM definition. In yet another embodiment, the disclosure encompasses anti-A beta amyloid antibodies that comprise the VH and VL CDRs of BIIB037 based on the contact definition.

[0107] Antibody BIIB037 and other antibodies for use in the present invention can be prepared using known methods, hi some embodiments, the antibodies are expressed in Chinese Hamster Ovary (CHO) cell lines.

[0108] The maximum tolerated dose of an anti-Aβ antibody is the amount of antibody that will produce a clinically significant response in the treatment of Alzheimer's disease consistent with safety. The main safety concern when treating patients with the methods of the invention is the occurrence of ARIA, particularly ARIA-E or ARIA-H. The methods of the invention allow for the use of higher doses of antibody BIIB037 for the treatment of patients with AD than were possible using previously known protocols.

[0109] It will be understood that dose adjustments can be made during the treatment protocol. For example, for safety or efficacy reasons, the dose can be increased so that the effect of anti-Aβ antibody against AD can be enhanced, or the dose can be decreased so that ARIA rate and severity can be reduced. If a dose is missed, the patient should preferably receive the missed dose and then resume administration by continuing according to the described regimen.

[0110] In certain embodiments, the anti-Aβ antibody is administered to the patient by intravenous infusion after dilution in saline. When using this method of administration, each infusion step in the titration regime of the present invention will typically take about 1 hour.

[0111] The dose ranges and other numerical values ​​herein include amounts having the same effect as the numerically described amounts shown by treating Alzheimer's disease in patients, and reducing the incidence or susceptibility of patients to ARIA compared to individuals not treated by the method of the present invention. At the very least, each numerical parameter should be interpreted in light of the number of significant digits, applying ordinary rounding techniques. In addition, any numerical value inherently contains certain errors from the standard deviation of its measurement, and such values ​​are within the scope of the present invention.

[0112] treatment The present disclosure provides methods and compositions for the treatment of diseases associated with the accumulation and deposition of beta amyloid, such as, inter alia, Alzheimer's disease (AD), Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia. In some embodiments, the methods of treating AD described herein include (a) inhibiting AD, e.g., arresting its onset, (b) alleviating AD, e.g., causing regression of AD, or (c) prolonging survival compared to expected survival if not treated.

[0113] In some embodiments, the agent is a therapeutic agent. In some embodiments, the treatment has a disease-modifying effect. As used herein, a disease-modifying effect means that the treatment retards or slows the underlying pathological or pathophysiological disease process and / or there is an improvement in the clinical signs and symptoms of AD compared to placebo.

[0114] In some embodiments, treatment results in symptomatic improvement, even if for a limited period of time, which may consist of enhanced cognition, more autonomy, and / or improvement in neuropsychiatric and behavioral dysfunction.

[0115] In some embodiments, the present disclosure relates to a method for slowing clinical decline or disease progression or for alleviating symptoms. Slowing clinical decline or disease progression directly impacts patients and caregivers. It slows disability, maintains independence, and allows patients to lead normal lives for a longer period of time. Relieving symptoms as much as possible can gradually improve cognitive, functional, and behavioral symptoms, as well as mood.

[0116] The present disclosure describes, inter alia, a titration regimen (sequential administration of increasing doses of an anti-beta amyloid antibody) for treating Alzheimer's disease. In some cases, the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease.

[0117] In some provided methods of treating Alzheimer's disease, anti-beta amyloid antibodies are administered to a human patient in incremental amounts over a period of time. The procedure of sequentially administering antibodies to a patient is referred to herein as "titration" because it involves administering carefully measured amounts of a standardized preparation of known concentration until the procedure is completed.

[0118] One of the advantages of the titration regimen of the present invention is that it allows AD patients to be administered higher doses of monoclonal antibodies without incurring the same degree of ARIA as observed with standard dose regimens.In certain embodiments, the higher dose comprises a dose or multiple doses of anti-Aβ antibody of 10 mg / kg of subject's body weight.Without intending to be limited to any particular mechanism, it is believed that titration results in lower initial amyloid clearance and slower clearance during overall treatment.

[0119] Titration of anti-Aβ antibodies (e.g., BIIB037) is performed in multiple doses. For example, two doses of the antibody can be administered to the patient at a dose per dose less than the minimum therapeutic dose, followed by four doses of the antibody at a dose per dose approximately equal to the minimum therapeutic dose. This regime can then be followed by multiple doses at a dose per dose greater than the minimum therapeutic dose but less than the maximum tolerated dose until there is an acceptable change in the patient's AD. For example, doses can be administered at approximately 4-week intervals for approximately 52 weeks (a total of 14 doses). Progress can be monitored by regular evaluation.

[0120] In some cases, the disclosure features a method for reducing tau or treating Alzheimer's disease by reducing Abeta and / or tau in a human patient in need thereof, the method including sequentially administering multiple doses of an anti-Aβ antibody (e.g., BIIB037) to the human patient in increasing amounts over a period of time, where multiple doses of 1 mg of antibody per kg of the human patient's body weight are administered to the human patient at intervals of about 4 weeks, multiple doses of 3 mg of antibody per kg of the human patient's body weight are administered to the human patient at intervals of about 4 weeks, multiple doses of 6 mg of antibody per kg of the human patient's body weight are administered to the human patient at intervals of about 4 weeks, and multiple doses of 10 mg of antibody per kg of the human patient's body weight are administered to the human patient at intervals of about 4 weeks. By multiple doses is meant at least two (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 123, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) doses.

[0121] An exemplary protocol according to the present disclosure, designated Protocol A, comprises: (A) administering to a patient an anti-beta amyloid antibody in an amount of 1 mg per kg of the patient's body weight; (B) 4 weeks after step (A), administering to the patient an anti-beta amyloid antibody in an amount of 1 mg per kg of the patient's body weight; (C) 4 weeks after step (B), administering to the patient an anti-beta amyloid antibody in an amount of 3 mg per kg of the patient's body weight; (D) 4 weeks after step (C), administering to the patient an anti-beta amyloid antibody in an amount of 3 mg per kg of the patient's body weight; (E) 4 weeks after step (D), administering to the patient an anti-beta amyloid antibody in an amount of 6 mg per kg of the patient's body weight; (F) 4 weeks after step (E), administering to the patient an anti-beta amyloid antibody in an amount of 6 mg per kg of the patient's body weight; (G) after step (F), at consecutive intervals of 4 weeks, administering to the patient an anti-beta amyloid antibody in an amount of 10 mg per kg of the patient's body weight.

[0122] In other words, protocol A involves administering to the patient a first dose of an anti-beta amyloid antibody in an amount of 1 mg per kg of the patient's body weight, followed by a second dose in an amount of 1 mg per kg of body weight 4 weeks after the first dose. At a 4 week interval after the second dose, antibody doses 3 and 4 are administered to the patient in an amount of 3 mg per kg of body weight. At a 4 week interval after administration of dose 4, antibody doses 5 and 6 are administered to the patient in an amount of 6 mg per kg of body weight. Then, 4 weeks after administration of dose 6, antibody dose 7 is administered to the patient in an amount of 10 mg per kg of body weight.

[0123] In some cases, after dose 7 of Protocol A, 5, 6, 7, 8, 9, or 10 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of body weight. In certain cases, at least 10, at least 11, at least 12, at least 13, or at least 14 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of body weight of the subject. In certain cases, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of body weight of the subject. In certain cases, 15-16, 15-17, 15-18, 15-19, 15-20, 15-21, 15-22, 15-23, 15-24, or 15-25 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of body weight of the subject. In certain instances, the doses are administered at consecutive intervals of four weeks. In certain instances, the doses are administered intravenously to the patient.

[0124] In some cases, after Dose 7 of Protocol A, at least 10 doses of an anti-beta amyloid antibody are administered to the patient (e.g., intravenously) in an amount of 10 mg per kg of the subject's body weight at 4 week intervals without interruption.

[0125] Another exemplary protocol according to the present disclosure, designated Protocol B, is (a) administering to a subject an anti-A beta amyloid antibody in an amount of 1 mg per kg of the subject's body weight; (b) 4 weeks after step (a), administering to the subject an anti-A beta amyloid antibody in an amount of 3 mg per kg of the subject's body weight; (c) 4 weeks after step (b), administering to the subject an anti-A beta amyloid antibody in an amount of 6 mg per kg of the subject's body weight; (d) after step (c), administering at least 10 doses of an anti-Abeta amyloid antibody in an amount of 10 mg per kg of the subject's body weight at consecutive intervals of 4 weeks.

[0126] In some cases, after step (d) of protocol B, an additional dose of anti-beta amyloid antibody is administered to the patient in an amount of 10 mg per kg of body weight. In certain cases, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 doses of anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of the subject's body weight. In certain cases, at least 21, at least 22, at least 23, at least 24, at least 24, or at least 25 doses of anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of the subject's body weight. In certain instances, 11-12, 11-13, 11-14, 11-15, 11-16, 11-17, 11-18, 11-19, 11-20, or 11-25 doses of the anti-beta amyloid antibody are administered to the patient in an amount of 10 mg per kg of the subject's body weight. In certain instances, the additional doses are administered at successive intervals of 4 weeks. In certain instances, the doses are administered intravenously to the patient.

[0127] In certain cases, when a patient develops amyloid-related imaging abnormalities (ARIA), e.g., ARIA-E, during the course of treatment, the treatment is suspended until the ARIA resolves. In some cases, the treatment is suspended for 1 to 15 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15) weeks for the ARIA to resolve, and then resumed. In certain cases, if a subject develops ARIA-E and / or ARIA-H with severe clinical symptoms, or ARIA-H with 10 or more minor hemorrhages and / or 2 or more focal areas of superficial hemosiderosis, or any new concomitant major hemorrhage, the treatment is permanently discontinued.

[0128] In certain cases, when a patient develops an amyloid-related imaging abnormality (ARIA) during the course of treatment under Protocol A or B, the patient continues to receive the above doses without a reduction in dosage. In some cases, the dosage may be administered after the ARIA has resolved.

[0129] If treatment is interrupted for any reason (e.g., missed doctor visit or doctor's recommendation due to ARIA or other side effects), the patient should continue at the same or higher dose upon resumption of treatment. For example, if the patient has already received two doses of anti-beta amyloid antibody at 3 mg / kg before interruption, the patient should receive a dose of 6 mg / kg upon resumption of treatment. If the patient has already received two doses of anti-beta amyloid antibody at 6 mg / kg before interruption, the patient should receive a dose of 10 mg / kg upon resumption of treatment. If the patient has already received two doses of anti-beta amyloid antibody at 10 mg / kg before interruption, the patient should receive a dose of 10 mg / kg upon resumption of treatment and continue to receive the 10 mg / kg dose for as long as possible.

[0130] The present disclosure also features methods and compositions for treating mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's dementia, or mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof. The method includes administering multiple doses of an anti-Abeta amyloid antibody to a human subject, the method includes administering at least six doses of the antibody at four consecutive weeks, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least seven doses of the antibody at four consecutive weeks, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least eight doses of the antibody at four consecutive weeks, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least 9 doses of the antibody at 4 consecutive week intervals, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least 10 doses of the antibody at 4 consecutive week intervals, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least 11 doses of the antibody at 4 consecutive week intervals, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least 12 doses of the antibody at 4 consecutive week intervals, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least 13 doses of the antibody at 4 consecutive week intervals, each dose being in an amount of 10 mg per kg of the subject's body weight. In some cases, the method includes administering at least 14 doses of the antibody at consecutive intervals of 4 weeks, each dose being in an amount of 10 mg / kg of the subject's body weight. In some cases, the method includes administering at least 15 doses of the antibody at consecutive intervals of 4 weeks, each dose being in an amount of 10 mg / kg of the subject's body weight. In certain cases, all of the doses specified are administered without interruption if the human subject develops ARIA during the course of treatment.In certain cases, if the dose is interrupted due to ARIA or other side effects, treatment will continue with the same or higher dose of antibody: if the patient was on the highest dose (10 mg / kg) of Protocol A, the patient will continue to receive a dose of 10 mg / kg of antibody upon resumption of treatment after the interruption.

[0131] In some cases, the anti-beta amyloid antibody of the above protocols and methods comprises a VH and a VL comprising the six CDRs of BIIB037. In certain cases, the anti-beta amyloid antibody comprises a VH and a VL of BIIB037. In other cases, the anti-beta amyloid antibody comprises a heavy chain and a light chain of BIIB037. In some cases, the anti-A beta amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises a complementarity determining region (VHCDR1) having an amino acid sequence of SEQ ID NO:3, a VHCDR2 having an amino acid sequence of SEQ ID NO:4, and a VHCDR3 having an amino acid sequence of SEQ ID NO:5, and the VL comprises a VLCDR1 having an amino acid sequence of SEQ ID NO:6, a VLCDR2 having an amino acid sequence of SEQ ID NO:7, and a VLCDR3 having an amino acid sequence of SEQ ID NO:8. In some cases, the anti-beta amyloid antibody comprises a VH comprising or consisting of SEQ ID NO:1, and a VL comprising or consisting of SEQ ID NO:2. In some cases, the anti-Abeta amyloid antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of SEQ ID NO:10 and the light chain comprises or consists of SEQ ID NO:11.

[0132] Plasma p-tau Plasma levels of phosphorylated tau (p-tau) are increased in Aβ-positive human patients with mild cognitive impairment and are further increased in Aβ-positive human patients with AD. Clinical progression of AD is associated with changes in several different biomarkers prior to detection of measures of atrophy by MRI or changes in global cognitive and ADL function. For example, Aβ42 (CSF and plasma) levels are among the first detectable changes associated with cortical Aβ pathology, followed by changes in amyloid detected by PET, and then changes in p-tau in CSF and plasma. See Hansson O. Nat Med. 2021;27:954-963, incorporated herein by reference in its entirety.

[0133] Without wishing to be bound by theory, it has been suggested that soluble p-tau may mediate the relationship between amyloid aggregates and tau aggregates. For example, increased levels of amyloid aggregates may lead to increased levels of soluble p-tau, which in turn may lead to increased tau tangle density. See Mattsson-Carlgren N, et al. EMBO Mol Med. 2021; 13: e14022 and Mattsson-Carlgren N, et al. Sci Adv. 2020; 6: eaaz2387. Together, this suggests that amyloid-induced tau aggregation and spreading (and the resulting cognitive decline) may be driven by increased soluble p-tau levels.

[0134] Conversely, the present disclosure encompasses the recognition that a reduction in amyloid aggregates can result in a reduction in p-tau levels, which can slow the accumulation of tau aggregates (and resultant clinical decline).

[0135] Various methods of the disclosure include determining p-tau levels in the plasma of a human subject. Tau can be phosphorylated at a variety of different positions. In some embodiments, p-tau comprises tau having phosphorylation at one or more sites selected from Y18, S46, T50, S69, T71, S113, T123, T153, T175, T181, S184, S85, S191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414 / S416, S422, T427, S433, and S435.

[0136] In some embodiments, p-tau is referred to herein as p-tau. 181 In some embodiments, p-tau is or comprises phosphorylation at position 181, also referred to as p-tau. 217 Also referred to as phosphorylation at position 217.

[0137] In some embodiments, p-tau levels in the plasma of a human subject are determined at one or more time points.

[0138] In some embodiments, the plasma p-tau level of a human subject is determined at a first and a second time point, the first time point being a baseline or reference measurement, and the second time point occurring after one or more administrations of an anti-beta amyloid antibody. In some embodiments, the first time point is a baseline occurring before administration of the anti-beta amyloid antibody. In some embodiments, the plasma p-tau level at the first time point is an adjusted baseline. In some embodiments, the plasma p-tau level at the first time point is an unadjusted baseline.

[0139] In some embodiments, plasma p-tau levels at the second time point are reduced by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% compared to the first time point (e.g., baseline). In some embodiments, plasma p-tau levels at the second time point are reduced by at least 10% compared to the first time point (e.g., baseline).

[0140] In some embodiments, the p-tau level in the plasma of the human subject is compared to a baseline measurement of p-tau in plasma. In some embodiments, the baseline measurement of p-tau in plasma is, for example, from a healthy human subject or a human subject diagnosed with AD who is not receiving treatment.

[0141] In some embodiments, the p-tau level in the plasma of the human subject is compared to the baseline level of p-tau in subjects administered a placebo. In some embodiments, the p-tau level in the plasma of the human subject is reduced by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 24%, or at least 25% compared to the p-tau level of patients in the placebo group at the same time point.

[0142] method In some embodiments, the present disclosure provides methods of treating, monitoring, and / or evaluating diseases associated with beta-amyloid accumulation and deposition, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0143] In some embodiments, methods provided include methods of treating a human subject. In some embodiments, methods provided include methods of monitoring a therapeutic response in a human subject. In some embodiments, methods provided include methods of determining a therapeutic regimen for a human subject. In some embodiments, methods provided include methods of monitoring a cognitive status in a human subject.

[0144] In some embodiments, the present disclosure provides a method for selecting a patient for treatment with an anti-beta amyloid antibody, comprising determining p-tau levels in the plasma of a human subject. In some embodiments, the present disclosure provides a method for determining a dosage of an anti-beta amyloid antibody to be administered to a human subject, comprising determining p-tau levels in the plasma of a human subject. In some embodiments, the present disclosure provides a method for selecting a patient to receive an anti-beta amyloid antibody for cognitive support services, comprising determining p-tau levels in the plasma of a human subject.

[0145] In some embodiments, methods provided include a method of characterizing or evaluating the effectiveness of an anti-beta amyloid antibody in a human subject comprising determining p-tau levels in the plasma of the human subject.

[0146] In some embodiments, the present disclosure provides a method for monitoring therapeutic response in a human subject having or suspected of having a disease associated with beta-amyloid accumulation and deposition, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia, comprising determining p-tau levels in the plasma of the human subject.

[0147] In some embodiments, the present disclosure provides methods of reducing plasma p-tau in a human subject having or suspected of having a disease associated with beta-amyloid accumulation and deposition, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0148] In some embodiments, the methods provided include administering an effective amount of an anti-beta amyloid antibody to a human subject. The route of administration of the anti-beta amyloid antibody of the present disclosure can be by any suitable route, including intravenous, subcutaneous. In some embodiments, the anti-beta amyloid antibody described herein is administered systemically to the human subject via infusion. In some embodiments, the anti-beta amyloid antibody is administered to the human subject by subcutaneous injection. In some embodiments, the anti-beta amyloid antibody is administered to the human subject by intravenous infusion.

[0149] In some embodiments, the disclosure provides a method comprising administering an effective amount of an anti-beta amyloid antibody to a human subject, wherein the level of plasma p-tau levels has been or will be determined in the human subject.

[0150] In some embodiments, the anti-beta amyloid antibody is administered to the subject in one or more doses. In some embodiments, the anti-beta amyloid antibody is administered to the subject as a multiple dose regimen.

[0151] composition In some embodiments, the present disclosure provides compositions for use in treating a human subject having a disease associated with the accumulation and deposition of beta-amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0152] In some embodiments, the human subject has one or more characteristics. In some embodiments, the human subject is an ApoE carrier. In some embodiments, the human subject has Down's syndrome. In some embodiments, the human subject is 65 years of age or older. In some embodiments, the human subject is 65-74 years of age. In some embodiments, the human subject is 75 years of age or older.

[0153] In some embodiments, the present disclosure provides compositions for use in treating a human subject with Alzheimer's disease, wherein the plasma p-tau level has been determined prior to treatment. In some embodiments, the human subject has a plasma p-tau level prior to administration that is at or above a baseline or threshold level. In some embodiments, the plasma p-tau level is determined prior to treatment. 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0154] In some embodiments, the disclosure provides a composition for use in treating a human subject having Alzheimer's disease, wherein the level of plasma p-tau is determined at a first time point occurring before treatment and at a second time point. In some embodiments, the second time point for determining the level of p-tau is after the human subject has received at least one dose of an anti-beta amyloid antibody. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 10 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 14 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 19 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the disclosure provides a composition for treating a human subject, wherein the change in the level of plasma p-tau between the first time point and the second time point meets or exceeds a reference level or threshold level. In some embodiments, the p-tau level in plasma is 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0155] In some embodiments, the compositions provided include an anti-beta amyloid antibody at a concentration of 50 mg / ml to 250 mg / ml, methionine at a concentration of 5 mM to 150 mM, Arg.HCl at a concentration of 50 mM to 200 mM, histidine at a concentration of 10 mM to 30 mM, PS80 at a concentration of 0.01% to 0.1%, and sucrose at a concentration of 0 to 3%. In some embodiments, the compositions further include a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM. In some embodiments, the compositions have a pH of 5.2 to 6.2. In some embodiments, the compositions have a pH of 5.2 to 6.0. In some embodiments, the compositions have a pH of 5.3 to 5.7. In some embodiments, the compositions have a pH of 5.5. In some cases, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some cases, the thiol-containing antioxidant is GSH. In some cases, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0156] In some embodiments, the composition comprises an anti-beta amyloid antibody at a concentration of 100 mg / ml, Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 10 mM to 30 mM, PS80 at a concentration of 0.01% to 0.1%, and sucrose at a concentration of 0 to 3%.

[0157] In some embodiments, the composition comprises an anti-beta amyloid antibody at a concentration of 100 mg / ml, Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%.

[0158] In some embodiments, the composition comprises an anti-beta amyloid antibody at a concentration of 175 mg / ml, Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 10 mM to 30 mM, PS80 at a concentration of 0.01% to 0.1%, and sucrose at a concentration of 0 to 3%. In some embodiments, the composition further comprises a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM. In some cases, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some cases, the thiol-containing antioxidant is GSH. In some cases, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0159] In some embodiments, the composition comprises an anti-beta amyloid antibody at a concentration of 175 mg / ml, Arg.HCl at a concentration of 150 mM, methionine at a concentration of 10 mM, histidine at a concentration of 20 mM, and PS80 at a concentration of 0.05%. In some embodiments, the composition further comprises a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM. In some cases, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, a combination of GSH and GSSG, cystine, cysteine, and a combination of cysteine ​​and cystine. In some cases, the thiol-containing antioxidant is GSH. In some cases, the thiol-containing antioxidant is GSSG. In some cases, the thiol-containing antioxidant is a combination of GSH and GSSG.

[0160] kit Kits including compositions comprising anti-beta amyloid antibodies for administration to a human subject, and instructions for use are also provided by the present disclosure. In some embodiments, the instructions direct administration to a human subject having one or more characteristics. In some embodiments, the instructions direct administration to a human subject who is an ApoE carrier. In some embodiments, the instructions direct administration to a human subject who has Down's syndrome. In some embodiments, the instructions direct administration to a human subject who is 65 years of age or older. In some embodiments, the instructions direct administration to a human subject who is 65-74 years of age. In some embodiments, the instructions direct administration to a human subject who is 75 years of age or older.

[0161] In some embodiments, the instructions direct administration to a human subject whose plasma p-tau levels are above a baseline or threshold level. 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level.

[0162] In some embodiments, kits for use in accordance with the present disclosure may include instructions for processing samples, running tests on the samples, interpreting the results, etc.

[0163] In some embodiments, the instructions are for determining p-tau levels in the plasma of a human subject at a first and a second time point. In some embodiments, the first time point for determining p-tau levels is before the human subject receives a dose of an anti-beta amyloid antibody. In some embodiments, the second time point for determining p-tau levels is after the human subject receives at least one dose of an anti-beta amyloid antibody. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 10 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 14 doses of an anti-beta amyloid antibody have been administered to the human subject. In some embodiments, the second time point for determining the level of plasma p-tau is after at least 19 doses of an anti-beta amyloid antibody have been administered to the human subject.

[0164] In some embodiments, the instructions direct continued administration to a human subject whose change in plasma p-tau levels between the first and second time points meets or exceeds a baseline or threshold level. 181 and / or p-tau 217 In some embodiments, the p-tau level is determined by measuring plasma p-tau 181 It is a level. EXAMPLES

[0165] The present invention is further illustrated by the following non-limiting examples. These examples are provided to aid in the understanding of the present invention, but are not intended to, and should not be construed as, limiting the scope of the present invention in any way. The examples do not include detailed descriptions of conventional methods that would be well known to those skilled in the art (such as molecular cloning techniques). Unless otherwise stated, parts are parts by weight, molecular weights are average molecular weights, and temperatures are given in degrees Celsius. Those skilled in the art will understand that the order of steps is not necessarily absolute and may be varied to achieve the same results in a particular embodiment.

[0166] Example 1: Overview of Phase 3 Study The efficacy and safety of aducanumab in subjects with mild cognitive impairment (MCI) due to Alzheimer's disease, or mild Alzheimer's disease dementia, was evaluated in two identically designed Phase 3 studies, Study 1 and Study 2. The studies were designed based on an understanding of the mechanism of action of aducanumab, results from previous studies, and current understanding of the disease process and underlying pathology. Table 1 provides an overview of the study design. [Table 1]

[0167] These Phase 3 studies recruited early stage patients who were Aβ positive as assessed by Aβ PET scan (by visual reading) and met clinical criteria for either MCI due to Alzheimer's disease or mild Alzheimer's dementia (as defined by NIA-AA criteria). Enrollment was monitored to ensure that approximately 80% of the Phase 3 study population included subjects with a baseline clinical stage of MCI due to Alzheimer's disease (according to the investigator's clinical assessment). Subjects were also required to have a CDR global score of 0.5, an RBANS score of 85 or less (based on delayed memory index score), and an MMSE score of 24-30 (inclusive), and had to have at least 6 years of education or work experience. Subjects were between 50 and 85 years of age at screening. Subjects with medical or neurological conditions other than Alzheimer's disease that may have contributed to the participant's cognitive impairment were excluded. Participants were in good health except for Alzheimer's disease.

[0168] Of note, the Phase 3 protocol also required subjects to undergo ApoE genotyping, given that the ε4 allele is a major risk factor for Alzheimer's disease. Both ApoE ε4 carriers and non-carriers were enrolled in both Phase 3 studies, but differential dosing based on carrier status was limited to only the "low" dose of aducanumab. See Figure 1.

[0169] Example 2: Study 1 Endpoints The primary endpoint results for modified intention-to-treat (mITT) and opportunity-to-complete (OTC) subjects who had the opportunity to complete the 78-week visit are summarized in Table 2.

[0170] In the high-dose group, the benefit of aducanumab compared with placebo in mean change on CDR-SB was -0.40 (23% less decline, nominal p=0.0101).

[0171] The low-dose group also showed less decline on CDR-SB than placebo, but the difference was smaller than that of the high-dose group and did not reach statistical significance.

[0172] [Table 2]

[0173] Secondary efficacy endpoint results for the mITT and OTC datasets are summarized in Table 3.

[0174] In the high-dose group, statistically significant differences from placebo (nominal p-value <0.05) were observed for all secondary endpoints in both data sets, except for MMSE in the mITT data set. The low-dose group did not show statistical significance for any of the three secondary endpoints in either the mITT or OTC data sets. However, small numerical advantages were observed for the low dose compared to placebo for all endpoints except MMSE.

[0175] [Table 3]

[0176] As a tertiary endpoint of Study 1, brain Aβ was measured by PET and quantified as the standardized uptake value ratio (SUVR). Serial assessments of brain Aβ plaque levels, measured by Aβ PET and quantified as SUVR, were performed in a subset of subjects participating in the longitudinal Aβ PET substudy. PET scans in the longitudinal substudy were 18 was performed using F-florbetapir Aβ PET tracer (except for a small number of subjects in which a different tracer was used). 18 The results of participants who underwent F-florbetapir PET scans are summarized here.

[0177] For the analysis of the effect of aducanumab on brain Aβ plaque levels as measured by PET, standard uptake value ratios (SUVR; ratio of radiotracer uptake in areas expected to have Aβ pathology to a reference area with minimal or no Aβ pathology) were calculated for a complex region of interest including the major cortical areas of the brain (frontal, parietal, lateral temporal, sensorimotor, anterior, and parts of the posterior cingulate membrane) using the whole cerebellum as the reference region [Ostrowitzki et al., Alzheimers Res. Ther. 8;9(1):95(2017); Chiao et al., J Nucl Med. 60(1):100-106(2019); Sevigny, Nature 537(7618):50-6(2016)]. This SUVR for the complex of regions was used as the primary endpoint for the Aβ PET analysis. A negative change from baseline in the composite SUVR indicates a reduction in Aβ plaque levels, and a negative treatment difference (aducanumab minus placebo) favors aducanumab.

[0178] Figure 2 shows the time- and dose-dependent decrease in brain Aβ levels. At week 26, coinciding with the end of the titration phase, the adjusted mean change from baseline in Aβ PET complex SUVR was -0.070 and -0.076 for the low and high dose groups, respectively, compared to 0.007 for the placebo group. Due to the similarity of doses in the titration phase, no distinction between the low and high dose groups was expected. At week 78, the adjusted mean change from baseline in Aβ PET complex SUVR was -0.165 and -0.272 for the low and high dose groups, respectively, compared to 0.019 for the placebo group.

[0179] Example 3: Study 2 Endpoints The results of the mITT and OTC analysis of the primary endpoint show that the high dose of aducanumab did not reduce attrition compared to placebo (Table 4). The low dose group did not show nominal statistical significance for the primary endpoint. However, a small numerical advantage was observed for the low dose over placebo. This difference was similar in magnitude to the difference between the low dose and placebo in Example 1.

[0180] [Table 4]

[0181] Results of the mITT and OTC analyses of secondary endpoints show no statistically significant differences in decline for MMSE, ADAS-Cog13, or ADCS-ADL-MCI compared with placebo (Table 5). However, small numerical advantages were observed for the low dose over placebo for these endpoints. For ADAS-Cog13, or ADCS-ADL-MCI, the results for the high dose group were similar to those for the low dose group.

[0182] [Table 5]

[0183] As a tertiary endpoint of Study 2, brain Aβ was measured by PET and quantified as the standardized uptake value ratio (SUVR). As in the study of Example 2, 18 A longitudinal Aβ PET substudy was performed using F-florbetapir Aβ PET tracer. As can be seen in Figure 3, aducanumab produced a time- and dose-dependent reduction in brain Aβ levels. At week 26, coinciding with the end of the titration phase, the adjusted mean change from baseline in Aβ PET complex SUVR was −0.066 in both the low and high dose aducanumab groups compared to −0.002 in the placebo group. Due to the similarity of doses in the titration phase, no distinction between the low and high dose groups was expected. At week 78, the adjusted mean change from baseline in Aβ PET complex SUVR was −0.168 and −0.238 in the low and high dose aducanumab groups, respectively, compared to −0.005 in the placebo group.

[0184] Example 4: Plasma levels of p-tau from Study 1 and Study 2 This example uses data from the Phase 3 aducanumab trials described in Examples 1-3 to demonstrate that treatment with an exemplary anti-Aβ antibody, aducanumab, reduces plasma p-tau levels, specifically, plasma p-tau 181 We explain the analysis of the impact on the level.

[0185] Participants with plasma samples at baseline and week 78 were evaluated. A total of 6447 plasma samples from study 1 and study 2 subjects were analyzed by Quanterix Simoa p-tau in a CLIA laboratory at Frontage Laboratories (Exton, PA). 181 Analyzed using the Advantage V2 kit. A summary of subjects from each study population is provided in Table 6 below.

[0186] [Table 6]

[0187] A more detailed description of these patients is given in Plasma p-tau 181 In the analysis population, baseline demographics and characteristics of Alzheimer's disease were similar between groups and are shown in Table 7.

[0188] [Table 7]

[0189] Plasma p-tau was measured in patients treated with placebo, low-dose anti-Aβ antibody, and high-dose anti-Aβ antibody. 181 The adjusted mean change in plasma p-tau levels was assessed and the results are shown in Figures 4 and 5 for the Study 1 and Study 2 populations, respectively. 181 The levels were 3.264 pg / mL and 3.185 pg / mL, respectively, with median baseline levels of 2.980 pg / mL in Study 1 and 3.080 pg / mL in Study 2. In the placebo group, plasma p-tau levels from baseline in both Study 1 and Study 2 were 181 There was a time-dependent increase in plasma p-tau at week 78 in the high-dose aducanumab group versus placebo (8% and 9% increases from baseline, respectively). 181 The mean change from baseline in levels was -0.424 (95% CI, -0.5607 to -0.2880; P < 0.0001) in study 1 and -0.484 vs. placebo (95% CI, -0.5978 to -0.3692; P < 0.0001) in study 2, reflecting a 13% and 15% reduction from baseline, respectively.

[0190] Plasma p-tau 181 The effect of aducanumab on plasma p-tau levels increased as the total cumulative dose increased. The mean cumulative dose received by week 78 was 127 in study 1 and 122 in study 2. Subgroup analyses of the subset of high-dose subjects defined by total cumulative dose received by week 78 were performed. 181Reductions in mean change from baseline in plasma p-tau across aducanumab treatment arms relative to placebo were seen across all three cumulative dose groups (<100 mg / kg, 110-149 mg / kg, and ≥150 mg / kg). 181 The treatment effect on plasma p-tau levels was greater (data not shown). For the highest total cumulative dose (≥150 mg / kg) at week 78, plasma p-tau levels were 181 Decreases from baseline in levels were observed in both Study 1 and Study 2 (17% and 19% decreases, respectively).

[0191] This analysis demonstrates that treatment with aducanumab, an exemplary anti-Aβ antibody, reduces plasma p-tau 181 Furthermore, it was shown that plasma p-tau levels were significantly reduced. 181 The effect of aducanumab on levels was observed to be both time- and dose-dependent.

[0192] Example 5: Plasma p-tau correlates with changes in amyloid PET SUVR This example shows plasma p-tau levels, here p-tau 181 To describe the relationship between anti-beta amyloid antibody-induced changes in and brain amyloid levels expressed as amyloid PET standardized uptake value ratio (SUVR).

[0193] Figures 6 and 7 show baseline plasma p-tau for the Study 1 and Study 2 populations, respectively. 181 A scatter plot of change from baseline vs. change from baseline florbetapir amyloid PET complex SUVR (reference region = cerebellum) is shown. Subjects were evaluated at week 78 and divided into categories of subjects receiving placebo (circles), subjects receiving "low dose" anti-Aβ antibody treatment (squares), and subjects receiving "high dose" anti-Aβ antibody treatment (triangles). p-Tau 181 There was a dose-dependent correlation between the reduction in levels and the reduction in amyloid deposits.

[0194] Furthermore, those subjects with lower SUVR also had lower plasma p-tau 181 As shown in Figures 8A and 8B, baseline plasma p-tau was observed to have a greater reduction from baseline in subjects with a baseline florbetapir amyloid PET complex SUVR of 1.10 or less (filled circles, solid line) compared to subjects with a baseline florbetapir amyloid PET complex SUVR of >1.10 (open circles, dashed line). 181 There was a larger change from the mean mean of 0.01 to 0.01 in the mean of ...

[0195] This example shows plasma p-tau 181 We demonstrate that the therapeutic effect of aducanumab on amyloid PET SUVR was associated with a reduction in amyloid PET SUVR.

[0196] Example 6: Greater reductions in plasma p-tau are associated with improved clinical measures This example describes the relationship between plasma p-tau levels and clinical outcomes. Specifically, plasma p-tau, e.g., plasma p-tau 181 Greater reductions in plasma p-tau were associated with less clinical decline by multiple measures of clinical efficacy. As shown in Table 8 below, 181 Correlations between and clinical efficacy were observed in the expected direction across four different clinical measures in patients from both Study 1 and Study 2.

[0197] [Table 8]

[0198] These findings support the finding that the underlying disease pathology is associated with fundamental biomarkers, e.g., p-tau 181 We demonstrate that changes in plasma p-tau were associated with a statistically significant slowing of clinical decline as measured by CDR-SB, MMSE, ADAS-Cog13, and ADCS-ADL-MCI. 181The treatment effect of aducanumab on AD was associated with reduced cognitive and functional decline.

[0199] Together, these examples demonstrate plasma phosphorylated tau in patients with early Alzheimer's disease. 181 (p-tau 181 This paper highlights important new data from approximately 7,000 plasma samples from aducanumab Phase 3 trials that examine for the first time the effect of aducanumab on Alzheimer's disease (AD) and its correlation with amyloid beta plaques and disease progression, as measured by the endpoint of clinical decline. Amyloid beta plaques and the accumulation of tau protein tangles in brain cells are two hallmark pathologies of Alzheimer's disease, and this disclosure demonstrates a correlation between plasma p-tau reduction, amyloid beta plaque levels, and clinical decline in Alzheimer's disease.

[0200] Example 7: Subgroup analysis of plasma p-tau This example describes an analysis of the effect of treatment with aducanumab, an anti-beta amyloid antibody, on plasma p-tau levels in different subgroups evaluated at week 78. Specifically, this example describes the effect of treatment with aducanumab, an anti-beta amyloid antibody, on plasma p-tau levels in subjects from Study 1 and Study 2. 181 We provide a subgroup analysis of the cohort at baseline, with subgroups differentiated by age (≤64, 65–74, or ≥75 years), ApoE ε4 status (carrier or noncarrier), and baseline clinical stage (MCI due to AD or mild AD dementia).

[0201] The results are shown in Figure 9 (for low-dose treated patients) and Figure 10 (for high-dose treated patients). Results were based on MMRM (mixed model for repeated measures) models for each subgroup with change from baseline as the dependent variable. Subgroup analyses were also performed based on gender (male / female) and baseline AD medication use (data not shown).

[0202] Plasma p-tau 181Reductions in plasma p-tau levels were observed in both high- and low-dose aducanumab treatment groups compared to placebo across subgroups in both Study 1 and Study 2. Results showed that overall plasma p-tau levels from all subjects were significantly lower in both high- and low-dose aducanumab treatment groups compared to placebo. 181 Overall, subgroup analyses demonstrated a statistically significant increase in plasma p-tau in subjects treated with aducanumab for all subgroups examined. 181 These data support that aducanumab has therapeutic efficacy across subjects.

[0203] Plasma p-tau 181 Reductions in CI were seen in both male and female subjects, and in subjects stratified by baseline AD symptomatic treatment, compared to placebo. This reduction was seen across treatment arms (both low and high dose) in both studies at week 78, with no clear trends among subjects stratified by sex or baseline AD treatment.

[0204] Furthermore, plasma p-tau was significantly lower in individuals aged 75 years or older at baseline and in ApoE ε4 non-carriers. 181 A significant decrease in plasma p-tau levels was consistently observed in subjects aged 75 years and older. 181 The reduction in plasma p-tau levels from baseline and placebo is also reflected in Table 9 below. 181 Similarly, Table 10 provides the relative percent change in plasma p-tau levels from baseline and placebo for ApoE carriers and non-carriers. 181 Provides the relative rate of change in level.

[0205] [Table 9]

[0206] [Table 10]

[0207] As mentioned above, plasma p-tau 181 A reduction in is associated with improved clinical measures. Thus, the present disclosure recognizes that certain subgroups (e.g., subjects aged 75 years or older at baseline and / or subjects who are ApoE ε4 non-carriers) may have improved benefit from treatment with an anti-beta amyloid antibody (e.g., aducanumab).

[0208] In summary, the plasma p-tau 181 Subgroup analyses showed that plasma p-tau in all participants treated with aducanumab 181 We found a consistent decrease in levels, with even greater declines in patients aged 75 years or older and ApoE ε4 non-carriers at baseline, which may be associated with improved benefit from treatment with aducanumab.

[0209] Example 8: Subgroup analysis based on baseline amyloid and baseline p-tau levels This example describes further subgroup analyses of the effect of treatment with aducanumab, an anti-beta amyloid antibody, on plasma p-tau levels. Specifically, this example describes the effect of treatment with aducanumab, an anti-beta amyloid antibody, on plasma p-tau levels in subjects from Study 1 and Study 2 at Week 78. 181 Subgroup analyses of baseline amyloid PET SUVR and baseline plasma p-tau 181 are differentiated by level.

[0210] Subjects were stratified into quartiles of relative baseline levels. Results of subgroup analyses of baseline amyloid PET SUVR are shown in Figure 11 (for high-dose treated patients) and Figure 12 (for low-dose treated patients). Baseline plasma p-tau 181 The results of the level subgroup analysis are shown in Figure 13 (for high-dose treated patients) and Figure 14 (for low-dose treated patients).

[0211] Plasma p-tau 181Reductions in levels were across all quartiles of baseline amyloid PET SUVR and across baseline plasma p-tau 181 This was consistently observed in both high- and low-dose aducanumab treatment arms compared to placebo in both Studies 1 and 2, across all baseline levels of PET SUVR and all baseline plasma p-tau 181 This supports the idea that it is an effective treatment for subjects at this level.

[0212] Furthermore, as shown in Figures 13 and 14, the highest baseline plasma p-tau 181 In the subgroup with levels, i.e., those in the fourth quartile, plasma p-tau 181 As mentioned above, it was consistently observed that there was a large decrease in plasma p-tau levels. 181 Decreased plasma p-tau levels are associated with clinical response. 181 This supports that subjects with these levels may exhibit an increased response to treatment with an anti-beta amyloid antibody (e.g., aducanumab).

[0213] Example 9: Effect of treatment on plasma p-tau levels in a long-term extension study This example describes an analysis of the effect of treatment with aducanumab, an anti-beta amyloid antibody, on plasma p-tau levels in a long-term extension study. The long-term extension study included a placebo-controlled trial period and a long-term extension (LTE) period. Subjects were randomized into "early-start" and "late-start" treatment arms. Early-start subjects were subjects randomized to aducanumab at the beginning of the placebo-controlled period who continued on their originally assigned treatment in the LTE period, including "early-start low-dose" and "early-start high-dose" subjects. Late-start subjects were subjects randomized to placebo at the beginning of the placebo-controlled period who were then randomized to receive dose-blinded aducanumab during the LTE period (low:high 1:1), including "late-start low-dose" and "late-start high-dose" subjects.

[0214] The results are shown in Figures 15 and 16. In both Study 1 and Study 2, plasma p-tau in late-start subjects 181 Levels increased during the placebo-controlled period and began to decrease in the long-term extension period once subjects began receiving aducanumab treatment. At week 128, subjects in the late-start high-dose group had lower plasma p-tau levels than subjects in the late-start low-dose group. 181 The decrease in levels was greater, consistent with greater exposure in the long-term extension out to 128 weeks.

[0215] Plasma p-tau in subjects in the early start group 181 Levels continued to decrease in the long-term extension in both Study 1 and Study 2. Comparisons of the late-start and early-start groups within each study revealed statistically significant differences at both 104 and 128 weeks. For example, plasma p-tau levels in the early-start high-dose group compared with the late-start high-dose group were significantly lower at 104 weeks than in the early-start high-dose group. 181 The changes from baseline in were -0.541 (p<0.0001) and -0.908 (p<0.0001) at Week 104, and -0.289 (p=0.1265) and -0.640 (p<0.0001), respectively, for Study 1 and Study 2. Similar trends were observed for subjects through Week 134 (data not shown).

[0216] This example demonstrates that higher doses of aducanumab are associated with greater reductions in plasma p-tau levels and that longer treatment periods beyond 78 weeks reduced plasma p-tau levels. 181 The results demonstrate that the levels continue to decrease. Exemplary embodiments 1. A method comprising determining p-tau levels in the plasma of a human subject and administering one or more doses of an anti-beta amyloid antibody to the human subject. 2. The method of embodiment 1, wherein the p-tau level in the plasma of the human subject is determined before the human subject receives a dose of the anti-beta amyloid antibody. 3. The method of embodiment 1 or 2, wherein the method further comprises determining p-tau levels in the plasma of the human subject at the first and second time points. 4. The method of embodiment 3, wherein said first time point is before said human subject receives a dose of said anti-beta amyloid antibody. 5. The method of embodiment 3 or 4, wherein said second time point is after said human subject has received at least one dose of said anti-beta amyloid antibody. 6. The method of any one of embodiments 3-5, wherein the second time point for determining the level of plasma p-tau is after at least 10 doses of an anti-beta amyloid antibody have been administered to the human subject. 7. The method of any one of embodiments 3-6, wherein the second time point for determining the level of plasma p-tau is after at least 14 doses of an anti-beta amyloid antibody have been administered to the human subject. 8. The method of any one of embodiments 3-7, wherein the second time point for determining the level of plasma p-tau is after at least 19 doses of an anti-beta amyloid antibody have been administered to the human subject. 9. The method of any one of embodiments 5-8, wherein if the first time point occurs before the second time point and the level of plasma p-tau at the first time point is higher than the level of plasma p-tau at the second time point, the method further comprises a second administration of the anti-beta amyloid antibody to the human subject. 10. The method of embodiment 9, wherein the second administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or greater than the dose of the anti-beta amyloid antibody administered to the human subject in a first administration. 11. The method of any one of embodiments 5-8, wherein if the first time point occurs before the second time point and the level of plasma p-tau at the first time point is lower than the level of plasma p-tau at the second time point, the method further comprises a second administration of the anti-beta amyloid antibody to the human subject. 12. The method of embodiment 11, wherein the second administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or less than the dose of the anti-beta amyloid antibody administered to the human subject in a first administration. 13. The p-tau level is plasma p-tau 181 or plasma p-tau 217 13. The method according to any one of embodiments 1 to 12, wherein the level 14. The method of any one of embodiments 1-13, wherein the human subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease. 15. The method of any one of embodiments 1 to 13, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, possibly of moderate severity, as determined by a pre-treatment CDR global score of 0.5 and a memory box score of 0.5 or greater. 16. The method of any one of embodiments 1 to 13, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, likely of moderate severity, as determined, for example, by a caregiver, with a history of subjective memory decline with gradual onset and slow progression over the last year prior to treatment. 17. The method of any one of embodiments 1-13, wherein the subject has been diagnosed with mild Alzheimer's disease dementia by the NIA-AA core clinical criteria for probable Alzheimer's disease dementia. 18. The method of any one of embodiments 1 to 13, wherein the subject has been diagnosed with mild Alzheimer's disease dementia, as determined by a pre-treatment CDR score of 0.5 to 1.0 and a memory box score of 0.5 or greater. 19. The method of any one of embodiments 1-18, wherein the anti-beta amyloid antibody is selected from aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab. 20. The method according to any one of embodiments 1 to 18, wherein the anti-beta amyloid antibody comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, as well as a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. 21. The method of any one of embodiments 1 to 18, wherein the anti-beta amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:1, and a VL comprising the amino acid sequence of SEQ ID NO:2. 22. The method of any one of embodiments 1 to 18, wherein the anti-beta amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain comprising the amino acid sequence of SEQ ID NO: 11. 23. The method of any one of embodiments 1-22, wherein the anti-beta amyloid antibody is administered intravenously or subcutaneously. 24. The method of any one of embodiments 1-23, comprising administering the dose of anti-beta amyloid antibody in an amount of 3 mg of antibody per kg of body weight of the human subject. 25. The method of any one of embodiments 1-24, comprising administering the dose of anti-beta amyloid antibody in an amount of 6 mg of antibody per kg of body weight of the human subject. 26. The method of any one of embodiments 1-25, comprising administering the dose of anti-beta amyloid antibody in an amount of 10 mg of antibody per kg of body weight of the human subject. 27. The method of any one of embodiments 1-26, comprising administering the anti-beta amyloid antibody as a multiple dose regimen including: multiple doses of 1 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks; multiple doses of 3 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks; multiple doses of 6 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks; and multiple doses of 10 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks. 28. (a) administering a dose of the anti-beta amyloid antibody to the human subject in an amount of 1 mg of antibody per kg of the body weight of the human subject; (b) 4 weeks after step (a), administering a dose of the antibody to the human subject in an amount of 1 mg of antibody per kg of the human subject's body weight; (c) 4 weeks after step (b), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of the human subject's body weight; (d) 4 weeks after step (c), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of the human subject's body weight; (e) 4 weeks after step (d), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of the human subject's body weight; (f) 4 weeks after step (e), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of the human subject's body weight; 28. The method of any one of embodiments 1-27, comprising: (g) administering, after step (f), at consecutive intervals of 4 weeks, doses of the antibody to the human subject in an amount of 10 mg of antibody per kg of body weight of the human subject. 29. The method of any one of embodiments 1-27, comprising administering a dose of said antibody at a cumulative dose of at least 150 mg of antibody per kg of body weight of said human subject. 30. The method of any one of embodiments 1-27, comprising administering a dose of said antibody at a cumulative dose of at least 200 mg of antibody per kg of body weight of said human subject. 31. The method of any one of embodiments 1-27, comprising administering a dose of the antibody in an amount of 10 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 52 weeks. 32. The method of any one of embodiments 1-27, comprising administering a dose of the antibody in an amount of 6 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 112 weeks. 33. Administering the antibody to the human subject in multiple doses, wherein the multiple doses include: (a) at least two doses of 3 mg of antibody per kg body weight of the human subject every four weeks; and (b) at least 30 doses of 6 mg of antibody per kg body weight of the human subject every 4 weeks. 34. The method of any one of embodiments 1 to 33, wherein the human subject is an ApoE carrier. 35. The method of any one of embodiments 1-33, wherein the human subject is an ApoE non-carrier. 36. The human subject, (i) were aged 65 years or older at baseline; (ii) were aged 65–74 years at baseline; or (iii) The method of any one of embodiments 1 to 35, wherein the patient is 75 years of age or older. 37. The method of any one of embodiments 1-36, wherein the human subject does not develop amyloid-related imaging abnormalities (ARIA) during the course of treatment that require discontinuation of treatment. 38. The method of any one of embodiments 1-37, wherein the method is a method of treating Alzheimer's disease (AD) in the human subject. 39. The method of any one of embodiments 1 to 38, wherein the method is a method for monitoring a therapeutic response in the human subject. 40. The method of any one of embodiments 1 to 38, wherein the method is a method for determining a treatment regimen for the human subject. 41. The method of any one of embodiments 1 to 38, wherein the method is a method for monitoring the cognitive state of the human subject. 42. A method comprising: determining p-tau levels in the plasma of a human subject who has received at least one dose of an anti-beta amyloid antibody; and adjusting the amount of anti-beta amyloid antibody in the dose administered to the human subject based on the determined plasma p-tau level. 43. A method for selecting patients for treatment with an anti-beta amyloid antibody, comprising determining p-tau levels in the plasma of a human subject. 44. A method for determining a dose of an anti-beta amyloid antibody to be administered to a human subject, comprising determining p-tau levels in the plasma of the human subject. 45. A method for selecting patients to receive an anti-beta amyloid antibody for cognitive support services, comprising determining p-tau levels in the plasma of a human subject. 46. ​​A method comprising determining p-tau levels in the plasma of a human subject who has received at least one dose of an anti-beta amyloid antibody. 47. The method of embodiment 46, comprising comparing the p-tau level in the plasma of the human subject with a reference plasma p-tau level. 48. The method of embodiment 47, wherein the reference plasma p-tau level is the p-tau level in the plasma of the human subject before receiving a dose of an anti-beta amyloid antibody. 49. The method of embodiment 47, wherein said reference plasma p-tau level is an average p-tau level in the plasma of a plurality of human subjects. 50. The method of embodiment 49, wherein the plurality of human subjects is a plurality of healthy human subjects with no evidence of AD. 51. The method of embodiment 49, wherein the plurality of human subjects is a plurality of human subjects having known levels of amyloid plaques. 52. The method of embodiment 49, wherein the plurality of human subjects is a plurality of human subjects having known levels of tau tangles. 53. The method of embodiment 49, wherein the plurality of human subjects is a plurality of human subjects having a predetermined level of cognition. 54. The method of any one of embodiments 47 to 53, wherein the human subject is classified as susceptible to cognitive deterioration if the p-tau level in the plasma of the human subject is higher than a reference plasma p-tau level. 55. The method of any one of embodiments 47 to 53, wherein the human subject is classified as susceptible to an increased number of amyloid plaques if the p-tau level in the plasma of the human subject is higher than a reference plasma p-tau level. 56. The method of any one of embodiments 47 to 53, wherein the human subject is classified as susceptible to an increased number of tau tangles if the p-tau level in the plasma of the human subject is higher than a reference plasma p-tau level. 57. The method of any one of embodiments 47-53, comprising administering to the human subject another dose of the anti-beta amyloid antibody if the p-tau level in the plasma of the human subject is higher than the baseline plasma p-tau level. 58. The method of embodiment 57, wherein administering to the human subject another dose of the anti-beta amyloid antibody comprises administering to the human subject a dose of the anti-beta amyloid antibody that is equal to or greater than a previous dose of the anti-beta amyloid antibody received by the human subject. 59. The plasma p-tau level is 181 or p-tau 217 The method of any one of the preceding embodiments, wherein the level is 60. A method comprising determining p-tau levels in the plasma of a human subject at baseline and administering one or more doses of an anti-beta amyloid antibody to subjects whose plasma p-tau levels exceed the reference level. 61. A composition for use in the method according to any one of embodiments 1 to 60. 62. A kit comprising the composition of embodiment 61 and instructions for use. 63. Use of an anti-beta amyloid antibody in the manufacture of a medicament for treating a disease in a human subject, said treatment comprising determining p-tau levels in the plasma of said human subject and administering one or more doses of an anti-beta amyloid antibody to said human subject, said disease comprising Alzheimer's disease (AD). 64. The use according to embodiment 63, wherein the p-tau level in the plasma of the human subject is determined before the human subject receives a dose of the anti-beta amyloid antibody. 65. The use according to embodiment 63 or 64, wherein the treatment further comprises determining p-tau levels in the plasma of the human subject at the first and second time points. 66. The use of embodiment 65, wherein the first time point is before the human subject receives a dose of the anti-beta amyloid antibody. 67. The use of embodiment 65 or 66, wherein the second time point is after the human subject has received at least one dose of the anti-beta amyloid antibody. 68. The use according to any one of embodiments 65 to 67, wherein the second time point for determining the level of plasma p-tau is after at least 10 doses of an anti-beta amyloid antibody have been administered to the human subject. 69. The use according to any one of embodiments 65 to 68, wherein the second time point for determining the level of plasma p-tau is after at least 14 doses of an anti-beta amyloid antibody have been administered to the human subject. 70. The use according to any one of embodiments 65 to 69, wherein the second time point for determining the level of plasma p-tau is after at least 19 doses of an anti-beta amyloid antibody have been administered to the human subject. 71. The use of any one of embodiments 67 to 70, wherein if the first time point occurs before the second time point and the level of plasma p-tau at the first time point is higher than the level of plasma p-tau at the second time point, the treatment further comprises a second administration of the anti-beta amyloid antibody to the human subject. 72. The use of embodiment 71, wherein the second administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or greater than the dose of the anti-beta amyloid antibody administered to the human subject in the first administration. 73. The use of any one of embodiments 67 to 70, wherein if the first time point occurs before the second time point and the level of plasma p-tau at the first time point is lower than the level of plasma p-tau at the second time point, the treatment further comprises a second administration of the anti-beta amyloid antibody to the human subject. 74. The use of embodiment 73, wherein the second administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or less than the dose of the anti-beta amyloid antibody administered to the human subject in a first administration. 75. The p-tau level is plasma p-tau 181 Levels or plasma p-tau 217The use according to any one of embodiments 63 to 74, wherein the level 76. The use of any one of embodiments 63 to 75, wherein the human subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease. 77. The use of any one of embodiments 63 to 75, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, possibly of moderate severity, as determined by a pre-treatment CDR global score of 0.5 and a memory box score of 0.5 or greater. 78. The use of any one of embodiments 63 to 75, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, possibly of moderate severity, as determined, for example, by a history of subjective memory decline with gradual onset and slow progression over the last year prior to treatment, as confirmed by a caregiver. 79. The use of any one of embodiments 63-75, wherein the subject has been diagnosed with mild Alzheimer's disease dementia by the NIA-AA core clinical criteria for probable Alzheimer's disease dementia. 80. The use of any one of embodiments 63 to 75, wherein the subject has been diagnosed with mild Alzheimer's disease dementia, as determined by a pre-treatment CDR score of 0.5 to 1.0 and a memory box score of 0.5 or greater. 81. The use according to any one of embodiments 63 to 80, wherein the anti-beta amyloid antibody is selected from aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab. 82. The use according to any one of embodiments 63 to 80, wherein the anti-beta amyloid antibody comprises a VHCDR1 having the amino acid sequence of SEQ ID NO: 3, a VHCDR2 having the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 having the amino acid sequence of SEQ ID NO: 5, as well as a VLCDR1 having the amino acid sequence of SEQ ID NO: 6, a VLCDR2 having the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 having the amino acid sequence of SEQ ID NO: 8. 83. The use according to any one of embodiments 63 to 80, wherein the anti-beta amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO:1, and a VL comprising the amino acid sequence of SEQ ID NO:2. 84. The use according to any one of embodiments 63 to 80, wherein the anti-beta amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10, and a light chain comprising the amino acid sequence of SEQ ID NO: 11. 85. The use according to any one of embodiments 63 to 84, wherein the anti-beta amyloid antibody is administered intravenously or subcutaneously. 86. The use according to any one of embodiments 63 to 85, wherein the treatment comprises administering a dose of the anti-beta amyloid antibody in an amount of 3 mg of antibody per kg of body weight of the human subject. 87. The use according to any one of embodiments 63 to 86, wherein the treatment comprises administering a dose of the anti-beta amyloid antibody in an amount of 6 mg of antibody per kg of body weight of the human subject. 88. The use according to any one of embodiments 63 to 87, wherein the treatment comprises administering a dose of the anti-beta amyloid antibody in an amount of 10 mg of antibody per kg of body weight of the human subject. 89. The use of any one of embodiments 63 to 88, wherein the treatment comprises administering the anti-beta amyloid antibody as a multiple dose regimen comprising: multiple doses of 1 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks; multiple doses of 3 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks; multiple doses of 6 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks; and multiple doses of 10 mg of antibody per kg of the human patient's body weight administered to the human patient at intervals of 4 weeks. 90. The treatment, (a) administering a dose of the anti-beta amyloid antibody to the human subject in an amount of 1 mg of antibody per kg of the body weight of the human subject; (b) 4 weeks after step (a), administering a dose of the antibody to the human subject in an amount of 1 mg of antibody per kg of the human subject's body weight; (c) 4 weeks after step (b), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of the human subject's body weight; (d) 4 weeks after step (c), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of the human subject's body weight; (e) 4 weeks after step (d), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of the human subject's body weight; (f) 4 weeks after step (e), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of the human subject's body weight; The use of any one of embodiments 63 to 89, comprising: (g) administering, after step (f), at consecutive intervals of 4 weeks, doses of the antibody to the human subject in an amount of 10 mg of antibody per kg of body weight of the human subject. 91. The use according to any one of embodiments 63 to 89, wherein the treatment comprises administering doses of the antibody at a cumulative dose of at least 150 mg of antibody per kg of body weight of the human subject. 92. The use according to any one of embodiments 63 to 89, wherein the treatment comprises administering doses of the antibody at a cumulative dose of at least 200 mg of antibody per kg of body weight of the human subject. 93. The use of any one of embodiments 63 to 89, wherein the treatment comprises administering a dose of the antibody in an amount of 10 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 52 weeks. 94. The use of any one of embodiments 63 to 89, wherein the treatment comprises administering a dose of the antibody in an amount of 6 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 112 weeks. 95. The treatment comprises administering the antibody to the human subject in multiple doses, the multiple doses comprising: (a) at least two doses of 3 mg of antibody per kg body weight of the human subject every four weeks; and (b) at least 30 doses of 6 mg of antibody per kg body weight of the human subject every 4 weeks. 96. The use according to any one of embodiments 63 to 95, wherein the human subject is an ApoE carrier. 97. The use according to any one of embodiments 63 to 95, wherein the human subject is an ApoE non-carrier. 98. The human subject, (i) were aged 65 years or older at baseline; (ii) were aged 65–74 years at baseline; or (iii) The use of any one of embodiments 63 to 97, wherein the patient is 75 years of age or older. 99. The use of any one of embodiments 63 to 98, wherein the human subject does not develop amyloid-related imaging abnormalities (ARIA) during the course of treatment that require discontinuation of treatment. 100. The use according to any one of embodiments 63 to 99, wherein the treatment comprises monitoring the therapeutic response in the human subject. 101. The use according to any one of embodiments 63 to 99, wherein the treatment comprises determining a treatment regimen for the human subject. 102. The use according to any one of embodiments 63 to 99, wherein the treatment comprises monitoring the cognitive status of the human subject. 103. A method comprising determining p-tau levels in plasma, the plasma being an in vitro sample obtained from a human subject that has received at least one dose of an anti-beta amyloid antibody, and adjusting the amount of anti-beta amyloid antibody in a dose administered to the human subject based on the determined plasma p-tau level. 104. A method for selecting a patient for treatment with an anti-beta amyloid antibody, comprising determining p-tau levels in plasma, wherein the plasma is an in vitro sample obtained from a human subject. 105. A method for determining a dose of an anti-beta amyloid antibody to be administered to a human subject, comprising determining p-tau levels in plasma, wherein the plasma is an in vitro sample obtained from the human subject. 106. A method for selecting a patient to receive an anti-beta amyloid antibody for cognitive support services, comprising determining p-tau levels in plasma, wherein the plasma is an in vitro sample obtained from a human subject. 107. A method comprising determining p-tau levels in plasma, wherein the plasma is an in vitro sample obtained from a human subject that has received at least one dose of an anti-beta amyloid antibody. 108. The method of embodiment 107, comprising comparing the p-tau level in the plasma with a reference plasma p-tau level. 109. The method of embodiment 108, wherein the reference plasma p-tau level is the p-tau level in plasma obtained from the human subject before receiving a dose of an anti-beta amyloid antibody. 110. The method of embodiment 108, wherein said reference plasma p-tau level is an average p-tau level in plasma obtained from multiple human subjects. 111. The method of embodiment 110, wherein the plurality of human subjects is a plurality of healthy human subjects with no evidence of AD. 112. The method of embodiment 110, wherein the plurality of human subjects is a plurality of human subjects having known levels of amyloid plaques. 113. The method of embodiment 110, wherein the plurality of human subjects is a plurality of human subjects having known levels of tau tangles. 114. The method of embodiment 110, wherein the plurality of human subjects is a plurality of human subjects having a predetermined level of cognition. 115. The method of any one of embodiments 108 to 114, wherein the human subject is classified as susceptible to cognitive deterioration if the p-tau level in the plasma is higher than a baseline plasma p-tau level. 116. The method of any one of embodiments 108 to 114, wherein the human subject is classified as susceptible to an increased number of amyloid plaques if the p-tau level in the plasma is higher than a reference plasma p-tau level. 117. The method of any one of embodiments 108 to 114, wherein the human subject is classified as susceptible to an increased number of tau tangles if the p-tau level in the plasma is higher than a reference plasma p-tau level. 118. The method of any one of embodiments 108-114, comprising administering to the human subject another dose of an anti-beta amyloid antibody if the p-tau level in the plasma is higher than the baseline plasma p-tau level. 119. The method of embodiment 118, wherein administering to the human subject another dose of the anti-beta amyloid antibody comprises administering to the human subject a dose of the anti-beta amyloid antibody that is equal to or greater than a previous dose of the anti-beta amyloid antibody received by the human subject. 120. The method of any one of embodiments 103 to 119, wherein the anti-beta amyloid antibody is selected from aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab. 121. The plasma p-tau level is 181 or p-tau 217 The use according to any one of embodiments 63 to 102, wherein the level 122. The plasma p-tau level is 181 or p-tau 217 The method of any one of embodiments 103 to 120, wherein the level is 123. Use of an anti-beta amyloid antibody in the manufacture of a medicament for treating a disease, the treatment comprising determining p-tau levels in the plasma of a human subject at baseline and administering one or more doses of an anti-beta amyloid antibody to subjects whose plasma p-tau levels exceed the reference level. 124. A drug formulated as a dosing regimen comprising an anti-beta amyloid antibody for use in a method for treating Alzheimer's disease (AD) in a human subject, the dosing regimen comprising multiple doses of the anti-beta amyloid antibody, and p-tau levels in the plasma of the human subject are determined at a first time point and a second time point. 125. The drug of embodiment 124, wherein the anti-beta amyloid antibody is selected from aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab. 126. A drug formulated as a dosing regimen comprising an anti-beta amyloid antibody for use in a method, the dosing regimen comprising multiple doses of an anti-beta amyloid antibody, and p-tau levels in the plasma of the human subject are determined at a first time point and a second time point; The anti-beta amyloid antibody VHCDR1 having the amino acid sequence of SEQ ID NO:3, VHCDR2 having the amino acid sequence of SEQ ID NO:4, and VHCDR3 having the amino acid sequence of SEQ ID NO:5, and The drug comprises VLCDR1 having the amino acid sequence of SEQ ID NO:6, VLCDR2 having the amino acid sequence of SEQ ID NO:7, and VLCDR3 having the amino acid sequence of SEQ ID NO:8. 127. The method is (i) a method for treating Alzheimer's disease (AD); (ii) methods for monitoring therapeutic response in human subjects with Alzheimer's disease (AD); (iii) a method for determining a treatment regimen for a human subject having Alzheimer's disease (AD); (iv) a method for monitoring the cognitive status of a human subject with Alzheimer's disease (AD), and / or (v) The drug of embodiment 126, which is a method for selecting an Alzheimer's disease patient for treatment with an anti-beta amyloid antibody. 128. The plasma p-tau level is 181 or p-tau 217A drug described in any one of embodiments 124 to 127, wherein the level is 129. An anti-beta amyloid antibody for use in a method for treating Alzheimer's disease (AD) in a human subject, the treatment comprising: determining plasma p-tau levels in a sample from the human subject; administering one or more doses of an anti-beta amyloid antibody; The anti-beta amyloid antibody VHCDR1 having the amino acid sequence of SEQ ID NO:3, VHCDR2 having the amino acid sequence of SEQ ID NO:4, and VHCDR3 having the amino acid sequence of SEQ ID NO:5, and The anti-beta amyloid antibody comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. 130. An anti-beta amyloid antibody for use in a method for monitoring therapeutic response in a human subject with Alzheimer's disease (AD), the method comprising: determining plasma p-tau levels in a sample from the human subject; administering one or more doses of an anti-beta amyloid antibody; The anti-beta amyloid antibody VHCDR1 having the amino acid sequence of SEQ ID NO:3, VHCDR2 having the amino acid sequence of SEQ ID NO:4, and VHCDR3 having the amino acid sequence of SEQ ID NO:5, and The anti-beta amyloid antibody comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. 131. An anti-beta amyloid antibody for use in a method for determining a treatment regimen for a human subject with Alzheimer's disease (AD), the method comprising: determining plasma p-tau levels in a sample from the human subject; administering one or more doses of an anti-beta amyloid antibody; The anti-beta amyloid antibody VHCDR1 having the amino acid sequence of SEQ ID NO:3, VHCDR2 having the amino acid sequence of SEQ ID NO:4, and VHCDR3 having the amino acid sequence of SEQ ID NO:5, and The anti-beta amyloid antibody comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. 132. An anti-beta amyloid antibody for use in a method for monitoring the cognitive status of a human subject having Alzheimer's disease (AD), comprising: determining plasma p-tau levels in a sample from the human subject; administering one or more doses of an anti-beta amyloid antibody; The anti-beta amyloid antibody VHCDR1 having the amino acid sequence of SEQ ID NO:3, VHCDR2 having the amino acid sequence of SEQ ID NO:4, and VHCDR3 having the amino acid sequence of SEQ ID NO:5, and The anti-beta amyloid antibody comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:8. 133. The plasma p-tau level is 181 or p-tau 217 The anti-beta amyloid antibody according to any one of embodiments 129 to 132, wherein the level of the antibody is 0.01 to 0.1.

[0217] Incorporation by Reference All publications, patents, and patent applications mentioned herein are herein incorporated by reference in their entirety as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0218] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following claims.

Claims

1. A composition for use in a method for (i) treating Alzheimer's disease (AD) in a human subject, (ii) monitoring treatment response in a human subject with AD, (iii) determining a treatment plan for a human subject with AD, (iv) monitoring the cognitive status of a human subject with AD, or (v) selecting a patient for treatment with an anti-beta amyloid antibody, comprising said anti-beta amyloid antibody, said method comprising: Determining plasma p-tau levels in a human subject; administering one or more doses of the anti-beta amyloid antibody to the human subject, wherein the anti-beta amyloid antibody: a VHCDR1 having the amino acid sequence of SEQ ID NO:3, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5; and VLCDR1 having the amino acid sequence of SEQ ID NO:6, VLCDR2 having the amino acid sequence of SEQ ID NO:7, and VLCDR3 having the amino acid sequence of SEQ ID NO:8, Optionally, the composition is administered intravenously or subcutaneously. The composition.

2. Determining the plasma p-tau level of the human subject is a first time point, and the method further comprises determining the plasma p-tau level of the human subject at a second time point, and optionally: the first time point is before the human subject receives a dose of the anti-beta amyloid antibody; and / or the second time point is after the human subject has received at least one dose of the anti-beta amyloid antibody, and optionally the second time point comprises: (i) after at least 10 doses of the anti-beta amyloid antibody have been administered to the human subject; (ii) after at least 14 doses of the anti-beta amyloid antibody have been administered to the human subject; and / or (iii) after at least 19 doses of the anti-beta amyloid antibody have been administered to the human subject.

2. The composition of claim 1, wherein:

3. the first time point occurs before the second time point; (i) if the plasma p-tau level at the first time point is higher than the plasma p-tau level at the second time point, the method further comprises a second administration of the anti-beta amyloid antibody to the human subject, optionally wherein the second administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or greater than the dose of the anti-beta amyloid antibody administered to the human subject in the first administration; (ii) if the plasma p-tau level at the first time point is lower than the plasma p-tau level at the second time point, the method further comprises a second administration of the anti-beta amyloid antibody to the human subject, optionally wherein the second administration of the anti-beta amyloid antibody comprises a dose of the anti-beta amyloid antibody that is equal to or less than the dose of the anti-beta amyloid antibody administered to the human subject in the first administration; The composition of claim 2.

4. A composition for use in a method for (i) treating Alzheimer's disease (AD) in a human subject, (ii) monitoring treatment response in a human subject with AD, (iii) determining a treatment plan for a human subject with AD, (iv) monitoring the cognitive status of a human subject with AD, or (v) selecting a patient for treatment with an anti-beta amyloid antibody, comprising said anti-beta amyloid antibody, said method comprising: determining a baseline plasma p-tau level in the human subject; and administering to the human subject whose plasma p-tau level exceeds the baseline level: administering one or more doses of the anti-beta amyloid antibody, wherein the anti-beta amyloid antibody: a VHCDR1 having the amino acid sequence of SEQ ID NO:3, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5; and VLCDR1 having the amino acid sequence of SEQ ID NO:6, VLCDR2 having the amino acid sequence of SEQ ID NO:7, and VLCDR3 having the amino acid sequence of SEQ ID NO:8, Optionally, the composition is administered intravenously or subcutaneously. The composition.

5. the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, and optionally (i) the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, likely of moderate severity, as determined by a pre-treatment CDR global score of 0.5 and a memory box score of 0.5 or greater; (ii) the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease, likely of moderate severity, as determined, for example, by a caregiver, by a history of subjective memory decline with gradual onset and slow progression over the last year prior to treatment; (iii) the subject has been diagnosed with mild Alzheimer's disease dementia according to the NIA-AA core clinical criteria for probable Alzheimer's disease dementia, or (iv) the subject has been diagnosed with mild Alzheimer's disease dementia, as determined by a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or greater before treatment; The composition of claim 1 or 4.

6. The use, (i) administering the anti-beta amyloid antibody at a dose of 3 mg antibody / kg body weight of the human subject, 6 mg antibody / kg body weight of the human subject, or 10 mg antibody / kg body weight of the human subject; (ii) administering the anti-beta amyloid antibody as a multiple dose regimen comprising administering to the human patient multiple doses of 3 mg of antibody per kg of the human patient's body weight at intervals of 4 weeks, administering to the human patient multiple doses of 6 mg of antibody per kg of the human patient's body weight at intervals of 4 weeks, and administering to the human patient multiple doses of 10 mg of antibody per kg of the human patient's body weight at intervals of 4 weeks; (iii) (a) administering a dose of the anti-beta amyloid antibody to the human subject in an amount of 1 mg of antibody per kg of body weight of the human subject; (b) 4 weeks after step (a), administering a dose of the antibody to the human subject in an amount of 1 mg of antibody per kg of body weight of the human subject; (c) 4 weeks after step (b), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of body weight of the human subject; (d) 4 weeks after step (c), administering a dose of the antibody to the human subject in an amount of 3 mg of antibody per kg of body weight of the human subject; (e) 4 weeks after step (d), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of body weight of the human subject; (f) 4 weeks after step (e), administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of body weight of the human subject; (g) after step (f), in consecutive intervals of 4 weeks, administering doses of the antibody to the human subject in an amount of 10 mg of antibody per kg of body weight of the human subject; (iv) administering a dose of the antibody in an amount of 10 mg of antibody per kg of body weight of the human subject every 4 weeks for at least 52 weeks; (v) administering a dose of the antibody to the human subject in an amount of 6 mg of antibody per kg of body weight every 4 weeks for at least 112 weeks; and / or (vi) administering the antibody to the human subject in multiple doses, wherein the multiple doses comprise: (a) at least two doses of 3 mg of antibody per kg of body weight of the human subject every four weeks; (b) at least 30 doses of 6 mg of antibody per kg of body weight of the human subject every 4 weeks; 10. The composition of claim 1 or 4, comprising:

7. 10. The composition of claim 1 or 4, wherein the human subject does not develop an amyloid-related imaging abnormality (ARIA) during the course of treatment that requires discontinuation of the treatment with the anti-beta amyloid antibody.

8. A composition for use in a method, comprising an anti-beta amyloid antibody, said method comprising: determining plasma p-tau levels in a human subject who has received at least one dose of an anti-beta amyloid antibody; comparing the plasma p-tau level to a reference plasma p-tau level; The anti-beta amyloid antibody a VHCDR1 having the amino acid sequence of SEQ ID NO:3, a VHCDR2 having the amino acid sequence of SEQ ID NO:4, and a VHCDR3 having the amino acid sequence of SEQ ID NO:5; and The composition comprises a VLCDR1 having the amino acid sequence of SEQ ID NO:6, a VLCDR2 having the amino acid sequence of SEQ ID NO:7, and a VLCDR3 having the amino acid sequence of SEQ ID NO:

8.

9. the baseline plasma p-tau level is the plasma p-tau level of the human subject before receiving a dose of the anti-beta amyloid antibody; or the reference plasma p-tau level is an average of plasma p-tau levels of multiple human subjects; Optionally, said plurality of human subjects comprises: (i) a plurality of healthy human subjects with no evidence of AD; (ii) a plurality of human subjects with known levels of amyloid plaques; (iii) a plurality of human subjects with known levels of tau tangles; or (iv) a plurality of human subjects having a predetermined level of cognition; The composition of claim 8. (i) if the plasma p-tau level of the human subject is higher than the reference plasma p-tau level, the human subject is classified as susceptible to cognitive deterioration; or (ii) if the plasma p-tau level of the human subject is higher than the baseline plasma p-tau level, the human subject is classified as susceptible to an increased number of amyloid plaques; (iii) if the plasma p-tau level of the human subject is higher than the reference plasma p-tau level, the human subject is classified as susceptible to an increased number of tau tangles; or (iv) if the plasma p-tau level of the human subject is higher than the baseline plasma p-tau level, the method comprises administering a second dose of the anti-beta amyloid antibody to the human subject, optionally wherein the second dose is equal to or greater than the at least one dose of the anti-beta amyloid antibody received by the human subject. The composition of claim 8.

11. 9. The composition of any one of claims 1, 4 and 8, wherein the anti-beta amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO: 2, and optionally the anti-beta amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO:

11.

12. the human subject is an ApoE carrier or an ApoE non-carrier, and / or the human subject (i) Age 65 years or older at baseline; (ii) age 65-74 years at baseline, or (iii) 75 years of age or older; 9. The composition of any one of claims 1, 4 and 8.

13. The plasma p-tau level is １８１ or p-tau ２１７ It is a level 9. The composition of any one of claims 1, 4 and 8.

14. A kit comprising the composition of any one of claims 1, 4 and 8 and instructions for use.

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