Methods of treatment using an Anti-abeta protofibril antibody

Abstract

Disclosed herein are methods of selecting, monitoring, and treating a subject having Alzheimer's disease (AD) or suspected of having AD or another disorder associated with amyloid accumulation in the brain based on the risk of an ARIA event or cerebral hemorrhage. Also disclosed herein are methods of treating a subject suffering from or suspected of suffering from AD comprising subcutaneously administering an anti-A [beta] profibril antibody.

Description

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Application Serial No. 63 / 507,400, filed June 9, 2023; U.S. Provisional Application Serial No. 63 / 572,110, filed March 29, 2024; and U.S. Provisional Application Serial No. 63 / 648,077, filed May 15, 2024, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] This article discloses methods and dosing regimens for treating Alzheimer's disease (AD) in subjects with anti-Aβ primary fibrillary antibodies, as well as methods involving amyloid-associated imaging abnormalities (ARIA). Background Technology

[0003] Alzheimer's disease (AD) is a progressive, neurodegenerative disorder of unknown cause and the most common form of dementia in older adults. In 2006, there were 26.6 million cases of AD worldwide (range: 11.4-59.4 million) (Brookmeyer, R. et al., Forecasting the global burden of Alzheimer's Disease). Alzheimer's disease and dementia. (2007; 3:186-91), and it has been reported that more than 5 million people in the United States suffer from AD (Alzheimer's Association, Alzheimer's Association report, 2010 Alzheimer's disease facts and figures). Alzheimer's disease. stay] 2010; 6:158-94). By 2050, the global prevalence of Alzheimer's disease is projected to reach 106.8 million (range: 47.2 million to 221.2 million), with an estimated prevalence of 11 million to 16 million in the United States alone. (Brookmeyer, see above, and 2010 Alzheimer's disease facts and figures, see above).

[0004] The disease typically involves a general decline in cognitive function, which progresses slowly and leaves terminally ill patients bedridden. AD patients typically survive only 3 to 10 years after symptom onset, although known survival extremes are 2 to 20 years. (Hebert, LE, et al., Alzheimer disease in the US population: prevalence estimates using the 2000 census.) Arch Neurol. [Neurology Literature] (2003; 60:1119-1122.) Although the fact is that deaths caused by Alzheimer's disease are greatly underestimated because death certificates rarely attribute death to Alzheimer's, it remains the seventh leading cause of death in the United States and the fifth leading cause of death among Americans over the age of 65. (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures.) Alzheimer's disease and dementia. 2010; 6:158-94.) AD represents a heavy economic burden in industrialized countries, with significant impacts on healthcare systems and national treasuries, as well as on participants and their families. In the United States alone, total costs were estimated at $172 billion in 2010, including $123 billion for Medicare and Medicaid.

[0005] Histologically, the disease is characterized by neuroinflammatory plaques, primarily found in the associative cortex, limbic system, and basal ganglia. The main component of these plaques is amyloid-β peptide (Aβ). Aβ exists in various conformational states: monomers, oligomers, primary fibrils, and insoluble fibrils. The mechanistic relationship between Alzheimer's disease onset and Aβ production remains unclear. However, several anti-Aβ antibodies are currently undergoing clinical trials as potential therapeutic agents for Alzheimer's disease.

[0006] Despite recent developments in treatments for AD, including those targeting Aβ, better treatments are still needed, including more refined approaches to selecting suitable patients and calibrating responses to treatment events such as ARIA.

[0007] Therefore, this article discloses methods for selecting, monitoring, and treating AD patients to improve the condition of those patients who are unlikely to exhibit ARIA during treatment and / or resolve responses to ARIA. Summary of the Invention

[0008] One aspect of this disclosure relates to a method of treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ protofibrillary antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0009] Another aspect of this disclosure relates to a method for delaying clinical decline in a subject who has AD, is suspected of having AD, or is at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ protofibrillary antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0010] A further aspect of this disclosure relates to a method for reducing brain amyloid levels in subjects with AD, suspected AD, or at risk of AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0011] Another aspect of this disclosure relates to a method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ primary fibrillary antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0012] In some embodiments, subcutaneous administration of anti-Aβ proficiency antibodies at doses of 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) reduces biomarkers of AD pathology and / or provides lower systemic exposure (e.g., AUC) to the antibody compared to higher doses, such as 720 mg, for subcutaneous administration.

[0013] In some embodiments, subcutaneous administration of anti-Aβ protofibrillary antibodies at 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg), relative to higher doses of the antibody administered subcutaneously (such as 720 mg), reduces the risk of developing ARIA.

[0014] In some embodiments, anti-Aβ primary fibrillation antibody is administered at doses of 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 350 mg to 400 mg, 450 mg to 500 mg, or 550 mg to 600 mg. In some embodiments, anti-Aβ primary fibrillation antibody is administered subcutaneously at a dose of 500 mg.

[0015] In some embodiments, the dose is administered in two parts, for example, continuously.

[0016] In some embodiments, anti-Aβ primary fibrillary antibodies are administered once weekly.

[0017] In some embodiments, anti-Aβ primary fibrillary antibodies are administered every two weeks.

[0018] In some embodiments, anti-Aβ primary fibrillary antibodies are administered monthly.

[0019] In some embodiments, the anti-Aβ protofibrillary antibody is administered for a first time period, for example, at an initial dose according to an initial dosing regimen, and for a second time period, for example, at a maintenance dose according to a maintenance dosing regimen.

[0020] In some embodiments, the starting dosage regimen includes intravenous administration of each starting dose or subcutaneous administration of each starting dose.

[0021] In some embodiments, the maintenance dosing regimen includes subcutaneous administration of each maintenance dose or intravenous administration of each maintenance dose.

[0022] In some embodiments, the initial dosing regimen includes at least one initial dose administered intravenously and at least one initial dose administered subcutaneously.

[0023] In some embodiments, the maintenance dosing regimen includes at least one maintenance dose administered intravenously and at least one maintenance dose administered subcutaneously.

[0024] In some embodiments, the initial dose is greater than the maintenance dose.

[0025] In some embodiments, the starting dose of the anti-Aβ primary fibrillary antibody is 150 mg to 600 mg, for example 200 mg to 550 mg, preferably 500 mg, administered subcutaneously.

[0026] In some embodiments, the maintenance dose of the anti-Aβ primary fibrillary antibody is 150 mg to 500 mg, such as 360 mg, administered subcutaneously.

[0027] In some embodiments, the maintenance dose of the anti-Aβ primary fibrillary antibody is 250 mg, administered subcutaneously.

[0028] In some embodiments, the initial dose is administered weekly.

[0029] In some embodiments, a maintenance dose is administered weekly.

[0030] In some embodiments, a maintenance dose is administered every two weeks.

[0031] In some embodiments, the first time period is at least about 6 months, about 12 months, about 18 months, about 24 months, or about 30 months.

[0032] In some embodiments, the first time period is at least 18 months.

[0033] In some embodiments, the first time period is at least 24 months.

[0034] In some embodiments, the first time period continues until the subject tests negative for amyloid.

[0035] In some embodiments, an anti-Aβ protofibrillary antibody (e.g., BAN2401) is administered subcutaneously at a starting dose of 500 mg per week for at least 18 months, followed by a second period of subcutaneous administration at a maintenance dose of 250 mg per week.

[0036] In some embodiments, an anti-Aβ protofibrillary antibody (e.g., BAN2401) is administered subcutaneously at a starting dose of 500 mg per week for at least 24 months, followed by a second period of subcutaneous administration at a maintenance dose of 250 mg every two weeks.

[0037] In some embodiments, the second time period begins when one or more biomarkers in a subject indicate a reduction or slowing of AD progression.

[0038] In some embodiments, the second time period is at least about 6 months, about 12 months, about 18 months, about 24 months, about 36 months, about 42 months, about 48 months, about 54 months, about 60 months, or up to the subject's lifetime.

[0039] In some embodiments, maintenance doses are administered subcutaneously using a self-injector (AI).

[0040] In some embodiments, anti-Aβ primary fibrillary antibodies are administered intravenously every two weeks at a dose of 10 mg / kg relative to the subject's body weight.

[0041] In some embodiments, the anti-Aβ primary fibrillary antibody is contained in a pharmaceutical composition in the form of a pre-filled syringe.

[0042] In some embodiments, the anti-Aβ primary fibrillary antibody is included in a pharmaceutical composition via self-injector.

[0043] In some embodiments, the anti-Aβ protofibrillary antibody comprises a heavy chain complementary variable region and a light chain variable region, the heavy chain complementary variable region comprising the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0044] In some embodiments, the anti-Aβ protofibrillary antibody is BAN2401 (lencanemab).

[0045] In some embodiments, subjects exhibit changes and / or differences in measurements of one or more biomarkers associated with AD pathology prior to treatment.

[0046] In some embodiments, changes and / or differences in measurements are selected from: a. increased amyloid in the brain, for example, as measured by amyloid PET (e.g., a centiloid measure of about 20-40, or a centiloid measure of about 20-32), b. increased tau in the brain, for example, as measured by positron emission tomography (PET), c. decreased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217 and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio), neurogranulin and / or neurofilament light chains (NfL), and d. Decreased serum or plasma levels of Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217 and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0047] In some embodiments, subjects exhibit changes and / or differences in measurements of one or more biomarkers associated with AD pathology during and / or after treatment.

[0048] In some embodiments, changes and / or differences in measurements are selected from: a. reduced amyloid in the brain, e.g., as measured by amyloid PET (e.g., a percentage measure of about 20-40, e.g., about 20-32); b. reduced tau in the brain, e.g., as measured by positron emission tomography (PET); c. increased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or reduced total tau, p-tau (e.g., p-tau181, p-tau217 and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio), neurogranulin and / or neurofilament light chains (NfL); and d. Increased serum or plasma levels of Aβ1-42 / 1-40 ratio and / or decreased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217 and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0049] In some embodiments, the subject is amyloid-positive prior to administration, for example, as indicated by: PET assessment, CSF assessment of Aβ(1-42), CSF assessment of total tau, CSF assessment of p-tau (e.g., p-tau181, p-tau217 and / or p-tau231, p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio), MRI, retinal amyloid accumulation, and / or blood biomarker assessment (e.g., plasma Aβ1-42 / 1-40 ratio, plasma p-tau181, plasma p-tau217, plasma p-tau231 level, p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio).

[0050] In some embodiments, the subject is ApoE4 positive.

[0051] In some embodiments, the development of ARIA in the subject is monitored.

[0052] In some embodiments, the subjects were 65 to 80 years old.

[0053] In some embodiments, the subject is between 55 and 64 years of age and has at least one of the following risk factors: (i) a first-degree relative diagnosed with dementia before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid protein levels according to a PET or cerebrospinal fluid (CSF) test prior to administration.

[0054] In some embodiments, the subjects had Alzheimer's disease.

[0055] In some embodiments, the subjects had early-stage Alzheimer's disease.

[0056] In some embodiments, the subject has been diagnosed with a. mild cognitive impairment of moderate probability due to Alzheimer's disease, and / or has been diagnosed with mild Alzheimer's dementia; b. mild cognitive impairment of moderate probability due to Alzheimer's disease according to the National Institute on Aging and Alzheimer's Association (NIA-AA) Core Clinical Guidelines; c. mild cognitive impairment of moderate probability due to Alzheimer's disease according to a CDR total score of 0.5 and a memory box score of 0.5 or higher before treatment; d. mild cognitive impairment of moderate probability due to Alzheimer's disease according to, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year before treatment, as confirmed by an informed party; e. mild Alzheimer's dementia according to the NIA-AA Core Clinical Guidelines for probable Alzheimer's dementia; or f. mild Alzheimer's dementia according to a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher before treatment.

[0057] In some embodiments, the subject is suspected of having AD.

[0058] In some embodiments, the subject is a subject at risk of developing AD.

[0059] In some embodiments, subjects at risk of developing AD have pre-AD.

[0060] In some embodiments, the subjects did not have cognitive impairment.

[0061] In some embodiments, prior to administration, the subject's overall clinical dementia grade (CDR) score was 0.

[0062] In some embodiments, prior to administration, the subject has undergone educational adaptation and has a Mini-Mental State Examination (MMSE) score greater than or equal to 27.

[0063] In some embodiments, prior to the administration, the subject's Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II) score was at least one standard deviation lower than the age-adjusted mean in the WMS-IV LMII, with the score being less than or equal to 15 for subjects aged 50 to 64 years, less than or equal to 12 for subjects aged 65 to 69 years, less than or equal to 11 for subjects aged 70 to 74 years, less than or equal to 9 for subjects aged 75 to 79 years, and less than or equal to 7 for subjects aged 80 to 90 years.

[0064] One aspect of this disclosure relates to a method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), wherein the administration is according to a dosing regimen comprising: intravenous administration of the antibody at an initial dose of 10 mg / kg relative to the subject's body weight every two weeks; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, 18 or 24 months after the initial dose.

[0065] One aspect of this disclosure relates to a method for delaying clinical decline in a subject with, suspected of having, or at risk of having Alzheimer's disease (AD), comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: intravenous administration of the antibody at an initial dose of 10 mg / kg relative to the subject's body weight every two weeks; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, 18 months after the initial dose.

[0066] Another aspect of this disclosure relates to a method for reducing brain amyloid levels in subjects with, suspected of having, or at risk of having Alzheimer's disease (AD), comprising administering to the subject an anti-Aβ primary fibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), wherein the administration is according to a dosing regimen comprising: intravenous administration of the antibody at an initial dose of 10 mg / kg relative to the subject's body weight every two weeks; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, 18 or 24 months after the initial dose.

[0067] A further aspect of this disclosure relates to a method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: intravenous administration of the antibody at an initial dose of 10 mg / kg relative to the subject's body weight every two weeks; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, 18 or 24 months after the initial dose.

[0068] In some embodiments, the initial dose of the antibody administered intravenously is administered for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

[0069] In some embodiments, the initial dose of the antibody administered intravenously is administered for at least 18 months.

[0070] In some embodiments, the initial dose of the antibody is administered intravenously for at least 24 months.

[0071] In some embodiments, a maintenance dose of the antibody is administered weekly.

[0072] In some embodiments, a maintenance dose of the antibody is administered every two weeks.

[0073] In some embodiments, a maintenance dose of the antibody is administered using a vial syringe.

[0074] In some embodiments, an AI is used to administer a maintenance dose of the antibody.

[0075] One aspect of this disclosure relates to a method of treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3), the administration being according to a dosing regimen comprising: subcutaneous administration of the antibody at an initial dose of 500 mg weekly; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, after 18 or 24 months of the initial dose.

[0076] Another aspect of this disclosure relates to a method for delaying clinical decline in a subject with, suspected of having, or at risk of having Alzheimer's disease (AD), comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), wherein the administration is according to a dosing regimen comprising: subcutaneous administration of the antibody at an initial dose of 500 mg weekly; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, after 18 or 24 months from the initial dose.

[0077] A further aspect of this disclosure relates to a method for reducing brain amyloid levels in subjects with, suspected of having, or at risk of having Alzheimer's disease (AD), comprising administering to the subject an anti-Aβ primary fibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), wherein the administration is according to a dosing regimen comprising: subcutaneous administration of the antibody at an initial dose of 500 mg weekly; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, after 18 or 24 months of the initial dose.

[0078] Another aspect of this disclosure relates to a method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising administering to the subject an antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: subcutaneous administration of the antibody at an initial dose of 500 mg weekly; and subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks, for example, after 18 or 24 months of the initial dose.

[0079] In some embodiments, the initial dose of the antibody administered subcutaneously is for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

[0080] In some embodiments, the initial dose of the antibody administered subcutaneously is administered for at least 18 months.

[0081] In some embodiments, the initial dose of the antibody is administered subcutaneously for at least 24 months.

[0082] In some embodiments, the initial dose of antibody is administered using a vial-syringe.

[0083] In some embodiments, an AI is used to administer the initial dose of the antibody.

[0084] In some embodiments, a maintenance dose of the antibody is administered weekly.

[0085] In some embodiments, a maintenance dose of the antibody is administered every two weeks.

[0086] In some embodiments, a maintenance dose of the antibody is administered using a vial syringe.

[0087] In some embodiments, an AI is used to administer a maintenance dose of the antibody.

[0088] In some embodiments, the anti-Aβ protofibrillary antibody comprises a heavy chain complementary variable region and a light chain variable region, the heavy chain complementary variable region comprising the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0089] In some embodiments, the anti-Aβ protofibrillary antibody is BAN2401 (lencanemab).

[0090] In some embodiments, subjects exhibit changes in measurements of one or more biomarkers associated with AD pathology prior to treatment.

[0091] In some embodiments, the changes in the measured values ​​are selected from: a. increased amyloid in the brain, for example, as measured by amyloid PET (e.g., a percentage measure of about 20-40, for example, a percentage measure of about 20-32), b. increased tau in the brain, for example, as measured by positron emission tomography (PET), c. decreased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217 and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, neurogranulin and / or neurofilament light chains (NfL), and d. Decreased serum or plasma levels of Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217 and / or P-tau231, p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP) and / or neurofilament light chain (NfL)).

[0092] In some embodiments, subjects exhibit changes and / or differences in measurements of one or more biomarkers associated with AD pathology during and / or after treatment.

[0093] In some embodiments, changes and / or differences in measurements are selected from: a. reduced amyloid in the brain, e.g., as measured by amyloid PET (e.g., a percentage measure of about 20-40, e.g., about 20-32); b. reduced tau in the brain, e.g., as measured by positron emission tomography (PET); c. increased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or reduced total tau, p-tau (e.g., p-tau181, p-tau217 and / or p-tau231), p-tau181 / np-tau181 ratio, and / or p-tau217 / np-tau217 ratio), neurogranulin and / or neurofilament light chains (NfL); and d. Increased serum or plasma levels of Aβ1-42 / 1-40 ratio and / or decreased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217 and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0094] In some embodiments, the subject is amyloid-positive prior to administration, for example, as indicated by PET assessment, CSF assessment of Aβ(1-42), MRI, or retinal amyloid accumulation.

[0095] In some embodiments, the subject is ApoE4 positive.

[0096] In some embodiments, the development of ARIA in the subject is monitored.

[0097] In some embodiments, the subjects were 65 to 80 years old.

[0098] In some embodiments, the subject is between 55 and 64 years of age and has at least one of the following risk factors: (i) a first-degree relative diagnosed with dementia before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid protein levels according to a PET or cerebrospinal fluid (CSF) test prior to administration.

[0099] In some embodiments, the subjects had Alzheimer's disease.

[0100] In some embodiments, the subjects had early-stage Alzheimer's disease.

[0101] In some embodiments, the subject has been diagnosed with a. mild cognitive impairment of moderate probability due to Alzheimer's disease, and / or has been diagnosed with mild Alzheimer's dementia; b. mild cognitive impairment of moderate probability due to Alzheimer's disease according to the National Institute on Aging and Alzheimer's Association (NIA-AA) Core Clinical Guidelines; c. mild cognitive impairment of moderate probability due to Alzheimer's disease according to a CDR total score of 0.5 and a memory box score of 0.5 or higher before treatment; d. mild cognitive impairment of moderate probability due to Alzheimer's disease according to, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year before treatment, as confirmed by an informed party; e. mild Alzheimer's dementia according to the NIA-AA Core Clinical Guidelines for probable Alzheimer's dementia; or f. mild Alzheimer's dementia according to a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher before treatment.

[0102] In some embodiments, the subject is suspected of having AD.

[0103] In some embodiments, the subject is a subject at risk of developing AD.

[0104] In some embodiments, subjects at risk of developing AD have pre-AD.

[0105] In some embodiments, the subjects did not have cognitive impairment.

[0106] In some embodiments, prior to administration, the subject's overall clinical dementia grade (CDR) score was 0.

[0107] In some embodiments, prior to administration, the subject has undergone educational adaptation and has a Mini-Mental State Examination (MMSE) score greater than or equal to 27.

[0108] In some embodiments, prior to the administration, the subject's Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II) score was at least one standard deviation lower than the age-adjusted mean in the WMS-IV LMII, with the score being less than or equal to 15 for subjects aged 50 to 64 years, less than or equal to 12 for subjects aged 65 to 69 years, less than or equal to 11 for subjects aged 70 to 74 years, less than or equal to 9 for subjects aged 75 to 79 years, and less than or equal to 7 for subjects aged 80 to 90 years.

[0109] A further aspect of this disclosure relates to a method of treating a subject who has early-stage Alzheimer's disease (AD), is suspected of having early-stage AD, or is at risk of developing early-stage AD, and has received a primary anti-Aβ antibody, the method comprising: administering to the subject a secondary anti-Aβ antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: intravenous administration of the secondary antibody at a maintenance dose of 10 mg / kg relative to the subject's body weight every two weeks or monthly; or subcutaneous administration of the secondary antibody at a maintenance dose of 250 mg every week or every two weeks.

[0110] Another aspect of this disclosure relates to a method for delaying clinical decline in a subject who has received a first anti-Aβ antibody, comprising: administering to the subject a second anti-Aβ antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), wherein the administration is according to a dosing regimen comprising: intravenous administration of the second antibody at a maintenance dose of 10 mg / kg relative to the subject's body weight every two weeks or monthly; or subcutaneous administration of the second antibody at a maintenance dose of 250 mg every week or every two weeks.

[0111] One aspect of this disclosure relates to a method for reducing brain amyloid levels in a subject who has received a first anti-Aβ antibody, the method comprising: administering to the subject a second anti-Aβ antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: intravenous administration of the second antibody at a maintenance dose of 10 mg / kg relative to the subject's body weight every two weeks or monthly; or subcutaneous administration of the second antibody at a maintenance dose of 250 mg every week or every two weeks.

[0112] A further aspect of this disclosure relates to a method for maintaining amyloid levels in a subject who has received a first anti-Aβ antibody, the method comprising: administering to the subject a second anti-Aβ antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: intravenous administration of the second antibody at a maintenance dose of 10 mg / kg relative to the subject's body weight every two weeks or monthly; or subcutaneous administration of the second antibody at a maintenance dose of 250 mg every week or every two weeks.

[0113] One aspect of this disclosure relates to a method of treating a subject with early-stage Alzheimer's disease (AD), suspected of having early-stage AD, or at risk of developing early-stage AD, the method comprising: administering a first anti-Aβ antibody to the subject; administering a second anti-Aβ antibody to the subject comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: intravenous administration of the second antibody at a maintenance dose of 10 mg / kg relative to the subject's body weight every two weeks or monthly; or subcutaneous administration of the second antibody at a maintenance dose of 250 mg every week or every two weeks.

[0114] In some embodiments, a maintenance dose of the antibody is administered subcutaneously using a vial-syringe.

[0115] In some embodiments, an AI is used to administer a subcutaneous maintenance dose of the antibody.

[0116] In some embodiments, the primary anti-Aβ antibody is selected from aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, or solanezumab.

[0117] In some embodiments, the first anti-Aβ antibody is donamumab.

[0118] Another aspect of this disclosure relates to a method of treating a subject with early-stage Alzheimer's disease (AD), suspected of having early-stage AD, or at risk of developing early-stage AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosing regimen comprising: intravenous administration of the antibody every two weeks at a first starting dose of 10 mg / kg relative to the subject's body weight; subcutaneous administration of the antibody weekly at a second starting dose of 720 or 500 mg; and subcutaneous administration of the antibody weekly at a dose of 250 mg, for example, after 18 or 24 months of treatment with the starting dose.

[0119] In some embodiments, the subjects are using thrombolytic agents or antiplatelet agents, but not anticoagulants.

[0120] In some embodiments, the subject is receiving an antiplatelet drug.

[0121] In some embodiments, the subject is receiving a thrombolytic agent.

[0122] In some embodiments, the thrombolytic agent is selected from the group consisting of aspirin or fibrinolytic agents.

[0123] In some embodiments, the subject is receiving aspirin.

[0124] In some embodiments, the subject is receiving a fibrinolytic agent.

[0125] In some embodiments, the subject has experienced a brain hemorrhage event (e.g., microbleed or intracerebral hemorrhage) or an ARIA event prior to treatment, or has an increased risk of such events.

[0126] In some embodiments, the subject did not have a brain hemorrhage event, such as a microbleed or intracerebral hemorrhage, or an ARIA event prior to treatment.

[0127] Listed Examples 1. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of having AD, the method comprising administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) proficiency antibody, wherein the subject has not experienced a brain hemorrhage event prior to treatment, such as microbleeds or intracerebral hemorrhage, and / or wherein the subject has not exhibited any changes prior to treatment, such as a reduction in white matter as measured by brain imaging.

[0128] 2. A method for selecting subjects with AD, suspected AD, or at risk of developing AD to be treated with an anti-amyloid β (Aβ) primary fibrillary antibody, the method comprising: a. Determine that the subject has not had and / or currently has no cerebral hemorrhage events prior to the treatment, such as microbleeds or intracerebral hemorrhages, and / or has not yet shown changes, such as a reduction in white matter as measured by brain imaging; b. Select subjects treated with a therapeutically effective dose of anti-amyloid β (Aβ) primary fibrillary antibody.

[0129] 3. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) profibrillary antibody, wherein the subject is using a thrombolytic agent or an antiplatelet agent but not an anticoagulant.

[0130] 4. The method as described in Example 3, wherein the subject is receiving an antiplatelet drug.

[0131] 5. The method as described in Example 3, wherein the subject is receiving a thrombolytic agent.

[0132] 6. The method as described in Example 5, wherein the thrombolytic agent is selected from the group consisting of aspirin or fibrinolytic agents.

[0133] 7. The method as described in Example 6, wherein the subject is receiving aspirin.

[0134] 8. The method as described in Example 6, wherein the subject is receiving a fibrinolytic agent.

[0135] 9. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) primary fibrillary antibody, wherein the subject is not treated with an anticoagulant.

[0136] 10. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) protofibrillary antibody, wherein the subject has an increased risk of developing ARIA events or cerebral hemorrhage events (e.g., microbleeds or intracerebral hemorrhage), the method further comprising administering steroids and / or monitoring the subject's brain (e.g., by MRI).

[0137] 11. The method as described in Example 10, wherein the subject has experienced a brain hemorrhage event, such as a microbleed or intracerebral hemorrhage, or an ARIA event prior to treatment.

[0138] 12. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of having AD, the method comprising administering a therapeutically effective dose of an anti-amyloid β (Aβ) proficiency antibody to the subject, detecting ARIA events, such as severe ARIA events, ARIA-H, ARIA-E, and administering a steroid.

[0139] 13. The method as described in any one of Examples 1-12, wherein the method reduces brain amyloid protein.

[0140] 14. A method for treating severe ARIA in a subject receiving an anti-amyloid beta (Aβ) protofibrillary antibody, the method comprising administering a steroid and / or monitoring the subject’s brain (e.g., by MRI).

[0141] 15. The method of any one of Examples 1-14, wherein the anti-Aβ primary fibrillary antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0142] 16. The method of any one of Examples 1-15, wherein the anti-Aβ primary fibrillary antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8.

[0143] 17. The method of any one of Examples 1-16, wherein the anti-Aβ primary fibrillary antibody comprises BAN2401 (lencanemab).

[0144] 18. The method of any one of Examples 1-17, wherein the therapeutically effective dose of the anti-Aβ primary fibrillary antibody comprises an intravenous infusion of 10 mg / kg relative to the subject's body weight.

[0145] 19. The method as described in any one of Examples 1-17, wherein the therapeutically effective dose of the anti-Aβ primary fibrillary antibody comprises subcutaneous administration of about 250 to 720 mg.

[0146] 20. The method as described in any one of Examples 1-17, wherein the therapeutically effective dose of the anti-Aβ primary fibrillary antibody comprises a subcutaneous administration of 250 mg.

[0147] 21. The method as described in any one of Examples 1-17, wherein the therapeutically effective dose of the anti-Aβ primary fibrillary antibody comprises a subcutaneous administration of 360 mg.

[0148] 22. The method as described in any one of Examples 1-17, wherein the therapeutically effective dose of the anti-Aβ primary fibrillary antibody comprises a subcutaneous administration of 500 mg.

[0149] 23. The method as described in any one of Examples 1-17, wherein the therapeutically effective dose of the anti-Aβ primary fibrillary antibody comprises a subcutaneous administration of 720 mg.

[0150] 24. The method as described in any one of Examples 1-19, wherein the effective dose of treatment is administered subcutaneously weekly via a self-injector.

[0151] 25. The method as described in any one of Examples 1-18, wherein the effective dose of treatment is administered weekly.

[0152] 26. The method as described in any one of Examples 1-17 and 19-24, wherein the effective dose of treatment is administered every 2 weeks.

[0153] 27. The method as described in any one of Examples 1-26, wherein the frequency of administration is reduced after 18 months of treatment, for example, to once every 2, 4, 6, 8, 10 or 12 weeks.

[0154] 28. The method as described in any one of Examples 1 to 27, wherein the therapeutically effective dose is reduced after 18 months of treatment, for example, reduced to a subcutaneous dose of 360 mg or 250 mg, or maintained at an intravenous dose of 10 mg / kg.

[0155] 29. The method as described in any one of Examples 22 or 24 to 28, wherein the therapeutically effective dose is reduced from a weekly dose of 500 mg administered subcutaneously to a weekly dose of 360 mg administered subcutaneously or a weekly dose of 250 mg administered subcutaneously.

[0156] 30. The method as described in any one of Examples 24 to 28, wherein the therapeutically effective dose is reduced from a weekly subcutaneous dose of 720 mg to a weekly subcutaneous dose of 360 mg or 250 mg. 31. The method as described in any one of Examples 1-30, wherein the second therapeutic agent is administered to the subject sequentially or simultaneously.

[0157] 32. The method as described in Example 31, wherein the second therapeutic agent is an anti-tau antibody.

[0158] 33. The method as described in Example 32, wherein the anti-tau antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO:15 (HCDR1), SEQ ID NO:16 (HCDR2), and SEQ ID NO:17 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO:18 (LCDR1), SEQ ID NO:19 (LCDR2), and SEQ ID NO:20 (LCDR3).

[0159] 34. The method as described in Example 32 or 33, wherein the anti-tau antibody or its antigen-binding fragment comprises the heavy chain variable region of SEQ ID NO: 21 and the light chain variable region of SEQ ID NO: 22.

[0160] 35. The method of any one of Examples 1-34, wherein the method further comprises monitoring ARIA, such as ARIA-E and / or ARIA-H, such as as observed by MRI.

[0161] 36. The method as described in any one of Examples 1-35, wherein the method does not require a titration step before administering a first therapeutically effective dose of the anti-Aβ primary fibrillary antibody to the subject.

[0162] 37. The method as described in any one of Examples 1-36, wherein compared with pre-treatment and / or compared with untreated control subjects, the method causes: a. Improvement of one or more cerebrospinal fluid biomarkers (e.g., Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, p-tau (e.g., p-tau181, p-tau217 and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, neurogranulin, neurofilament light (NfL) peptide, phosphorylated tau) or mitigation of deterioration of one or more cerebrospinal fluid biomarkers; and / or b. Decrease in plasma or serum biomarkers (e.g., Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), tau phosphorylated at 231 (P-tau231)), the P-tau181 / NP-tau181 ratio and / or the P-tau217 / NP-tau217 ratio, glial fibrillary acidic protein (GFAP) and / or neurofilament light (NfL)) or a slowing of the increase in such plasma or serum biomarkers.

[0163] 38. The method as described in any one of Examples 1-37, wherein the treatment a. Delaying clinical decline, as determined by ADCOMS; b. Delay clinical decline, as determined by ADAS MCI-ADL; c. Delay clinical decline, as determined by modified iADRS; d. Delay clinical decline, as determined by CDR-SB; or e. Delay clinical decline, as determined by ADAS-Cog.

[0164] 39. The method as described in Example 37 or Example 38, wherein the results are measured at least 6 months after administration of the first effective therapeutic dose.

[0165] 40. The method as described in any one of Examples 37-39, wherein the result is measured at least 12 months after administration of the first therapeutically effective dose.

[0166] 41. The method as described in any one of Examples 37-39, wherein the result is measured at least 13 months after administration of the first therapeutically effective dose.

[0167] 42. The method as described in any one of Examples 37-39, wherein the result is measured at least 18 months after administration of the first therapeutically effective dose.

[0168] 43. The method as described in any one of Examples 37-42, wherein the subject is switched from the initial dose regimen to the maintenance dose regimen.

[0169] 44. The method as described in Example 43, wherein the switching to the maintenance dose occurs at least 6 months (e.g., 6 months, 13 months, or 18 months) after the start of the initial dosing regimen or after the subject has become amyloid-negative (e.g., determined by improvement in biomarkers).

[0170] 45. The method as described in Example 43 or Example 44, wherein the initial dosing regimen comprises an intravenous infusion of a therapeutically effective dose of 10 mg / kg every two weeks relative to the subject's body weight.

[0171] 46. ​​The method as described in Example 43 or 44, wherein the starting dose regimen comprises subcutaneous administration of the anti-Aβ primary fibrillary antibody at a therapeutically effective dose of 720 mg.

[0172] 47. The method as described in Example 43 or 44, wherein the starting dose regimen comprises subcutaneous administration of the anti-Aβ primary fibrillary antibody at a therapeutically effective dose of 500 mg.

[0173] 48. The method of any one of Examples 43-47, wherein the maintenance dosing regimen comprises intravenous infusion of a therapeutically effective dose of 10 mg / kg per month relative to the subject's body weight.

[0174] 49. The method of any one of Examples 43-47, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Aβ primary fibrillary antibody at a therapeutically effective dose of 360 mg.

[0175] 50. The method of any one of Examples 43-47, wherein the maintenance dosing regimen comprises subcutaneous administration of the anti-Aβ primary fibrillary antibody at a therapeutically effective dose of 250 mg weekly.

[0176] 51. The method of any one of Examples 43-45, wherein the maintenance dosing regimen comprises the same dosing regimen as the initial dosing regimen.

[0177] 52. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of having AD, the method comprising selecting a patient who is not using an anticoagulant and administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) primary fibrillary antibody.

[0178] 53. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising selecting a patient who has not received a thrombolytic agent and administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) primary fibrillary antibody.

[0179] 54. A method for treating Alzheimer's disease (AD), suspected AD, or at risk of developing AD in a subject, the method comprising selecting a patient on anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent), administering the subject a therapeutically effective dose of antiamyloid β (Aβ) profibrinolytic antibody, and monitoring the patient's ARIA.

[0180] 55. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of having AD, the method comprising administering to the subject a therapeutically effective dose of an anti-amyloid β (Aβ) profibrinolytic antibody, administering an anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent, antiplatelet agent) if necessary, and monitoring the subject's ARIA.

[0181] 56. A method for treating Alzheimer's disease (AD) in subjects who have Alzheimer's disease (AD), are suspected of having AD, or are at risk of developing AD, the method comprising: a. Administer a therapeutically effective dose of anti-amyloid β (Aβ) primary fibrillary antibody to the subject; b. Discontinue administration of the anti-amyloid β (Aβ) profibrinolytic antibody to the subject when the subject is given an anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent, antiplatelet agent); c. Resume administration of the anti-amyloid β (Aβ) primary fibrinolytic antibody to the subject after the period during which the anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent, antiplatelet agent) is no longer administered, or after that period. d. Monitor the subject's ARIA.

[0182] 57. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of having AD, comprising selecting a patient on anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent, antiplatelet agent) and delaying administration of an anti-amyloid β (Aβ) profibrinolytic antibody to the subject until treatment with said anticoagulant or said thrombolytic agent is completed.

[0183] 58. The method of any one of Examples 1 to 57, wherein the subject showed changes and / or differences in measurements of one or more biomarkers associated with AD pathology prior to treatment compared to reference measurements (e.g., measurements from healthy controls).

[0184] 59. The method as described in Example 58, wherein the change in the measured value is selected from: a. Increased amyloid protein in the brain, for example, as measured by amyloid PET (e.g., approximately 20-40 percentile, e.g., approximately 20-32 percentile). b. Increased tau in the brain, for example, as measured by positron emission tomography (PET). c. Decreased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217, p-tau231, p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio), neurogranulin and / or neurofilament light chain (NfL), and d. Decreased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, P-tau231, P-tau181 / NP-tau181 ratio and / or P-tau217 / NP-tau217 ratio), glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0185] 60. The method of any one of Examples 1 to 59, wherein the subject is amyloid-positive prior to treatment, for example, as indicated by: PET assessment, CSF assessment of Aβ(1-42), MRI, retinal amyloid accumulation and / or blood biomarker assessment (e.g., Aβ1-42 / 1-40 ratio, plasma p-tau181, plasma p-tau217, plasma p-tau231 level, p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio).

[0186] 61. The method as described in any one of Examples 1-60, wherein the subject is ApoE4 positive.

[0187] 62. The method as described in any one of Examples 1-61, wherein the development of ARIA in the subject is monitored.

[0188] 63. The method as described in any one of Examples 1-62, wherein the subject is 65 to 80 years old.

[0189] 64. The method as described in any one of Examples 1-62, wherein the subject is 55 to 64 years old and has at least one of the following risk factors: (i) A first-degree relative who was diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Prior to the administration, test for elevated brain amyloid protein levels using PET or cerebrospinal fluid (CSF).

[0190] 65. The method as described in any one of Examples 1-64, wherein the subject has Alzheimer's disease.

[0191] 66. The method as described in any one of Examples 1-65, wherein the subject has early Alzheimer's disease.

[0192] 67. The method as described in any one of Examples 1-66, wherein the subject has been diagnosed with... a. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease and / or already diagnosed with mild Alzheimer's dementia; b. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, according to the National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical guidelines; c. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, based on a total CDR score of 0.5 and a memory box score of 0.5 or higher before treatment; d. Mild cognitive impairment of moderate probability due to Alzheimer's disease, based on, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to treatment, as confirmed by an informed person. e. Mild Alzheimer's disease dementia according to the NIA-AA core clinical guidelines for possible Alzheimer's dementia; or f. Mild Alzheimer's dementia is indicated by a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher prior to treatment.

[0193] 68. The method as described in any one of Examples 1-67, wherein the subject is suspected of having AD. 69. The method as described in any one of Examples 1-68, wherein the subject is a subject at risk of developing AD.

[0194] 70. The method as described in Example 69, wherein a subject at risk of developing AD has pre-AD (pre-AD).

[0195] 71. The method as described in Example 69 or Example 70, wherein the subject does not have cognitive impairment.

[0196] 72. The method as described in any one of Examples 69-71, wherein the subject's overall clinical dementia grade (CDR) score is 0. 73. The method according to any one of Examples 69-72, wherein prior to the administration, the subject has an Educational Adaptation score of 27 or greater on the Mini-Mental State Examination (MMSE).

[0197] 74. The method according to any one of Examples 69-73, wherein prior to the administration, the subject's Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II) score is at least one standard deviation lower than the age-corrected mean in WMS-IV LMII, wherein the score is less than or equal to 15 for subjects aged 50 to 64 years, less than or equal to 12 for subjects aged 65 to 69 years, less than or equal to 11 for subjects aged 70 to 74 years, and less than or equal to 9 for subjects aged 75 to 79 years.

[0198] 75. A method of treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ primary fibrillary antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0199] 76. A method for delaying clinical decline in a subject with AD, suspected of having AD, or at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ protofibrillary antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0200] 77. A method for reducing brain amyloid levels in subjects with AD, suspected AD, or at risk of AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0201] 78. A method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, for example 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0202] 79. The method of any one of Examples 75 to 78, wherein the antibody administered subcutaneously at 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg), reduces biomarkers of AD pathology and / or provides lower systemic exposure (e.g., AUC) to the antibody than for a higher dose administered subcutaneously, such as 720 mg.

[0203] 80. The method of any one of Examples 75 to 79, wherein subcutaneous administration of the antibody at 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) reduces the risk of developing ARIA compared to a higher dose of the antibody administered subcutaneously (such as 720 mg).

[0204] 81. The method of any one of Examples 75-80, wherein the anti-Aβ primary fibrillary antibody is administered at a dose of 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 350 mg to 400 mg, 450 mg to 500 mg, or 550 mg to 600 mg.

[0205] 82. The method as described in any one of Examples 75-81, wherein the anti-Aβ primary fibrillary antibody is administered subcutaneously at a dose of 500 mg.

[0206] 83. The method as described in any one of Examples 75-82, wherein the dose is administered in two parts, for example, continuously.

[0207] 84. The method as described in any one of Examples 75-83, wherein the anti-Aβ primary fibrillary antibody is administered once weekly.

[0208] 85. The method as described in any one of Examples 75-83, wherein the anti-Aβ primary fibrillary antibody is administered once every two weeks.

[0209] 86. The method as described in any one of Examples 75-83, wherein the anti-Aβ primary fibrillary antibody is administered once a month.

[0210] 87. The method of any one of Examples 75-86, wherein the anti-Aβ protofibrillary antibody is administered for a first time period, for example, according to an initial dosing regimen, at an initial dose, and for a second time period, for example, according to a maintenance dosing regimen, at a maintenance dose.

[0211] 88. The method as described in Example 87, wherein the starting dose is 500 mg.

[0212] 89. The method as described in Example 87 or Example 88, wherein the initial dose is greater than the maintenance dose.

[0213] 90. The method as described in any one of Examples 87-89, wherein the maintenance dose is 360 mg.

[0214] 91. The method as described in any one of Examples 87-90, wherein the maintenance dose is 250 mg.

[0215] 92. The method as described in any one of Examples 87-91, wherein the initial dose is administered weekly.

[0216] 93. The method as described in any one of Examples 87-92, wherein the maintenance dose is administered weekly.

[0217] 94. The method as described in any one of Examples 87-92, wherein the maintenance dose is administered every two weeks.

[0218] 95. The method as described in any one of Examples 87 to 94, wherein the first time period is at least about 6 months, about 12 months, about 18 months, about 24 months, or about 30 months.

[0219] 96. The method as described in Example 95, wherein the first time period is at least 18 months.

[0220] 97. The method as described in Example 95 or Example 96, wherein the first time period is at least 24 months.

[0221] 98. The method as described in any one of Examples 87-97, wherein the first time period continues until the subject is amyloid-negative.

[0222] 99. The method as described in any one of Examples 87-98, wherein the anti-protofibrillary antibody (e.g., BAN2401) is administered subcutaneously at an initial dose of 500 mg per week for at least 18 months, and then subcutaneously at a maintenance dose of 250 mg per week for a second period.

[0223] 100. The method as described in any one of Examples 87-98, wherein the anti-protofibrillary antibody (e.g., BAN2401) is administered subcutaneously at an initial dose of 500 mg per week for at least 18 months, and then subcutaneously at a maintenance dose of 360 mg every two weeks for a second period.

[0224] 101. The method of any one of Examples 87 to 100, wherein the second time period begins when one or more biomarkers of the subject indicate a reduction or slowing of AD progression.

[0225] 102. The method as described in any one of Examples 87-101, wherein the second time period is at least about 6 months, about 12 months, about 18 months, about 24 months, about 36 months, about 42 months, about 48 months, about 54 months, about 60 months, or up to the subject's lifetime.

[0226] 103. The method as described in any one of Examples 87-102, wherein the maintenance dose is administered subcutaneously using a self-injector (AI).

[0227] 104. The method of any one of Examples 75-103, wherein the anti-Aβ primary fibrillary antibody is administered intravenously followed by subcutaneous administration to the subject.

[0228] 105. The method of any one of Examples 75-103, wherein the anti-Aβ primary fibrillary antibody is administered subcutaneously to the subject prior to intravenous administration of the antibody.

[0229] 106. The method as described in Example 104 or Example 105, wherein the intravenous infusion is 10 mg / kg relative to the subject's body weight, administered every two weeks.

[0230] 107. The method of any one of Examples 75-106, wherein the anti-Aβ primary fibrillary antibody is contained in a pharmaceutical composition in the form of a pre-filled syringe.

[0231] 108. The method of any one of Examples 75-106, wherein the anti-Aβ primary fibrillary antibody is contained in a pharmaceutical composition presented as a self-injector.

[0232] 109. The method of any one of Examples 75-108, wherein the anti-Aβ primary fibrillary antibody comprises a heavy chain complementary variable region and a light chain variable region, the heavy chain complementary variable region comprising the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0233] 110. The method of any one of Examples 75-108, wherein the anti-Aβ primary fibrillary antibody is BAN2401 (lencanemab).

[0234] 111. The method as described in any one of Examples 75-110, wherein the subject exhibits changes in measurements of one or more biomarkers associated with AD pathology prior to treatment.

[0235] 112. The method as described in Example 111, wherein the change in the measured value is selected from: a. Increased amyloid protein in the brain, for example, as measured by amyloid PET (e.g., approximately 20-40 percentile, e.g., approximately 20-32 percentile). b. Increased tau in the brain, for example, as measured by positron emission tomography (PET). c. Decreased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231), p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio, neurogranulin and / or neurofilament light chain (NfL), and d. Decreased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0236] 113. The method as described in any one of Examples 75-112, wherein the subject is amyloid-positive prior to administration, for example, as indicated by: PET assessment, CSF assessment of Aβ(1-42), MRI, retinal amyloid accumulation and / or blood biomarker assessment (e.g., plasma Aβ1-42 / 1-40 ratio, plasma p-tau181, plasma p-tau217, plasma p-tau231 level, p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio).

[0237] 114. The method as described in any one of Examples 75-113, wherein the subject is ApoE4 positive.

[0238] 115. The method as described in any one of Examples 75-114, wherein the development of ARIA in the subject is monitored.

[0239] 116. The method as described in any one of Examples 75-115, wherein the subject is 65 to 80 years old.

[0240] 117. The method as described in any one of Examples 75-115, wherein the subject is 55 to 64 years old and has at least one of the following risk factors: (i) A first-degree relative who was diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Prior to the administration, test for elevated brain amyloid protein levels using PET or cerebrospinal fluid (CSF).

[0241] 118. The method as described in any one of Examples 75-117, wherein the subject has Alzheimer's disease.

[0242] 119. The method as described in any one of Examples 75-118, wherein the subject has early Alzheimer's disease.

[0243] 120. The method as described in any one of Examples 75-119, wherein the subject has been diagnosed with... a. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease and / or already diagnosed with mild Alzheimer's dementia; b. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, according to the National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical guidelines; c. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, based on a total CDR score of 0.5 and a memory box score of 0.5 or higher before treatment; d. Mild cognitive impairment of moderate probability due to Alzheimer's disease, based on, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to treatment, as confirmed by an informed person. e. Mild Alzheimer's disease dementia according to the NIA-AA core clinical guidelines for possible Alzheimer's dementia; or f. Mild Alzheimer's dementia is indicated by a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher prior to treatment.

[0244] 121. The method as described in any one of Examples 75-117, wherein the subject is suspected of having AD.

[0245] 122. The method as described in any one of Examples 75-117, wherein the subject is a subject at risk of developing AD.

[0246] 123. The method as described in Example 122, wherein the subject at risk of developing AD has pre-AD.

[0247] 124. The method as described in Example 123 or Example 124, wherein the subject does not have cognitive impairment.

[0248] 125. The method as described in any one of Examples 122-124, wherein the subject’s overall clinical dementia grade (CDR) score was 0 prior to the administration.

[0249] 126. The method according to any one of Examples 122-125, wherein prior to the administration, the subject has an Educational Adaptation score of 27 or greater on the Mini-Mental State Examination (MMSE).

[0250] 127. The method according to any one of Examples 122-126, wherein prior to the administration, the subject's Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II) score is at least one standard deviation lower than the age-corrected mean in WMS-IV LMII, wherein the score is less than or equal to 15 for subjects aged 50 to 64 years, less than or equal to 12 for subjects aged 65 to 69 years, less than or equal to 11 for subjects aged 70 to 74 years, less than or equal to 9 for subjects aged 75 to 79 years, and less than or equal to 7 for subjects aged 80 to 90 years.

[0251] 128. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 months of administration at the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0252] 129. A method for delaying clinical decline in a subject with AD, suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 months of administration at the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0253] 130. A method for reducing brain amyloid levels in a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 months of administration at the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0254] 131. A method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising administering to the subject an antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 months of administration at the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0255] 132. The method as described in any one of Examples 128-131, wherein the maintenance dose is 500 mg.

[0256] 133. The method as described in any one of Examples 128-131, wherein the maintenance dose is 360 mg.

[0257] 134. The method as described in any one of Examples 128-131, wherein the maintenance dose is 250 mg.

[0258] 135. The method of any one of Examples 128 to 134, wherein the initial dose of the antibody is administered intravenously for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

[0259] 136. The method as described in any one of Examples 128-135, wherein the initial dose of the antibody is administered intravenously for at least 18 months.

[0260] 137. The method as described in any one of Examples 128-136, wherein the initial dose of the antibody is administered intravenously for at least 24 months.

[0261] 138. The method as described in any one of Examples 128-137, wherein the maintenance dose of the antibody is administered weekly.

[0262] 139. The method as described in any one of Examples 128-137, wherein the maintenance dose of the antibody is administered every two weeks.

[0263] 140. The method of any one of Examples 128-139, wherein the maintenance dose of the antibody is administered using a vial-syringe.

[0264] 141. The method as described in any one of Examples 128-139, wherein the maintenance dose of the antibody is administered using an AI.

[0265] 142. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered subcutaneously weekly at a starting dose of 500 mg; and For example, after 18 months of the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg weekly or every two weeks.

[0266] 143. A method for delaying clinical decline in a subject with Alzheimer's disease (AD), suspected AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered subcutaneously weekly at a starting dose of 500 mg; and For example, after 18 months of the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg weekly or every two weeks.

[0267] 144. A method for reducing brain amyloid levels in subjects with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered subcutaneously weekly at a starting dose of 500 mg; and For example, after 18 months of the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg weekly or every two weeks.

[0268] 145. A method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising administering to the subject an antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered subcutaneously weekly at a starting dose of 500 mg; and For example, after 18 months of the initial dose, the antibody can be administered subcutaneously at a maintenance dose of 250 mg weekly or every two weeks.

[0269] 146. The method of any one of Examples 142 to 145, wherein the initial dose of the antibody is administered subcutaneously for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

[0270] 147. The method as described in any one of Examples 142-146, wherein the initial dose of the antibody is administered subcutaneously for at least 18 months.

[0271] 148. The method as described in any one of Examples 142-147, wherein the initial dose of the antibody is administered subcutaneously for at least 24 months.

[0272] 149. The method as described in any one of Examples 142-148, wherein the initial dose of the antibody is administered using a vial-syringe.

[0273] 150. The method as described in any one of Examples 142-148, wherein the initial dose of the antibody is administered using an AI.

[0274] 151. The method as described in any one of Examples 142-150, wherein the maintenance dose of the antibody is administered weekly.

[0275] 152. The method as described in any one of Examples 142-150, wherein the maintenance dose of the antibody is administered every two weeks.

[0276] 153. The method as described in any one of Examples 142-152, wherein the maintenance dose of the antibody is administered using a vial-syringe.

[0277] 154. The method as described in any one of Examples 142-152, wherein the maintenance dose of the antibody is administered using an AI.

[0278] 155. The method of any one of Examples 128-154, wherein the anti-Aβ protofibrillary antibody comprises a heavy chain complementary variable region and a light chain variable region, the heavy chain complementary variable region comprising the amino acid sequence of SEQ ID NO: 7 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

[0279] 156. The method as described in any one of Examples 128-155, wherein the anti-Aβ primary fibrillary antibody is BAN2401 (lencanemab).

[0280] 157. The method as described in any one of Examples 128-156, wherein the subject exhibits changes in measurements of one or more biomarkers associated with AD pathology prior to treatment.

[0281] 158. The method as described in Example 157, wherein the change in the measured value is selected from: a. Increased amyloid protein in the brain, for example, as measured by amyloid PET (e.g., approximately 20-40 percentile, e.g., approximately 20-32 percentile). b. Increased tau in the brain, for example, as measured by positron emission tomography (PET). c. Decreased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, neurogranulin and / or neurofilament light chain (NfL), and d. Decreased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231, p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

[0282] 159. The method as described in any one of Examples 128-158, wherein the subject is amyloid-positive prior to administration, as indicated by PET assessment, CSF assessment of Aβ(1-42), MRI, or retinal amyloid accumulation.

[0283] 160. The method as described in any one of Examples 128-159, wherein the subject is ApoE4 positive.

[0284] 161. The method as described in any one of Examples 128-160, wherein the development of ARIA in the subject is monitored.

[0285] 162. The method as described in any one of Examples 128-161, wherein the subject is 65 to 80 years old.

[0286] 163. The method as described in any one of Examples 128-161, wherein the subject is 55 to 64 years old and has at least one of the following risk factors: (i) A first-degree relative who was diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Prior to the administration, test for elevated brain amyloid protein levels using PET or cerebrospinal fluid (CSF).

[0287] 164. The method as described in any one of Examples 128-163, wherein the subject has Alzheimer's disease.

[0288] 165. The method as described in any one of Examples 128-164, wherein the subject has early Alzheimer's disease.

[0289] 166. The method as described in any one of Examples 128-165, wherein the subject has been diagnosed with... a. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease and / or already diagnosed with mild Alzheimer's dementia; b. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, according to the National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical guidelines; c. Mild cognitive impairment due to moderate likelihood of Alzheimer's disease, based on a total CDR score of 0.5 and a memory box score of 0.5 or higher before treatment; d. Mild cognitive impairment of moderate probability due to Alzheimer's disease, based on, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to treatment, as confirmed by an informed person. e. Mild Alzheimer's disease dementia according to the NIA-AA core clinical guidelines for possible Alzheimer's dementia; or f. Mild Alzheimer's dementia is indicated by a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher prior to treatment.

[0290] 167. The method as described in any one of Examples 128-166, wherein the subject is suspected of having AD.

[0291] 168. The method as described in any one of Examples 128-163, wherein the subject is a subject at risk of developing AD.

[0292] 169. The method as described in Example 168, wherein the subject at risk of developing AD has pre-AD.

[0293] 170. The method as described in any one of Examples 168 or 169, wherein the subject does not suffer from cognitive impairment.

[0294] 171. The method as described in any one of Examples 168-170, wherein the subject’s overall clinical dementia grade (CDR) score was 0 prior to the administration.

[0295] 172. The method according to any one of Examples 168-171, wherein prior to the administration, the subject has an Educational Adaptation score of 27 or greater on the Mini-Mental State Examination (MMSE).

[0296] 173. The method according to any one of Examples 168-172, wherein prior to the administration, the subject's Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II) score is at least one standard deviation lower than the age-corrected mean in WMS-IV LMII, wherein the score is less than or equal to 15 for subjects aged 50 to 64 years, less than or equal to 12 for subjects aged 65 to 69 years, less than or equal to 11 for subjects aged 70 to 74 years, less than or equal to 9 for subjects aged 75 to 79 years, and less than or equal to 7 for subjects aged 80 to 90 years.

[0297] 174. A method for treating a subject with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 or 24 months of administration at the initial dose, the antibody is administered intravenously monthly at a dose of 10 mg / kg relative to the subject's body weight.

[0298] 175. A method for delaying clinical decline in a subject with Alzheimer's disease (AD), suspected AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 or 24 months of administration at the initial dose, the antibody is administered intravenously monthly at a dose of 10 mg / kg relative to the subject's body weight.

[0299] 176. A method for reducing brain amyloid levels in subjects with Alzheimer's disease (AD), suspected of having AD, or at risk of developing AD, the method comprising administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) of the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) of the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 or 24 months of administration at the initial dose, the antibody is administered intravenously monthly at a dose of 10 mg / kg relative to the subject's body weight.

[0300] 177. A method for converting an amyloid-positive subject to an amyloid-negative subject, the method comprising administering to the subject an antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered intravenously every two weeks at an initial dose of 10 mg / kg relative to the subject's body weight; and For example, after 18 months of this initial dose, the antibody is administered intravenously monthly at a dose of 10 mg / kg relative to the subject's body weight.

[0301] 178. A method for treating a subject who has early-stage Alzheimer's disease (AD), is suspected of having early-stage AD, or is at risk of developing early-stage AD, and has received a primary anti-Aβ antibody, the method comprising: The subject was administered a second anti-Aβ antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: The second antibody is administered intravenously every two weeks or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or The second antibody is administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0302] 179. A method for delaying clinical decline in subjects who have received a primary anti-Aβ antibody, the method comprising: The subject was administered a second anti-Aβ antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: The second antibody is administered intravenously every two weeks or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or The second antibody is administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0303] 180. A method for reducing brain amyloid levels in a subject who has received a primary anti-Aβ antibody, the method comprising: The subject was administered 150 mg to 600 mg, for example 200 mg to 550 mg (e.g., 500 mg), of a secondary anti-Aβ antibody comprising the following: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising the following: The second antibody is administered intravenously every two weeks or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or The second antibody is administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0304] 181. A method for maintaining amyloid levels in a subject who has received a primary anti-Aβ antibody, the method comprising: The subject was administered a second anti-Aβ antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: The second antibody is administered intravenously every two weeks or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or The second antibody is administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0305] 182. A method for treating a subject who has early-stage Alzheimer's disease (AD), is suspected of having early-stage AD, or is at risk of developing early-stage AD, the method comprising: The subject was given the first anti-Aβ antibody. The subject was administered a second anti-Aβ antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: The second antibody is administered intravenously every two weeks or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or The second antibody is administered subcutaneously at a maintenance dose of 250 mg, 360 mg, or 500 mg weekly or every two weeks.

[0306] 183. The method as described in any one of Examples 178-182, wherein the maintenance dose administered subcutaneously is 500 mg.

[0307] 184. The method as described in any one of Examples 178-182, wherein the maintenance dose administered subcutaneously is 360 mg.

[0308] 185. The method as described in any one of Examples 178-182, wherein the maintenance dose administered subcutaneously is 250 mg.

[0309] 186. The method of any one of Examples 178-185, wherein the maintenance dose of the subcutaneously administered antibody is administered using a vial-syringe.

[0310] 187. The method as described in any one of Examples 178-185, wherein the maintenance dose of the subcutaneously administered antibody is administered using an AI.

[0311] 188. The method of any one of Examples 178-187, wherein the first anti-Aβ antibody is selected from aducanumab, barbiturumab, cresolumab, donatumab, ganteizumab, lencanemab, or sorazurumab.

[0312] 189. The method as described in Example 188, wherein the first anti-Aβ antibody is donatamab.

[0313] 190. A method of treating a subject with early-stage Alzheimer's disease (AD), suspected of having early-stage AD, or at risk of developing early-stage AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody was administered subcutaneously weekly at a starting dose of 500 mg; and For example, after 18 or 24 months from the initial dose, the antibody can be administered subcutaneously at a dose of 360 mg weekly.

[0314] 191. A method of treating a subject with early-stage Alzheimer's disease (AD), suspected of having early-stage AD, or at risk of developing early-stage AD, the method comprising administering to the subject an anti-Aβ protofibrillary antibody comprising: three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), the administration being according to a dosage regimen comprising: The antibody is administered intravenously every two weeks at a first starting dose of 10 mg / kg relative to the subject's body weight; The antibody was administered subcutaneously weekly at a second starting dose of 720 or 500 mg; and For example, after 18 or 24 months from the initial dose, the antibody can be administered subcutaneously weekly at a dose of 360 or 250 mg. Attached Figure Description

[0315] Figure 1 The results of CDR-SB, ADAS-cog14, and ADCS MCI-ADL in Study 301 are shown.

[0316] Figure 2 The adjusted average change of CDR-SB relative to the baseline is shown in Study 301.

[0317] Figure 3 The adjusted mean change of ADAS-Cog14 relative to baseline is shown in Study 301.

[0318] Figure 4 The adjusted mean change of ADCS MCI-ADL relative to baseline is shown in Study 301.

[0319] Figure 5 This study showed a reduction in brain amyloid β plaques (amyloid β PET percentage units adjusted mean change relative to baseline) in Study 301.

[0320] Figure 6 The Health-Related Quality of Life Measure – EQ-5D-5L (Healthy Living Subjects) is shown.

[0321] Figure 7 The health-related quality of life measure - QOL-AD (total score of subjects) is shown.

[0322] Figure 8 The Health-Related Quality of Life Measure - QOL-AD (by proxy participants) is shown.

[0323] Figure 9 The study presents a health-related quality of life measure – Zarit Burden Interview – Research Partner Burden (total score).

[0324] Figure 10 The time it takes for the total CDR score to deteriorate is shown.

[0325] Figure 11 Slope analysis using CDR-SB is shown: observed data extrapolated to 2 years.

[0326] Figure 12 The changes in plasma GFAP after treatment are shown.

[0327] Figure 13 The data shows the ARIA rate and antithrombotic drug use in the core phase of the double-blind study in Clarity AD.

[0328] Figure 14 The data shows the ARIA rate and antithrombotic drug use based on genotype in the core phase of a double-blind study in Clarity AD.

[0329] Figure 15 The ARIA rate and antithrombotic drug use are shown in the Clarity AD core and OLE.

[0330] Figure 16 The data shows the ARIA rate and antithrombotic drug use based on genotype in Clarity AD core and OLE.

[0331] Figure 17 This shows the expected ARIA-E rate for self-injectors and IVs.

[0332] Figure 18 The average steady-state concentration via the application route is shown.

[0333] Figure 19 The baseline clinical characteristics of study 301 are shown.

[0334] Figure 20 The results of the primary endpoint and key secondary endpoints of Study 301 are shown.

[0335] Figure 21 The overall safety spectrum of Study 301 is shown.

[0336] Figure 22 The differences in ARIA and infusion-related responses between the two groups in Study 301 and placebo are shown.

[0337] Figure 23 The infusion-related response grade and timing of treatment in Study 301 are shown.

[0338] Figure 24 ARIA-E events were shown in 897 subjects who received placebo and in 898 subjects who received lencanezumab.

[0339] Figure 25 shows that approximately 90% of ARIA-E cases occur ≤ 6 months after treatment and resolve within 4 months of detection. Figure 25A The probability of ARIA-E occurring during weeks 0-76 is shown. Figure 25B The probability of ARIA-E occurring during weeks 0-120 is shown.

[0340] Figure 26 The incidence of ARIA-H (without ARIA-E) was shown to be similar between lencanezumab and placebo in Study 301.

[0341] Figure 27 It was shown that most ARIA-H events in Study 301 were microbleeds and surface iron deposition associated with ARIA-E.

[0342] Figure 28 The study showed that the incidence of ARIA was not increased when lencanezumab was used in conjunction with antiplatelet or anticoagulant agents, compared to lencanezumab alone.

[0343] Figure 29 The event rates for ARIA, ARIA-E, and ARIA-H based on APOE4 carrier status are shown.

[0344] Figure 30 A summary of ARIA cases is presented, showing the number of microbleeds and APOE4 status at baseline.

[0345] Figure 31 The concentration-time curves of lencanemab after a single intravenous (10 mg / kg; n = 30) dose and a single subcutaneous (700 mg; n = 29) dose are shown.

[0346] Figure 32 The concentration-time curves of lencanetumab after a single subcutaneous (700 mg) dose are shown in Japanese subjects (n = 5) and non-Japanese subjects (n = 24). Figure 33 shows the mean (SD) serum concentration-time curves of lencanezumab, presented in linear and semi-logarithmic dimensions, comparing subcutaneous administration via vial / syringe and subcutaneous administration via AI device.

[0347] Figure 34 The C60 levels of lencanemab in serum were shown after administration of 720 mg subcutaneously via a vial and syringe (via / syringe) or via self-injector (AI). max Box plot (PK analysis set).

[0348] Figure 35 The AUC of lencanemab in serum is shown after administration of 720 mg subcutaneous lencanemab via a vial and syringe (via / syringe) or via self-injector (AI). 0-inf Box plot (PK analysis set).

[0349] Figure 36 Box plots (PK analysis set) of AUC(0-t) of lencanemumab in serum are shown after 720 mg subcutaneous lencanemumab injection with vial and syringe (vial / syringe) or 720 mg subcutaneous lencanemumab injection with self-injector (AI).

[0350] Figure 37 An overview of the research design for Study 301 is shown, including the core study, extended study, and hypodermal study.

[0351] Figure 38 The effect of body weight on model-predicted lencanizumab exposure (and its rate) following weekly fixed administration of 720 mg SC (vial / syringe) and every two weeks fixed administration of 10 mg / kg IV is shown.

[0352] Figure 39The comparison shows the mean steady-state concentrations after 10 mg / kg IV every two weeks (Study 301 core and OLE) or 720 mg SC AI weekly (Study 301 OLE AI sub-study).

[0353] Figure 40 This shows the simulated mean steady-state concentration (C0.05) of lencanizate 500 mg QW administered using two AI devices in the 301 core and OLE phases of the study. ave,ss ) and the model predictions (observed) C of IV LEC10-BW ave,ss .

[0354] Figure 41 The model-predicted median (90% prediction interval) amyloid PET is shown after administration of lencanemab at 10 mg / kg IV every two weeks or lencanemab at 500 mg SC AI weekly.

[0355] Figure 42 The model-predicted mean (90% prediction interval) change of CDR-SB is shown after 10 mg / kg IV lencanemab every two weeks or 500 mg SC AI lencanemab weekly.

[0356] Figure 43 The study showed the expected changes in amyloid PET in subjects receiving 10 mg / kg IV lencanizumab for 18 or 24 months, followed by 360 mg SC AI weekly, compared to placebo or continuous 10 mg / kg IV lencanizumab.

[0357] Figure 44 The expected changes in CDR-SB were shown in subjects receiving 10 mg / kg IV lencanezumab for 18 or 24 months, followed by 360 mg SC AI weekly, compared to placebo or continuous 10 mg / kg IV lencanezumab.

[0358] Figure 45 The simulated amyloid PET profile over 4 years of IVLEC10-BW dosing is shown in subjects with baseline amyloid PET ≥ 60 and < 60 percent units, compared to maintenance doses of SC 360 mg QW (1x AI device) or LEC10-M initiated at 18 and 24 months. AI = self-injector, BW = every two weeks, CL = percent unit, IV = intravenous, PET = positron emission tomography, QW = weekly, Q4W = every 4 weeks.

[0359] Figure 46The simulated CDR-SB spectrum for 4 years of IV LEC10-BW dosing is shown in subjects with baseline amyloid PET ≥ 60 and < 60 percent units, compared to maintenance doses of SC 360 mg QW (1x AI device) or LEC10-M initiated at 18 and 24 months. AI = self-injector, BW = every two weeks, CL = percent unit, IV = intravenous, PET = positron emission tomography, QW = weekly, Q4W = every 4 weeks.

[0360] Figure 47 The model predicts plasma Aβ42 / 40 ratio and p-tau181 after different dosing regimens. AI = self-injector, BW = every two weeks, CI = confidence interval, QW = weekly, Q4W = every 4 weeks. Solid lines and shaded areas show the predicted median and 95% CI, respectively. p-tau181 = human tau protein phosphorylated at threonine at position 181.

[0361] Figure 48 The SC exposure is shown in comparison with that of healthy volunteers (Study 005) and the sub-study of Study 301 OLE AI device (AD subjects) to IV LEC10-BW. AD = Alzheimer's disease; HV = healthy volunteers; IV = intravenous; for IV and AD device, n = 168.

[0362] Figure 49 The SC exposure at a maintenance dose of 360 mg QW AI was shown to be within the LEC10-BW range.

[0363] Figure 50 The Kaplan-Meier (KM) diagram shows the actual duration of time to the event. Detailed Implementation

[0364] The "amyloid hypothesis" proposes that amyloid-β (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease (AD). Specifically, it hypothesizes that neurodegeneration in AD can be caused by the deposition of Aβ plaques in brain tissue, attributed to an imbalance between Aβ production and clearance, leading to the formation of tau-containing neurofibrillary tangles. Aβ peptides typically exist in a dynamic, continuous conformational state, causing species to evolve from monomeric Aβ into soluble Aβ aggregates, ranging from low-molecular-weight oligomers to higher-molecular-weight protofibrils, and ultimately into insoluble fibrils (plaques). Targeting these soluble and insoluble Aβ tangles and plaques could provide therapeutic benefits.

[0365] Various immunotherapies have been developed with the intention of reducing the amount of insoluble Aβ fibrils deposited in the brain. However, a simple correlation between the amount and progressive accumulation of insoluble amyloid plaques and the clinical course of AD has not been established. While therapeutic strategies continue to focus on removing insoluble amyloid plaques, an alternative approach could include reducing toxic Aβ aggregates, such as primary fibrils, which can contribute to the neurodegenerative features of AD. (See, for example, Doodort, J.-C. and May, P., “Overview on rodent models of Alzheimer's disease.” Curr. Protocols Neurosci. 2005; 9.22-1-9.22-6; Englund, H. et al., “Sensitive ELISA detection of amyloid-β protofibrils in biological samples.” J. Neurochem. 2007; 103:334-45; and Gotz, J. et al., “Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior and therapy.” Mol. Psychiat. 2004;) 9:664-83.) In various embodiments, when amyloid has been deposited in the brain, but the downstream neurodegenerative cascade believed to be triggered by amyloid deposition is still in its relatively early stages (i.e., limited brain tissue damage has occurred and associated clinical deficits are at a minimum), anti-Aβ protofibrillary antibodies such as BAN2401 and other anti-Aβ protofibrillary antibodies can be used to treat AD, for example, by slowing the progression of AD in subjects (e.g., those in the early stages of the disease).

[0366] In various embodiments, this document discloses methods for selecting patients suitable for treatment with anti-Aβ protofibrillary antibodies (such as BAN2401), wherein the patients have a low risk of developing ARIA, for example, wherein the patients have not had a cerebral hemorrhage event (e.g., microbleeds or intracerebral hemorrhage) prior to treatment, and / or wherein the patients are not ApoE4 carriers prior to treatment. In various embodiments, this document discloses methods for selecting patients suitable for treatment with anti-Aβ protofibrillary antibodies (such as BAN2401), wherein the patients have a low risk of developing ARIA, for example, wherein the patients have not shown changes in white matter (e.g., reduction) at the time of treatment. In various embodiments, this document discloses methods for selecting patients suitable for treatment with anti-Aβ protofibrillary antibodies (such as BAN2401), wherein the patients have a low risk of developing ARIA, for example, wherein the patients have not used anticoagulants or thrombolytic agents at the time of treatment, and / or wherein the patients are not ApoE4 carriers.

[0367] In various embodiments, this document discloses methods for treating patients with or suspected of having Alzheimer's disease, wherein the patient has a low risk of developing ARIA based on brain imaging. In some embodiments, patients without cerebral hemorrhage (e.g., microbleeds or intracerebral hemorrhage) at baseline imaging are administered an anti-amyloid β (Aβ) protofibrillary antibody (e.g., BAN2401). In some embodiments, patients who already have cerebral hemorrhage (e.g., microbleeds or intracerebral hemorrhage) at baseline imaging are not administered an anti-amyloid β (Aβ) protofibrillary antibody (e.g., BAN2401). In some embodiments, patients who do not exhibit changes in white matter as measured by brain imaging (e.g., reduction) prior to treatment are administered an anti-amyloid β (Aβ) protofibrillary antibody (e.g., BAN2401). In some embodiments, patients exhibiting changes in white matter as measured by brain imaging (e.g., reduction) are not administered an anti-amyloid β (Aβ) protofibrillary antibody (e.g., BAN2401).

[0368] In various embodiments, this document discloses methods for selecting and treating patients with or suspected of having Alzheimer's disease, wherein the patient has a lower risk of ARIA, for example, based on the use of anticoagulants or thrombolytic agents. In some embodiments, a therapeutically effective dose of an anti-amyloid β (Aβ) protoplasmic antibody (e.g., BAN2401) is administered to a patient receiving aspirin. In some embodiments, a therapeutically effective dose of an anti-amyloid β (Aβ) protoplasmic antibody (e.g., BAN2401) is administered to a patient receiving an antiplatelet drug. In some embodiments, a therapeutically effective dose of an anti-amyloid β (Aβ) protoplasmic antibody (e.g., BAN2401) is administered to a patient receiving a thrombolytic agent and / or an anticoagulant. In some embodiments, patients receiving anticoagulants are not selected for treatment with an anti-amyloid β (Aβ) protoplasmic antibody (e.g., BAN2401). In some embodiments, patients receiving thrombolytic agents are not selected for treatment with an anti-amyloid β (Aβ) protoplasmic antibody (e.g., BAN2401).

[0369] In various embodiments, this document discloses methods for treating patients with or suspected of having Alzheimer's disease, where the patient has an increased risk of ARIA events or cerebral hemorrhage (e.g., microbleeds, intracerebral hemorrhage), wherein the patient is administered an anti-amyloid β (Aβ) protofibrillary antibody (e.g., BAN2401) and also a steroid. In some embodiments, a steroid is administered to a patient receiving an anti-amyloid β (Aβ) protofibrillary antibody and having a severe ARIA event.

[0370] In some embodiments, additional patient demographic data (such as age and, in cases where the subject is a carrier of the apolipoprotein Eε4 gene allele) may be used to select patients to be treated in combination with: baseline status of cerebral hemorrhage (e.g., presence or absence of microbleeds or intracerebral hemorrhage), baseline status of white matter, and / or treatment with anticoagulants or thrombolytic agents, and / or additional biomarkers indicating positivity for amyloid (e.g., West et al., Mol Neurodegen [Molecular Neurodegenerative Diseases] (2021) 16-30, Jansen et al., JAMA [Journal of the American Medical Association] (2015) 1924-1938, Ossenkoppele et al., JAMA [Journal of the American Medical Association] (2015) 1939-1950).

[0371] In some embodiments, one or more additional biomarkers (e.g., one or more blood biomarkers (such as the ratio of Aβ42 to Aβ40 and / or p-tau181)) may be used, for example, in conjunction with brain measurements (such as amyloid or tau PET measurements) to select patients. In some embodiments, biomarkers associated with AD pathology include (but are not limited to) one or more of the following: • Amyloid protein in the brain (e.g., as measured by amyloid positron emission tomography (PET)). • Tau in the brain (e.g., as measured by tau PET); • Cerebrospinal fluid (CSF) biomarkers, such as the following CSF levels: Aβ42, Aβ40, Aβ42 / Aβ40 ratio, total tau, p-tau (e.g., p-tau181, p-tau217, p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio; neurogranulin; neurofilament light chain (NfL) and / or glial fibrillary acidic protein (GFAP). • Blood biomarkers, such as plasma and / or serum levels of the following: Aβ42, Aβ40, Aβ42 / Aβ40 ratio, total tau, p-tau (e.g., p-tau181, p-tau217, p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio; neurogranulin; neurofilament light chain (NfL) and / or glial fibrillary acidic protein (GFAP). • Biomarkers in other bodily fluids (e.g., urine, saliva, tears, sweat, etc.); • Genetic biomarkers (e.g., ApoE4, PSEN1, and / or PSEN2); • Abnormalities in the eye and / or retinal vascular system (e.g., as measured by optical coherence tomography (OCT) or optical coherence tomography angiography (OCTA); and / or Abnormalities in brain structure, function, and / or vascular system (e.g., as measured by magnetic resonance imaging (MRI), electroencephalography (EEG), and / or single-photon emission computed tomography (SPECT)). In some embodiments, the subject's age and / or tau PET and / or at least one additional biomarker, apolipoprotein E ε4 gene allele-normalized measurements, are used to evaluate whether samples from the subject (e.g., plasma samples) indicate that the subject is suitable for treatment with a primary fibrillary antibody such as BAN2401 (e.g., whether the subject is amyloid-positive) and / or to monitor treatment. For example, in some embodiments, a patient who is a carrier of the apolipoprotein E ε4 gene allele may be considered amyloid-positive if the biomarker level is below the level required to indicate amyloid positivity in a non-carrier subject. In some embodiments, patients who are carriers of the apolipoprotein E ε4 gene allele may have a higher risk of developing ARIA in response to treatment with anti-amyloid β (Aβ) protofibrillary antibodies (e.g., BAN2401) compared to patients who are not carriers, and may be warned of the increased risk by a physician, monitored for ARIA, and / or advised against using anti-amyloid β (Aβ) protofibrillary antibodies (e.g., BAN2401). Similarly, in another instance, older subjects may be considered amyloid-positive when biomarker levels are below the levels required to indicate positivity in younger subjects. In some embodiments, biomarker levels are used in recipient operating characteristic (ROC) analyses to predict amyloid positivity. In some embodiments, additional patient demographics, such as age and whether the subject is a carrier of the apolipoprotein E ε4 gene allele, may be used in ROC analyses along with biomarker levels to predict amyloid positivity. In some embodiments, the prediction of amyloid positivity in patients is used to determine the dose or frequency of treatment.

[0372] Cognitive and functional decline can be measured using techniques known in the art, including scoring methods such as CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, Modified iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, anti-Aβ primary fibrillation antibody (e.g., BAN2401) is administered at a therapeutically effective dose to reduce or delay cognitive decline. In some embodiments, anti-Aβ primary fibrillation antibody (e.g., BAN2401) is administered as a therapeutically effective dose comprising an intravenous infusion of 10 mg / kg relative to the subject's body weight. In some embodiments, anti-Aβ primary fibrillation antibody (e.g., BAN2401) is administered as a therapeutically effective dose comprising a subcutaneous administration of 720 mg. In some embodiments, this method results in a reduction in cognitive decline, as measured by ADCOMS, compared to untreated subjects. In some embodiments, the method results in at least 24% (e.g., at least 29%) less cognitive decline compared to untreated subjects, as measured by ADCOMS. In some embodiments, the method results in reduced cognitive decline compared to untreated subjects, as measured by CDR-SB. In some embodiments, the method results in at least 26% (e.g., at least 27%) less cognitive decline compared to untreated subjects, as measured by CDR-SB. In some embodiments, the method results in reduced cognitive decline compared to untreated subjects, as measured by ADAS-Cog14. In some embodiments, the method results in at least 26% (e.g., at least 47%) less cognitive decline compared to untreated subjects, as measured by ADAS-Cog14. In some embodiments, the method results in reduced cognitive decline compared to untreated subjects, as measured by ADCS MCI-ADL. In some embodiments, the method results in at least 37% less cognitive decline compared to untreated subjects, as measured by ADCS MCI-ADL. In some embodiments, the method reduces the risk of progression to subsequent stages of AD, as measured by the CDR total score, for example, a higher score in subsequent evaluations indicates progression to the next stage of AD, while no change in score indicates remaining in the same stage of AD. In some embodiments, results are measured at least 6 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody. In some embodiments, results are measured at least 12 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody. In some embodiments, results are measured at least 13 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody. In some embodiments, results are measured at least 18 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody.

[0373] Anti-Aβ protofibrillary antibodies (such as BAN2401) can be formulated in pharmaceutical compositions disclosed in, for example, PCT / IB2021 / 000155 (WO 2021 / 186245), which is incorporated herein by reference. In some embodiments, the composition comprises 80 mg / mL to 120 mg / mL BAN2401, 240 mM to 360 mM arginine, 0.03% w / v to 0.08% w / v polysorbate 80, and 30 mM to 70 mM citrate buffer. In some embodiments, the arginine is arginine, arginine hydrochloride, or a combination thereof. In some embodiments, the composition comprises a liquid dosage form containing 100 mg / mL BAN2401, 50 mmol / L citrate, 350 mmol / L arginine, and 0.05% polysorbate 80. In some embodiments, the composition comprises 80 mg / mL to 240 mg / mL BAN2401, 140 mM to 260 mM arginine hydrochloride, 0.01% w / v to 0.1% w / v polysorbate 80, and 15 mM to 35 mM histidine buffer. In some embodiments, the composition comprises a liquid dosage form comprising 100 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.

[0374] In some embodiments, BAN2401 is formulated as disclosed in PCT / IB2021 / 000155 (WO 2021 / 186245), which is incorporated herein by reference. In some embodiments, the composition comprises 80 mg / mL to 240 mg / mL BAN2401, 140 mM to 260 mM arginine hydrochloride, 0.01% w / v to 0.1% w / v polysorbate 80, and 15 mM to 35 mM histidine buffer. In some embodiments, the composition comprises a liquid dosage form comprising 200 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.

[0375] In some embodiments, this document provides a treatment method comprising administering a therapeutically effective dose of anti-Aβ proficiency antibody until a desired improvement is achieved in one or more biomarkers, such as until an increase in the ratio of Aβ1-42 to Aβ1-40 in a fluid sample (e.g., a blood sample) and / or a decrease in the level of p-tau181 in a fluid sample (e.g., a blood sample). In some embodiments, treatment is continued until tau PET levels have improved relative to untreated control subjects, and / or until the ratio of Aβ1-42 to Aβ1-40 in a fluid sample (e.g., a blood sample) is equal to or greater than 0.092. In some embodiments, treatment is continued until amyloid PET or tau PET levels have improved relative to untreated control subjects. In some embodiments, treatment is continued until tau PET levels have improved relative to untreated control subjects and / or florbetapir amyloid PET SUVr negative is less than 1.17. In some embodiments, one or more biomarkers include serum or plasma GFAP measurements. In some embodiments, treatment is continued until the subject is amyloid-negative. In some embodiments, after the desired improvement is achieved by one or more biomarkers, the subject will switch to a maintenance dose. In some embodiments, in addition to anti-Aβ protofibrillary antibodies, the maintenance dosing regimen may also include one or more additional treatments, such as administration of E2814.

[0376] In some embodiments, this document provides a treatment method comprising administering a therapeutically effective dose of anti-Aβ primary fibrillary antibody until a desired improvement in cognitive outcomes or other measures of treatment outcome is achieved in a subject (e.g., a subject with Alzheimer's disease, pre-AD, or early Alzheimer's disease). In some embodiments, the treatment method comprises administering a therapeutically effective dose of anti-Aβ primary fibrillary antibody for at least 18 months, or, for example, until a desired improvement in cognitive outcomes is achieved in the subject. Cognitive and functional decline can be measured using techniques known in the art, including scoring methods such as CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, Modified iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, the treatment method, including administering a therapeutically effective dose of anti-Aβ primary fibrillary antibody, continues until the method results in a reduction in cognitive decline, as measured by ADCOMS, compared to an untreated subject. In some embodiments, the efficacy of the treatment method can be evaluated using the CDR total score, which can be used to determine whether a patient has progressed or maintained a stage of AD during treatment, for example, a higher score on subsequent evaluations indicates AD progression, while no change in the score indicates no AD progression. In some embodiments, the treatment method continues until, compared to an untreated subject, the method results in at least 24% (e.g., at least 29%) less cognitive decline, as measured by ADCOMS. In some embodiments, the treatment method continues until, compared to an untreated subject, the method results in a reduction in cognitive decline, as measured by CDR-SB. In some embodiments, the treatment method continues until, compared to an untreated subject, the method results in at least 26% (e.g., at least 27%) less cognitive decline, as measured by CDR-SB. In some embodiments, the treatment method continues until, compared to an untreated subject, the method results in a reduction in cognitive decline, as measured by ADAS-Cog14. In some embodiments, the treatment method continues until, compared to an untreated subject, the method results in at least 26% (e.g., at least 47%) less cognitive decline, as measured by ADAS-Cog14. In some embodiments, the method reduces cognitive decline compared to untreated subjects, as measured by ADCS MCI-ADL. In some embodiments, the method reduces cognitive decline by at least 37% compared to untreated subjects, as measured by ADCS MCI-ADL. In some embodiments, the results are measured at least 6 months after administration of a therapeutically effective amount of at least one anti-Aβ protofibrillary antibody.In some embodiments, results are measured at least 12 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody. In some embodiments, results are measured at least 13 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody. In some embodiments, results are measured at least 18 months after administration of a therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody.

[0377] Treatment methods involving intravenous administration of anti-Aβ profibrillary antibodies (including administration) are disclosed in PCT / US2022 / 073576 and PCT / US2022 / 079571, and are incorporated herein by reference. In some embodiments, treatment comprises intravenous administration of anti-Aβ profibrillary antibodies (e.g., BAN2401 at 10 mg / kg) at 10 mg / kg every two weeks, for example, for at least 18 months or, for example, until the patient becomes amyloid-negative. In some embodiments, treatment comprises intravenous administration of anti-Aβ profibrillary antibodies (e.g., BAN2401 at 10 mg / kg) at 10 mg / kg every two weeks, for example, for at least 18 months or, for example, until the patient becomes amyloid-negative, followed by a maintenance dose. In some embodiments, the maintenance dose may be the same as the treatment dose, or it may involve a reduced dose and / or frequency of administration.

[0378] Methods of treatment (including administration) via subcutaneous administration of anti-Aβ profibrillary antibodies are disclosed in PCT / US2022 / 073576; PCT / US2022 / 079571; and PCT / US2022 / 041926 and are incorporated herein by reference. In some embodiments, treatment includes weekly subcutaneous administration of anti-Aβ profibrillary antibodies (e.g., BAN2401 administered at 720 mg), for example, for at least 18 months or, for example, until the patient becomes amyloid-negative. In some embodiments, treatment includes once-weekly subcutaneous administration of BAN2401, for example, by subcutaneously injecting 720 mg once-weekly in two simultaneous (e.g., sequential) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of a subcutaneous preparation, for example, until the patient becomes amyloid-negative or, for example, for at least 18 months. In some embodiments, treatment includes weekly subcutaneous administration of BAN2401, for example, by administering 720 mg subcutaneously once weekly in two simultaneous (e.g., sequential) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation, for example, until the patient becomes amyloid-negative or for example, for at least 18 months. In some embodiments, treatment includes, for example, weekly subcutaneous administration of BAN2401 at a dose of 720 mg, for example, for at least 18 months or for example, until the patient becomes amyloid-negative, and then switching to a weekly subcutaneous maintenance dose, for example, a dose of 360 mg. In some embodiments, treatment includes, for example, weekly subcutaneous administration of BAN2401 at a dose of 720 mg, for example, for at least 18 months or for example, until the patient becomes amyloid-negative, and then switching to a bi-weekly subcutaneous maintenance dose, for example, a dose of 720 mg. In some embodiments, the treatment method includes weekly subcutaneous administration of BAN2401, for example by two simultaneous (e.g., sequential) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation followed by a weekly subcutaneous injection of 720 mg, for example, for at least 18 months. In some embodiments, the treatment method includes once-weekly subcutaneous administration of BAN2401, for example by two simultaneous (e.g., sequential) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation followed by a weekly subcutaneous injection of 720 mg, for example, for at least 18 months, followed by a switch to a maintenance dose. In some embodiments, the maintenance dose may be the same as the treatment dose, or it may involve a reduced dose and / or frequency of administration. In some embodiments, the treatment method includes using biomarker levels to determine when to switch to a maintenance intravenous or subcutaneous dose at a set time point (e.g., after 18 months). In some embodiments, the maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections).In some embodiments, treatment includes: intravenous administration of anti-Aβ primary fibrillation antibody at 10 mg / kg every two weeks (e.g., BAN2401 at 10 mg / kg), followed by a switch to a subcutaneous maintenance dose, e.g., a weekly subcutaneous maintenance dose, e.g., 720 mg. In some embodiments, treatment includes: intravenous administration of anti-Aβ primary fibrillation antibody at 10 mg / kg every two weeks, followed by a switch to a subcutaneous maintenance dose of 720 mg every two weeks.

[0379] In some embodiments, the treatment includes using biomarker levels to determine the transition from subcutaneous treatment to a maintenance dose. In some embodiments, the treatment includes subcutaneous administration of an anti-Aβ protofibrillary antibody, such as BAN2401, prior to transition to an intravenous maintenance dose. In some embodiments, the treatment includes: weekly subcutaneous administration of BAN2401, for example, a subcutaneous injection of 720 mg, comprising two simultaneous (e.g., sequential) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL), followed by transition to a maintenance dose. In some embodiments, the treatment includes weekly subcutaneous administration of BAN2401, for example, at a dose of 720 mg prior to transition to a maintenance dose. In some embodiments, the treatment includes weekly subcutaneous administration of BAN2401, followed by transition to an intravenous maintenance dose of 10 mg / kg every two weeks. In some embodiments, the maintenance dose is administered to the subject at the same amount and / or frequency as the dose during the treatment period. In some embodiments, the subject's maintenance dose is 50% of the dose during the treatment period.

[0380] In some embodiments, the patient begins with an intravenous maintenance dose, such as 10 mg / kg BAN2401 as disclosed above, and then switches to a subcutaneous maintenance dose, such as comprising two simultaneous (e.g., successive) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, resulting in a 720 mg subcutaneous injection. In some embodiments, the patient begins with a subcutaneous maintenance dose, such as a subcutaneous injection of 720 mg, comprising two simultaneous (e.g., successive) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, and then switches to an intravenous maintenance dose, such as administration of 10 mg / kg BAN2401 as disclosed above.

[0381] In some embodiments, if it is determined that the patient is no longer amyloid-negative, for example as assessed by blood, serum, or CSF biomarkers and / or as determined by amyloid PET SUVr, the patient is moved back from the maintenance dose to the initial treatment dose.

[0382] In some embodiments, a maintenance dose is administered to the subject at the same amount and / or frequency as the dose administered during the treatment period. In some embodiments, the maintenance dose to the subject is 50% of the dose administered during the treatment period. In some embodiments, the maintenance dose comprises two or more administrations, wherein the first administration is selected from the maintenance doses illustrated above, and the second and / or subsequent administrations comprise lower dosages and / or frequencies than the first or previous administrations, respectively. In some embodiments, the transition to a second or subsequent administration is determined based on one or more biomarkers illustrated above, wherein the level of the biomarker differs from (e.g., is higher than) the level of the first administration used to transition from the starting dose to the maintenance dose.

[0383] In some embodiments, treatment is discontinued if the patient no longer has early-stage AD, for example, as assessed by cognitive evaluation, PET SUVr and / or blood, CSF, or plasma biomarkers.

[0384] In some embodiments, the regression of a patient's amyloid levels after treatment discontinuation can be monitored by measuring tau PET levels and one or more biomarkers (e.g., volumetric MRI (vMRI), including whole brain volume, cortical thickness, and / or total hippocampal volume). In some embodiments, the regression of a patient's amyloid levels after treatment discontinuation can be monitored by measuring tau PET levels and one or more biomarkers (such as PET levels, including amyloid PET levels and / or fluorodeoxyglucose (FDG) PET levels). In some embodiments, the regression of a patient’s amyloid levels after treatment discontinuation can be monitored by measuring tau PET levels and one or more biomarkers, such as cerebrospinal fluid levels of biomarkers including CSF levels of Aβ1-42 and Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, p-tau (e.g., p-tau181, p-tau217 and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, neurogranulin and / or neurofilament light (NfL) peptide. In some embodiments, the regression of a patient’s amyloid levels after treatment discontinuation can be monitored by measuring tau PET levels and one or more biomarkers, such as serum or plasma levels of biomarkers including Aβ1-42, Aβ1-40 (including the ratio of Aβ1-42 to Aβ1-40), total tau, phosphorylated tau (P-tau) (including tau phosphorylated at 181 (P-tau181), 217 (P-tau217) and / or 231 (P-tau231), the ratio of p-tau181 / np-tau181, and / or the ratio of p-tau217 / np-tau217, glial fibrillary acidic protein (GFAP) and / or neurofilament light chain (NfL)).

[0385] In some embodiments, a patient's biomarkers may be monitored at least once after treatment is discontinued. In some embodiments, a patient's biomarkers may be monitored at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment is discontinued. In some embodiments, treatment may be restarted if a patient's biomarker levels become less favorable, for example, if tau PET levels increase at the same rate as in an untreated control.

[0386] In some embodiments, the subject has been diagnosed with early-stage AD. In some embodiments, the subject has been diagnosed with mild cognitive impairment due to a moderate probability of Alzheimer's disease, and / or has been diagnosed with mild Alzheimer's dementia.

[0387] Treatment methods using anti-Aβ protofibrillary antibodies, including treatment at effective doses, are disclosed in PCT / US2022 / 073576; PCT / US2022 / 079571; and PCT / US2022 / 041926, which are incorporated herein by reference. In some embodiments, the treatment method includes using biomarker levels (e.g., tau PET levels or the rate of change in tau PET levels) to allow monitoring and treatment decisions, such as changing the dose of BAN2401 and / or discontinuing treatment.

[0388] 1. Definition The following are definitions of the terms used in this application.

[0389] Unless the context clearly indicates otherwise, as used herein, the singular terms “a / an” and “the” include plural references.

[0390] As used herein, the phrase “and / or” means “any one or both” of the elements that are combined, that is, elements that are combined in some cases and not combined in others. Therefore, as a non-limiting example, when “A and / or B” is used in conjunction with open-ended language such as “including,” in some embodiments it may refer only to A (optionally including elements other than B); in other embodiments it may refer only to B (optionally including elements other than A); in still other embodiments it may refer to both A and B (optionally including other elements); and so on.

[0391] As used herein, “at least one” means one or more elements in the list of elements, but is not required to include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase “at least one,” whether related to or unrelated to those specifically identified elements. Thus, as a non-limiting example, “at least one of A and B” (or equivalently, “at least one of A or B”, or equivalently, “at least one of A and / or B”) may, in one embodiment, mean at least one (optionally including more than one) A without B (and optionally including elements other than B); in another embodiment, mean at least one (optionally including more than one) B without A (and optionally including elements other than A); in yet another embodiment, mean at least one (optionally including more than one) A and at least one (optionally including more than one) B (and optionally including other elements); and so on.

[0392] As used herein, “about” when used in conjunction with a dose, amount, or ratio includes a specified dose, amount, or ratio, or a range of doses, amounts, or ratios, as recognized by one of ordinary skill in the art, to provide a therapeutic effect equivalent to those obtained from the specified dose, amount, or ratio. The term “about” may refer to an acceptable error in a particular value as determined by one of ordinary skill in the art, which in part depends on how those values ​​are measured or determined. In some embodiments, the term “about” means within 5% of a given value or range.

[0393] When a number is described alone or as part of a numerical range, it should be understood that the number can vary above and below the stated value by a deviation of up to + / - 10%.

[0394] When this document lists value ranges, it is intended to encompass all values ​​and subranges within that range. For example, "2.5 mg / kg to 10 mg / kg" is intended to encompass, for example, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 2.5 mg / kg to 3 mg / kg, 2.5 mg / kg to 4.5 mg / kg, 3 mg / kg to 4.5 mg / kg, 4.5 mg / kg to 8 mg / kg, 2.5 mg / kg to 9 mg / kg, etc.

[0395] As used herein, “corrected mean change from baseline” refers to the change in a biomarker value over time calculated using statistical analysis. In some embodiments, a linear mixed-effects model (MMRM) is used to account for at least one additional covariate to determine the corrected mean change from baseline.

[0396] As used herein, “baseline” refers to an initial measurement (e.g., a measurement of cognitive function, brain structure, amyloid load, and / or liquid biomarkers) acquired at a first or early time point and used for comparison over time to assess changes in measurement. Changes in measurement over time compared to baseline can be used to assess disease progression and / or the effectiveness of treatments for the disease.

[0397] Amyloid β 1-42 (Aβ42) refers to amyloid β monomers derived from amino acids 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 13). Amyloid β 1-40 (Aβ1-40) refers to amyloid β monomers derived from amino acids 1 to 40 of the full-length protein (Table 5, SEQ ID NO: 14).

[0398] P-tau181 (also known as p-Tau181 or p-tau181) is human tau protein phosphorylated at position 181 (threonine). NP-tau181 (also known as np-Tau181 or np-tau181) refers to human tau that is not phosphorylated at position 181 (threonine). P-Tau181 / NP-Tau181 (p-Tau181 / np-Tau181, p-tau181 / np-tau181, P-Tau181R, p-Tau181R, or p-tau181R) can refer to the ratio of phosphorylated tau at position 181 to unphosphorylated tau at position 181 (threonine).

[0399] P-tau217 (also known as p-Tau217 or p-tau217) is human tau protein with threonine phosphorylation at position 217. NP-Tau217 (also known as np-Tau217 or np-tau217) refers to human tau with threonine unphosphorylated at position 217. P-Tau217 / NP-Tau217 (also known as p-Tau217 / np-Tau217, p-tau217 / np-tau217, P-Tau217R, p-Tau217R, or p-tau217R) can refer to the ratio of tau protein with threonine phosphorylation at position 217 to tau protein with threonine unphosphorylated at position 217.

[0400] P-tau231 (also known as p-Tau231 or p-tau231) is human tau protein phosphorylated at position 231 (threonine). NP-Tau231 (also known as np-Tau 231 or np-tau231) refers to human tau that is not phosphorylated at position 231 (threonine). P-Tau231 / NP-Tau231 (also known as p-Tau231 / np-Tau231, p-tau231 / np-tau231, P-Tau231R, p-Tau231R, or p-tau231R) can refer to the ratio of phosphorylated tau at position 231 to unphosphorylated tau at position 231 (threonine).

[0401] As used in this article, total tau or t-tau is a measure of total tau in a sample (e.g., CSF sample, plasma sample, serum sample).

[0402] Patients with “preclinical AD” or “early AD” (also referred to as “subjects”) as described in this article are cognitively normal individuals with moderate or elevated levels of amyloid in the brain, and can be identified by the presence or absence of memory impairment and an asymptomatic phase of emerging episodic memory and executive function deficits. Such patients can be identified by one or more biomarkers. Cognitive normality can include individuals with a CDR of 0, or individuals with scores within the normal range on cognitive tests (MMSE, International Shopping List Task, Logical Memory, etc.). Preclinical AD occurs prior to significant irreversible neurodegeneration and cognitive impairment, and is typically characterized by the presence of in vivo molecular biomarkers of AD without clinical symptoms. Preclinical AD biomarkers that can indicate the future development of Alzheimer's disease include, but are not limited to, one or more of the following: intermediate or elevated amyloid levels in the brain (e.g., measured in percentiles of approximately 20-40, e.g., approximately 20-32) via positron emission tomography (PET) of amyloid, fluorodeoxyglucose (FDG), or tau; Aβ1-42 cerebrospinal fluid levels and / or the Aβ1-42 / 1-40 ratio; total tau cerebrospinal fluid levels; p-tau cerebrospinal fluid levels (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and / or tau phosphorylated at 231 (P-tau231), the P-tau181 / NP-tau181 ratio, and / or the P-tau217 / NP-tau217 ratio); and neurogranulin levels in the brain. Cerebrospinal fluid levels, cerebrospinal fluid levels of neurofilament light peptide (NfL), and blood biomarkers such as those measured in serum or plasma (e.g., levels of Aβ1-42, the ratio of the two forms of amyloid-β peptide (Aβ1-42 / 1-40 ratio, e.g., between about 0.092 and 0.094 or below about 0.092), plasma levels of total tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217) and / or tau phosphorylated at 231 (P-tau231)), P-tau181 / NP-tau181 ratio and / or P-tau217 / NP-tau217 ratio), glial fibrillary acidic protein (GFAP), and neurofilament light peptide (NfL)).For example, it has been found that subjects treated with elenbecestat (E2609), a β-amyloid precursor protein cleaving enzyme (BACE) inhibitor, showed the greatest reduction in cognitive decline during treatment, with baseline amyloid positron emission tomography (PET) uptake ratios (SUVr values) of 1.4 to 1.9. See Lynch, SY et al., “Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease,” poster p. 389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, it has been found that subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 did not exhibit detectable sufficient cognitive decline, while subjects with SUVr levels above 1.6 showed a plateau effect, where amyloid levels had reached saturation and treatment did not induce changes in cognitive measures. See Dhadda, S. et al., “Baseline florbetapir amyloid PET standard update value ratio (SUVr) can predict clinical progression in prodromal Alzheimer's disease (pAD)”, poster p4-291, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA.

[0403] As used herein, “early AD” or “early Alzheimer’s disease” refers to a range of AD severity from mild cognitive impairment to mild Alzheimer’s dementia with moderate probability of AD. Subjects with early AD include those with mild Alzheimer’s dementia as defined herein and those with mild cognitive impairment (MCI) with moderate probability of AD as defined herein. In some embodiments, subjects with early AD have an MMSE score of 22 to 30 and a total Clinical Dementia Rating Scale (CDR) score of 0.5 to 1.0. Other methods for detecting early-stage AD disease may employ the following specified tests and assays, including the following National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical guidelines for probable Alzheimer's dementia: McKhann, GM et al., “The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.” Alzheimer Dement. [Alzheimer's Disease and Dementia] 2011; 7:263-9. Other methods include CDR-SB, ADCOMS Composite Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, Modified iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, subjects with early AD have evidence of elevated or positive amyloid-beta protein load in the brain. In some embodiments, elevated or positive amyloid-beta protein load in the brain is indicated and / or confirmed by PET assessment. In some embodiments, elevated or positive amyloid-beta protein load in the brain is indicated and / or confirmed by CSF assessment of biomarkers such as Aβ1-42 (e.g., water-soluble CSF biomarker analysis). In some embodiments, elevated or positive amyloid-beta protein load in the brain is indicated and / or confirmed by measuring p-tau181 levels.In some embodiments, MRI assessment indicates and / or confirms elevated or positive amyloid burden in the brain. In some embodiments, retinal amyloid accumulation indicates elevated or positive amyloid burden in the brain. In some embodiments, more than one assessment method is used.

[0404] "Amyloid protein" refers to unbranched fibrous tissue, typically extracellular, that is present in the body; additionally, the fibrous tissue binds to the dye Congo red and then exhibits green birefringence when observed between orthogonal polarizers. Amyloid-forming proteins have been identified and associated with serious diseases, including amyloid β-peptide (Aβ) associated with Alzheimer's disease (AD), islet amyloid polypeptide (IAPP) associated with type 2 diabetes, and prion protein (PrP) associated with spongiform encephalopathy. As used herein, "amyloid protein," "brain amyloid," and "amyloid β-peptide (Aβ)" are used interchangeably.

[0405] In some embodiments, subjects have “elevated amyloid” or “moderate amyloid” levels. Those skilled in the art will recognize that amyloid levels from amyloid PET can be reported in “percentage units” (CL) using a percentage unit method. (Klunk WE et al., The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET. Alzheimer's Dement. 2015; 11:1-15 e1-4). The percentage unit method measures tracers in the range of 0 CL to 100 CL, where 0 is considered the anchor point and represents the mean of young, healthy controls, and 100 CL represents the mean amyloid load present in subjects with mild to moderate severity of dementia due to AD. (Ibid.) As those skilled in the art will recognize, percentage unit thresholds can be varied, for example, improved based on new or additional scientific information. (See, for example, http: / / www.gaain.org / centiloid-project.) Elevated amyloid levels can be set relative to a baseline threshold in healthy controls determined by methods known to those skilled in the art (POSA). For example, a percentage value of 32.5 can be used as the threshold for “elevated amyloid,” and a “moderate amyloid” level refers to Aβ amyloid PET in the range of 20–32.5 CL (e.g., 30 CL). In another example, a percentage value of 40 can be used as the threshold for “elevated amyloid,” and a “moderate amyloid” level refers to Aβ amyloid PET in the range of 20–40 CL.

[0406] As used in this article, subjects with “mild Alzheimer’s dementia” or “mild AD dementia” were those who met the following National Institute on Aging and Alzheimer’s Association (NIA-AA) core clinical guidelines for possible Alzheimer’s dementia: McKhann, GM et al., “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging - Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.” Alzheimer Dement. [Alzheimer’s Disease and Dementia] 2011; 7:263-9. This article also includes subjects with CDR scores of 0.5 to 1.0 and memory box scores of 0.5 or higher at screening and baseline, as well as subjects who showed score variations on the Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII).

[0407] As used herein, subjects with “MCI of moderate probability due to AD” are those identified according to the NIA-AA core clinical criteria for mild cognitive impairment of moderate probability due to Alzheimer’s disease (see McKhann, above). For example, subjects may be symptomatic but not demented, with amyloid pathology, resulting in lower heterogeneity from subjects with mild Alzheimer’s dementia and similarity in cognitive and functional decline, as measured by the ADCOMS composite clinical score as defined herein. Subjects with a CDR score of 0.5 and a memory box score of 0.5 or higher at screening and baseline are also included. Furthermore, subjects with a history of subjective memory decline and gradual onset and slow progression within the most recent year prior to screening, as confirmed by informed witnesses, are also included in this study. Memory decline and / or episodic memory impairment can be assessed by changes in scores on the Wechsler Memory Scale-Modified Logical Memory Subscale II (WMS-R LM II).

[0408] As used herein, “control subject,” “untreated AD subject,” or “untreated control subject” refers to a subject who has not received or has received treatment for Alzheimer’s disease. In some embodiments, the control subject has Alzheimer’s disease. In some embodiments, the control subject has early Alzheimer’s disease or pre-Alzheimer’s disease. In some embodiments, the control subject has Alzheimer’s disease and has not been treated with anti-Aβ proficiency antibodies.

[0409] The terms "patient" and "subject" are used interchangeably.

[0410] As used herein, “MMSE” refers to the Mini-Mental State Examination, a cognitive tool commonly used for screening purposes and also frequently used longitudinally in Alzheimer's disease (AD) clinical trials. It has a 30-point scale, where higher scores indicate lower levels of impairment and lower scores indicate higher levels of impairment, ranging from 0 (highest level of impairment) to 30 (no impairment). In some embodiments, seven items measuring time and place orientation, registration, recall, attention, language, and drawing may be assessed as part of the MMSE score. (Folstein, MF et al., “Mini-mental state. A practical method for grading the cognitive state of patients for the clinician.” J Psychiatr. Res. 1975; 12:189-98.) As used in this article, "ADAS-Cog" refers to the Alzheimer's Disease Assessment Scale-Cognitive. ADAS-Cog is a commonly used cognitive scale in Alzheimer's disease trials. It is a structural scale that evaluates memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming and comprehension), orientation, conceptual practice (placing a letter in an envelope), and constructive practice (copying geometric designs). (Rosen, WG et al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984; 141:1356-64.) It can also obtain ratings for spoken language, language comprehension, difficulty in recalling words, ability to remember test instructions, maze and number cancellation. In some embodiments, ADAS-Cog refers to the Alzheimer's Disease Assessment Scale-Cognitive subscale.14 (ADAS-Cog14). In some embodiments, a modified form may be used herein, and scores may range from 0 to 90, where 0 indicates no impairment and 90 indicates the highest level of impairment. In some embodiments, the ADAS-Cog14 task includes memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, conceptual practice (placing a letter in an envelope), construction practice (copying geometric designs), spoken language, language comprehension, difficulty recalling words, ability to remember test instructions, mazes, and number cancellation (Rosen et al., 1984).

[0411] As used in this article, “CDR-SB” refers to the Clinical Dementiarating - Sum of Boxes scale. The CDR is a clinical scale describing five degrees of impairment in performance across six functional categories: memory, orientation, judgment and problem-solving, group activities, family and hobbies, and personal care. (Berg, L. et al., “Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment.” Ann. Neurol. 1988; 23:477-84.) The sum of box scores provides a measure of variability, with each category having a maximum possible score of 3 points, and the total score is the sum of the scores for each category, resulting in a total possible score from 0 to 18, where a higher score indicates a higher degree of impairment.

[0412] As used herein, “CDR Total,” “Total CDR” score, and “Total Dementia Assessment CDR” score are used interchangeably. As used herein, the Total CDR score is an assessment of the degree of impairment obtained in each of the six functional categories of the six categories of the CDR scale, and is synthesized into a single total rating (range 0 to 3) for the dementia CDR score, where 0 represents no cognitive impairment, 0.5 represents mild cognitive impairment, and 1-3 represent mild, moderate, and severe dementia, respectively. The Total CDR score can be used as a clinical measure of the severity of dementia. In some embodiments, the Total CDR score can be used to determine whether a patient has progressed or maintained a stage of AD, for example, a higher score on subsequent evaluations indicates AD progression, while no change in score indicates no AD progression.

[0413] As used in this article, “ADCOMS” refers to the Alzheimer’s Disease Composite Score, which is based on a composite clinical score analyzed from the following: four ADAS-Cog items (delayed word recall, orientation, word recognition, and difficulty in calling words), two Mini-Mental State Examination (MMSE) items (time orientation and drawing), and all six CDR-SB items (personal care, group affairs, family and hobbies, memory, orientation, and judgment and problem-solving), as discussed in the example and in the following literature: Wang, J. et al., “ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials.” J Neurol. Neurosurg. Psychiatry. 2016;87:993-999. ADCOMS was developed to be particularly sensitive to disease progression during the early stages of AD (i.e., prodromal AD or early AD).

[0414] In some embodiments, ADCOMS can be calculated using the following formula: in , and These are the item scores at time t corresponding to items from ADAS-cog, reverse MMSE scores, and CDR-SB, respectively (Wang, J. et al., “ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials”). ADCOMS is particularly sensitive to disease progression in the early stages of AD, i.e., during prodromal and mild AD.

[0415] As used in this article, “ADCS MCI-ADL” refers to the Alzheimer’s Disease Collaborative Study – Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical scale used to assess a patient’s ability level in six basic activities of daily living. Further examples are discussed in Kreutzer JS, DeLuca J., Caplan B. (eds.) Encyclopedia of Clinical Neuropsychology, Springer, New York, NY.

[0416] As used in this article, "modified iADRS" or "iADRS" refers to a composite tool that combines scores from ADAS Cog14 (all items) and ADCSMCI-ADL (all items). Modified iADRS scores can be used to assess disease progression. Improved iADRS score = [-1(ADAS-cog14) +90] + ADCS MCI-ADL.

[0417] As used herein, “ApoE4 positive” subjects and “ApoE4 carriers” refer to subjects who possess the ε4 variant of the apolipoprotein E (APOE) gene. As used herein, APOE4 status refers to a subject’s status as a gene carrier. The ε4 variant is one of several major alleles of the apolipoprotein gene. This gene is generally responsible for lipid metabolism. It has been found that carriers of apolipoprotein ε4 exhibit significantly higher amyloid retention rates compared to non-carriers. (Drzezga, A. et al., “Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.” Neurology. 2009; 72:1487-94.) In some embodiments, the subjects treated herein were alloconjugated carriers of the apolipoprotein E ε4 gene allele. In some embodiments, the subject is an allotype-conjugating carrier of the apolipoprotein E ε4 gene allele. The terms “ApoE4 negative” and “ApoE4 non-carrier” are used interchangeably.

[0418] As used herein, whether an early AD subject is “amyloid-positive” or “amyloid-negative” can be determined based on whether the subject has a positive amyloid load. In some embodiments, a subject is identified as amyloid-positive or amyloid-negative as indicated by longitudinal positron emission tomography (PET) assessment of an imaging agent (e.g., an amyloid imaging agent or a tau imaging agent) taken up in the brain. In some embodiments, an evaluation by tau PET imaging determines whether a subject is amyloid-positive or amyloid-negative. In some embodiments, a subject is “amyloid-negative” if the flubipicillin amyloid PET SUVr negative is less than 1.17. In some embodiments, a subject is identified as amyloid-positive or amyloid-negative by evaluating the level of a biomarker (e.g., the Aβ42 / 40 ratio) in a sample from the subject, alone or in combination with another method (such as a PET measurement of brain amyloid). In some embodiments, a subject is “amyloid-negative” if the Aβ42 / 40 ratio in the sample is at or above 0.092–0.094, for example, at about 0.092. In some embodiments, a subject is considered “amyloid-negative” if the Aβ42 / 40 ratio in the sample is greater than 0.092. In some embodiments, the presence of amyloid pathology is assessed via CSF evaluation using a biomarker (such as p-tau181), alone or in combination with another method (such as PET measurement of brain amyloid), to determine whether a subject is amyloid-positive or amyloid-negative. In some embodiments, qualitative visual readings from PET scans may be used to determine amyloid-positive and amyloid-negative by categorizing subjects based on PET image patterns as having “normal” or “abnormal” uptake. The reader will be trained and calibrated to identify brain PET images with abnormal or normal uptake patterns, or amyloid will be detected using semi-quantitative or quantitative methods. In some embodiments, thresholds are set to quantitatively determine whether Aβ brain load indicates a subject is amyloid-positive or amyloid-negative from biomarkers (e.g., serum or CSF) and / or PET scans. In some embodiments, MRI is used to determine whether a subject is amyloid-positive or amyloid-negative. In some embodiments, retinal amyloid accumulation is used to determine whether a subject is amyloid-positive or amyloid-negative. In some embodiments, behavioral / cognitive phenotypes are used to determine whether a subject is amyloid-positive or amyloid-negative.

[0419] As those skilled in the art will understand, digital, computer, and / or conventional (e.g., pen and paper) cognitive tests can be used to detect early cognitive changes that may indicate mild cognitive impairment and / or the risk of developing dementia, and therefore can be used to identify subjects who require treatments as disclosed herein. For example, such tests can screen for cognitive impairment and can potentially identify individuals with MCI. Artificial intelligence can be used to analyze cognitive test results to determine whether a case of mild cognitive impairment will progress to Alzheimer's disease within a year. Early diagnosis before symptoms begin can help physicians identify subjects who require treatments as disclosed herein earlier, potentially delaying the onset of neurodegenerative diseases or reducing their severity.

[0420] As used herein, the term "treatment" means any administration or application of a therapeutic agent for a subject's disease or disorder, and includes suppressing the disease, slowing disease progression, delaying progression, preventing its development, reversing disease progression (e.g., reversing the accumulation of Aβ fibrils), preventing the onset or development of the disease, alleviating or improving one or more symptoms or one or more underlying conditions of the disease, curing the disease, improving one or more clinical indicators, or preventing the recurrence of one or more symptoms of the disease. In some embodiments, treatment of a subject's AD includes administration, for example, intravenous infusion of an anti-amyloid β (Aβ) primary fibrils antibody. In some embodiments, treatment of a subject's AD includes administration (e.g., intravenous infusion) of a therapeutically effective dose of an anti-amyloid β (Aβ) primary fibrils antibody.

[0421] As used herein, the term "infusion" refers to the active administration of one or more agents over a period of, for example, approximately 60 minutes. In some embodiments, the anti-amyloid β (Aβ) profibrillary antibody described herein is administered systematically to human subjects via infusion. In some embodiments, the anti-amyloid β (Aβ) profibrillary antibody may alternatively be administered to human subjects via subcutaneous injection, for example. In some embodiments, the subcutaneous injection is given once weekly. In some embodiments, the subcutaneous injection is given once every two weeks. In some embodiments, the anti-amyloid β (Aβ) profibrillary antibody is administered to human subjects via intravenous infusion.

[0422] In some embodiments, a maintenance dose is administered to the subject. As used herein, the term "maintenance dose" refers to the dose administered to the subject to maintain the desired therapeutic effect. In some embodiments, the maintenance dose is administered weekly, bi-weekly, monthly, bi-monthly, or bi-monthly (quarterly) or every 24 weeks (six-monthly or semi-annually). In some embodiments, the maintenance dose comprises anti-Aβ protoporphyrin antibody. In some embodiments, the maintenance dose is administered as an intravenous infusion. In some embodiments, the intravenous infusion is a 10 mg / kg dose of BAN2401 administered every two weeks. In some embodiments, the intravenous infusion is a 10 mg / kg dose of BAN2401 administered monthly. In some embodiments, the maintenance dose is administered subcutaneously, orally, or nasally. In some embodiments, the maintenance dose is administered subcutaneously.

[0423] In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a bi-weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarterly subcutaneous injection. In some embodiments, the maintenance dose is administered weekly or at a less frequent frequency, such as every two weeks, every four weeks, monthly, every six weeks, every eight weeks (2 months), every three months (quarterly), or every six months (half-yearly). In some embodiments, the maintenance dose is administered as a 720 mg subcutaneous injection every two weeks. In some embodiments, the maintenance dose is administered as a 720 mg subcutaneous injection every two weeks, comprising two simultaneous (e.g., sequential) injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous preparation.

[0424] In some embodiments, the maintenance dose is administered as a weekly 250 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly 250 mg subcutaneous injection comprising injecting 1.25 mL of a 400 mg / 2 mL subcutaneous formulation. In some embodiments, the maintenance dose is administered as a weekly 360 mg subcutaneous injection comprising a single injection of a 360 mg SC formulation. In some embodiments, the maintenance dose is administered subcutaneously from a self-injector.

[0425] In some embodiments, the maintenance dose is administered as a subcutaneous injection of 720 mg or 500 mg every two weeks. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 500 mg every two weeks, comprising two simultaneous (e.g., sequential) injections of 250 mg (e.g., 2 x 1.25 mL of 400 mg / 2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 500 mg every two weeks, comprising a single injection of 500 mg (e.g., 2.5 mL of 400 mg / 2 mL) SC formulation. In some embodiments, the maintenance dose is administered subcutaneously from a self-injector.

[0426] In some embodiments, the maintenance dose is administered once or multiple times. In some embodiments, the maintenance dose is administered at a lower dose than during an earlier treatment process, and / or at a lower frequency than during an earlier treatment process.

[0427] In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may indicate an increase in amyloid levels in the brain. In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may begin to deteriorate, such as an increase in the plasma Aβ42 / 40 ratio, indicating an increase in amyloid levels in the brain. In some embodiments, the Aβ42 / 40 ratio of subjects receiving a maintenance dose may decrease. In some embodiments, subjects receive a selected maintenance dose such that the subject's Aβ42 / 40 ratio may decrease, but the Aβ42 / 40 ratio may remain above an amyloid positivity threshold, for example, for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0428] In some embodiments, after switching to a maintenance dose, a subject's biomarker levels may begin to increase or the rate of increase may increase. In some embodiments, such subjects may be transferred back to a treatment regimen. In some embodiments, for example, if the increase remains below the tauPET level or the rate of increase observed in control subjects with AD but not receiving anti-Aβ protofibrillary antibodies, the subject may maintain the maintenance dose.

[0429] As used herein, the term “prevention” means obtaining a favorable or desired outcome, including but not limited to preventive benefits. For preventive benefits, the composition may be administered to subjects at risk of developing Alzheimer’s disease; to subjects with one or more preclinical symptoms that are not clinical symptoms of Alzheimer’s disease; or to subjects with one or more physical symptoms of Alzheimer’s disease reported, even though a clinical diagnosis of Alzheimer’s disease has not been performed. As used herein, “prevention” may further include therapeutic benefits, meaning the eradication or improvement of the latent condition being treated or one or more associated physical symptoms.

[0430] As used herein, the term “ARIA” refers to amyloid-associated imaging abnormalities, such as those evaluated using MRI. Unbound by theory, ARIA may result from the presence of amyloid in the walls of cerebral blood vessels, leading to cerebral amyloid angiopathy (CAA). Unbound by theory, most Alzheimer’s disease patients pathologically have CAA, but most do not exhibit radiographic manifestations (microbleeds) or clinical manifestations (intracranial hemorrhage or inflammatory CAA). Unbound by theory, removal of amyloid by monoclonal antibodies (e.g., anti-Aβ protofibrillary antibodies) may increase the risk of ARIA. In some embodiments, ARIA includes amyloid-associated imaging abnormality edema / effusion (ARIA-E). In some embodiments, ARIA includes amyloid-associated imaging abnormality hemorrhage (ARIA-H). In some embodiments, the severity of ARIA can be classified by radiographic imaging such as MRI. In some embodiments, the severity of ARIA can be classified as mild, moderate, or severe based on radiographic imaging (e.g., MRI). In some embodiments, a mild ARIA-E event includes FLAIR high signal intensity in a sulcus and / or cortical / subcortical white matter confined to a location <5 cm. In some embodiments, moderate ARIA-E includes FLAIR high signal intensity of 5 cm to 10 cm in terms of a single maximum size or more than one affected site (each affected site measured <10 cm). In some embodiments, a severe ARIA-E event includes FLAIR high signal intensity >10 cm and associated gyral swelling and sulcus obliteration, and one or more individual / isolated affected sites may be noted. In some embodiments, a mild ARIA-H microbleeding event includes ≤ 4 newly occurring microbleeds. In some embodiments, a moderate ARIA-H microbleeding event includes 5 to 9 newly occurring microbleeds. In some embodiments, a severe ARIA-H microbleeding event includes 10 or more newly occurring microbleeds. In some embodiments, a mild ARIA-H surface iron deposition event includes one lesion area with surface iron deposition. In some embodiments, a moderate ARIA-H surface iron deposition event includes two lesion areas with surface iron deposition. In some embodiments, severe ARIA-H surface iron deposition events include >2 areas of surface iron deposition. In some embodiments, ARIA-H may include intracranial hemorrhage >1 cm.

[0431] As used herein, the term “clinical decline” refers to a worsening of one or more clinical symptoms of AD. Methods for measuring clinical decline may employ the tests and assays specified herein. In some embodiments, clinical decline is determined by a worsening of ADCOMS. In some embodiments, clinical decline is determined by a worsening of MMSE. In some embodiments, clinical decline is determined by a worsening of ADAS-Cog. In some embodiments, clinical decline is determined by a worsening of FAQ. In some embodiments, clinical decline is determined by a worsening of CDR-SB. In some embodiments, clinical decline is determined by a worsening of Wechsler Memory Scale-IV Logical Memory (subscale) I and / or (subscale) II. In some embodiments, clinical decline is determined by a worsening of CDR scores. In some embodiments, clinical decline refers to a worsening of one or more biomarkers of AD or brain measurements such as brain atrophy and / or amyloid accumulation (e.g., by PET or MRI).

[0432] As used herein, the term "blood sample" or "blood" refers to a sample of blood, including serum and / or plasma from human subjects. In some embodiments, blood may be collected from subjects to evaluate potential biomarkers for AD, including amyloid fragments and isotypes, tau, and other protein biomarkers (e.g., NFL), in relation to AD diagnosis, amyloid or tau burden, or disease alterations. In some embodiments, subjects are required to fast before collection at weeks 96 and 216, if possible. In other embodiments and / or at other time points, fasting is not required. Levels of pre-AD biomarkers that may indicate the development of Alzheimer's disease include, but are not limited to, brain amyloid levels, cerebrospinal fluid Aβ1-42 levels, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranulin levels, and cerebrospinal fluid neurofilament light chain protein (NfL) levels.

[0433] 2. ARIA Measurement The disclosures and methods discussed in this article partially reveal the finding that the risk of amyloid-related imaging abnormalities (ARIA) induced by treatment with anti-Aβ protofibrillary antibodies (such as BAN2401) may depend on the concomitant use of other medications (such as anticoagulants or thrombolytics) or the presence of cerebral hemorrhage and brain status at baseline.

[0434] In some embodiments, amyloid-associated imaging abnormalities (ARIAs) can be measured using tools known in the art, and may include those described herein. In some embodiments, ARIAs are measured by MRI. In some embodiments, ARIAs are classified as ARIAs with edema (ARIA-E) or ARIAs with hemosiderin deposition (ARIA-H). In some embodiments, ARIA-E can be observed on MRI as cerebral edema or sulcal effusion. In some embodiments, ARIA-H can be observed on MRI as cerebral microbleeds or surface iron deposition.

[0435] In some embodiments, the patient's ARIA is monitored by radiographic imaging (e.g., MRI) prior to treatment, such as treatment with an anti-Aβ protoplasmic antibody, for example, treatment with BAN2401. In some embodiments, the patient's ARIA is monitored by radiographic imaging (e.g., MRI) at least once after treatment (e.g., treatment with an anti-Aβ protoplasmic antibody, for example, treatment with BAN2401). In some embodiments, the patient's ARIA is monitored by radiographic imaging (e.g., MRI) more than once after treatment (e.g., treatment with an anti-Aβ protoplasmic antibody, for example, treatment with BAN2401). In some embodiments, the patient's ARIA may be monitored at least once after treatment is discontinued. In some embodiments, the patient's ARIA is monitored at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment is discontinued.

[0436] In some embodiments, subjects with ARIA experience headache, confusion, and / or seizures, and these can be used to identify subjects with ARIA or to indicate further evaluation for ARIA. In some embodiments, ARIA is evaluated at specified intervals during treatment. In some embodiments, ARIA is evaluated when a subject experiences symptoms of ARIA. In some embodiments, the maximum serum concentration (Cmax) of anti-Aβ primary fibrillary antibody can be used as a predictor of ARIA-E risk. In some embodiments, the use of a subcutaneous formulation reduces the risk of ARIA-E (e.g., due to a lower Cmax) compared to intravenous administration.

[0437] In some embodiments, ARIA can be categorized based on the severity of clinical symptoms. For example, mild clinical symptom severity may be characterized by noticing discomfort but not affecting normal daily activities. Moderate clinical symptom severity may be characterized by discomfort sufficient to reduce or affect normal daily activities. Severe clinical symptoms may lead to loss of work capacity or the ability to perform normal daily activities.

[0438] In some embodiments, ARIA-E can be classified by radiographic severity, for example, based on the degree of signal abnormality on MRI. In some embodiments, radiographic severity depends on signal abnormality on T2-weighted / fluid attenuation inversion recovery (FLAIR) sequences. In some embodiments, radiographic severity in ARIA-E can be classified as mild if FLAIR high signal intensity replaces sulci and / or cortical / subcortical white matter confined to a location <5 cm. In some embodiments, radiographic severity in ARIA-E can be classified as moderate if FLAIR high signal intensity is 5 cm to 10 cm in a single maximum size or in more than one affected site (each affected site measured <10 cm). In some embodiments, radiographic severity in ARIA-E can be classified as severe if FLAIR high signal intensity is >10 cm and accompanied by associated gyral swelling and sulcus disappearance. One or more individual / isolated affected sites may be noted.

[0439] In some embodiments, ARIA-H can be classified by radiographic severity, for example by the number and / or size of microbleeds, and / or by the number and / or size of lesion areas with surface iron deposition. In some embodiments, if ≤ 4 new microbleeds are present, the radiographic severity of ARIA-H (microbleeds) can be classified as mild. In some embodiments, if 5 to 9 new microbleeds are present, the radiographic severity of ARIA-H (microbleeds) can be classified as moderate. In some embodiments, if 10 or more new microbleeds are present, the radiographic severity of ARIA-H (microbleeds) can be classified as severe.

[0440] In some embodiments, if one lesion area with surface iron deposition is present, the radiographic severity of ARIA-H (surface iron deposition) can be classified as mild. In some embodiments, if two lesion areas with surface iron deposition are present, the radiographic severity of ARIA-H (surface iron deposition) can be classified as moderate. In some embodiments, if more than two lesion areas with surface iron deposition are present, the radiographic severity of ARIA-H (surface iron deposition) can be classified as severe.

[0441] In some embodiments, if the severity of clinical symptoms and radiographic severity are mild, treatment with anti-Aβ protofibrillary antibodies, such as BAN2401, can continue. For example, for ARIA-E, if the severity of clinical symptoms is asymptomatic and the radiographic severity is mild, treatment can continue. In some embodiments, for ARIA-E, if the severity of clinical symptoms and radiographic severity are mild, treatment can continue based on clinical judgment. In some embodiments, for ARIA-E, if the severity of clinical symptoms is moderate or severe, treatment can be suspended. In some embodiments, for ARIA-E, if the radiographic severity is moderate or severe, treatment can be suspended. In some embodiments, treatment can be suspended until MRI shows radiographic regression and symptom (if present) resolution. Subsequent MRIs can be performed 2–4 months after initial ARIA identification to assess regression. In some embodiments, treatment can be resumed after radiographic stabilization and symptom (if present) resolution. In some embodiments, treatment can be permanently discontinued.

[0442] In some embodiments, for ARIA-H, treatment may continue if the clinical severity is asymptomatic and the radiographic severity is mild. In some embodiments, for ARIA-H, treatment may be suspended if the clinical severity is symptomatic, regardless of whether the radiographic severity is mild, moderate, or severe. In some embodiments, treatment may be suspended until MRI shows radiographic regression and symptoms (if present) have resolved. Subsequent MRIs may be performed 2–4 months after initial ARIA identification to assess regression. In some embodiments, treatment may be resumed after radiographic stabilization and symptom (if present) resolution. In some embodiments, treatment may be permanently discontinued.

[0443] 3. Measurement of cerebral hemorrhage The disclosures and methods discussed herein partially reveal the finding that the risk of cerebral hemorrhage (e.g., microbleeds, intracerebral hemorrhage) induced by treatment with anti-Aβ protofibrosis antibodies (such as BAN2401) may depend on the presence of cerebral hemorrhage at baseline and the patient's brain condition. In some embodiments, patients who had cerebral hemorrhage (e.g., intracerebral hemorrhage, microbleeds) at baseline had an increased risk of developing ARIA.

[0444] The incidence and size of intracerebral hemorrhage can be measured using tools known in the art and may include those described herein. In some embodiments, intracerebral hemorrhage is measured by MRI. In some embodiments, intracerebral hemorrhage is measured by the number of hemorrhages. In some embodiments, intracerebral hemorrhage is measured by the size of the hemorrhage. In some embodiments, microbleeds are intracerebral hemorrhages with a diameter less than 1 cm as measured by radiographic imaging. In some embodiments, intracerebral hemorrhage refers to intracerebral hemorrhages with a diameter greater than 1 cm as measured by radiographic imaging.

[0445] In some embodiments, the patient's brain hemorrhage is monitored by radiographic imaging (e.g., MRI) prior to treatment, such as treatment with an anti-Aβ protoplasmic antibody, for example, with BAN2401. In some embodiments, a steroid is administered to a patient who has microbleeds or intracerebral hemorrhage at baseline after treatment with an anti-Aβ protoplasmic antibody, such as BAN2401. In some embodiments, the patient's brain hemorrhage is monitored by radiographic imaging (e.g., MRI) at least once after treatment (e.g., treatment with an anti-Aβ protoplasmic antibody, for example, treatment with BAN2401). In some embodiments, the patient's brain hemorrhage is monitored by radiographic imaging (e.g., MRI) more than once after treatment (e.g., treatment with an anti-Aβ protoplasmic antibody, for example, treatment with BAN2401).

[0446] In some embodiments, patients may be monitored after one or more administrations of anti-Aβ protofibrillary antibody (e.g., BAN2401), such as after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations. In some embodiments, treatment may continue if the severity of clinical symptoms and radiographic severity is asymptomatic or mild. In some embodiments, for example, treatment may be paused and / or discontinued if the severity of clinical symptoms and / or radiographic severity is moderate or severe.

[0447] In some embodiments, patients are monitored for cerebral hemorrhage at least once after treatment is discontinued. In some embodiments, patients are monitored for cerebral hemorrhage at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment is discontinued. In some embodiments, patients with microbleeds or intracerebral hemorrhage at baseline are not treated with anti-Aβ profibrillary antibodies (such as BAN2401). In some embodiments, patients without microbleeds or intracerebral hemorrhage at baseline are treated with anti-Aβ profibrillary antibodies (such as BAN2401). In some embodiments, patients with microbleeds or intracerebral hemorrhage at baseline who receive anti-Aβ profibrillary antibodies (such as BAN2401) are monitored more frequently, for example, for ARIA, compared to patients without microbleeds or intracerebral hemorrhage at baseline. In some embodiments, patients with CAA at baseline are not treated with anti-Aβ profibrillary antibodies (such as BAN2401). In some embodiments, treatment is discontinued in patients who develop CAA.

[0448] 4. Measurement of brain white matter The baseline state of white matter in a patient's brain and changes in a subject's white matter can be measured using tools known in the art, and may include those described herein. In some embodiments, the patient's white matter is assessed by MRI. In some embodiments, the thickness of the patient's white matter is assessed by radiographic imaging (e.g., MRI) prior to treatment (e.g., treatment with anti-Aβ proficiency antibodies, such as BAN2401). In some embodiments, patients with changes in white matter compared to baseline (e.g., decreased white matter thickness) have an increased risk of ARIA when receiving treatment with anti-Aβ proficiency antibodies (e.g., BAN2401). In some embodiments, changes in the patient's white matter are monitored by radiographic imaging (e.g., MRI) at least once after treatment (e.g., treatment with anti-Aβ proficiency antibodies, such as BAN2401). In some embodiments, the patient's white matter is monitored by radiographic imaging (e.g., MRI) more than once after treatment, such as after treatment with anti-Aβ proficiency antibodies, such as after treatment with BAN2401.

[0449] In some embodiments, patients may be monitored after one or more administrations of anti-Aβ protofibrillary antibody (e.g., BAN2401), such as after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations. In some embodiments, treatment may continue if the severity of clinical symptoms and radiographic severity is asymptomatic or mild. In some embodiments, for example, treatment may be paused and / or discontinued if the severity of clinical symptoms and / or radiographic severity is moderate or severe.

[0450] In some embodiments, patients are monitored for white matter changes at least once after treatment is discontinued. In some embodiments, patients' white matter changes are monitored at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment is discontinued. In some embodiments, subjects with changes or reductions in white matter (e.g., as measured by brain imaging relative to baseline) are not selected to receive treatment with anti-Aβ primary fibrillary antibodies (e.g., BAN2401). In some embodiments, subjects who did not have a reduction in white matter prior to treatment (e.g., as measured by brain imaging) are selected to receive treatment with anti-Aβ primary fibrillary antibodies (e.g., BAN2401).

[0451] 5. Patient selection based on cerebral hemorrhage and / or white matter lesions. In some embodiments, a subject's baseline microbleed or intracerebral hemorrhage status may increase the risk of ARIA events, intracerebral hemorrhage, or microbleed events after administration of an anti-Aβ protofibrillary antibody (e.g., BAN2401). In some embodiments, a patient is selected to receive treatment with an anti-Aβ protofibrillary antibody (such as BAN2401) if the patient has not experienced or currently does not have an ARIA event and / or intracerebral hemorrhage or microbleed prior to treatment. In some embodiments, subjects who have experienced or currently have intracerebral hemorrhage or microbleed at baseline are not selected to receive treatment with an anti-Aβ protofibrillary antibody (e.g., BAN2401). In some embodiments, subjects exhibiting changes or reductions in white matter (e.g., as measured by brain imaging relative to baseline) are not selected to receive treatment with an anti-Aβ protofibrillary antibody (e.g., BAN2401). In some embodiments, subjects who do not exhibit white matter reduction (e.g., as measured by brain imaging) prior to treatment are selected to receive treatment with an anti-Aβ protofibrillary antibody (e.g., BAN2401).

[0452] In some embodiments, subjects who have experienced or are currently experiencing intracerebral hemorrhage or microbleeds at baseline are selected to receive treatment with anti-Aβ protofibrillary antibodies (e.g., BAN2401) and are monitored for ARIA events (e.g., more frequently than subjects who have not yet shown white matter reduction) throughout treatment. In some embodiments, subjects exhibiting changes or reductions in white matter (e.g., as measured by brain imaging relative to baseline) are selected to receive treatment with anti-Aβ protofibrillary antibodies (e.g., BAN2401) and are monitored for ARIA events (e.g., more frequently than subjects who have not yet shown white matter reduction) throughout treatment. In some embodiments, subjects exhibiting changes or reductions in white matter may be monitored before treatment with anti-Aβ protofibrillary antibodies (e.g., BAN2401) and before one or more infusions of anti-Aβ protofibrillary antibodies (e.g., before the fifth, seventh, and fourteenth infusions). In some embodiments, subjects may be continuously monitored during treatment.

[0453] 6. Other risk factors for ARIA In some embodiments, other factors may influence a subject's risk of ARIA when treated with an anti-Aβ proficiency antibody (e.g., BAN2401). Risk factors in subjects may be monitored before or during administration of the anti-Aβ proficiency antibody. In some embodiments, subjects found to have risk factors prior to treatment may be excluded or treated with an alternative therapy derived from an anti-Aβ proficiency antibody (such as BAN2401). In some embodiments, subjects with risk factors may begin treatment with an anti-Aβ proficiency antibody (e.g., BAN2401), but may be monitored for ARIA more frequently, for example, during treatment than subjects without risk factors. In some embodiments, ARIA may be monitored by radiographic imaging of the subject's brain (e.g., via MRI). In some embodiments, treatment may be discontinued if a subject is found to have developed ARIA. In some embodiments, subjects without pre-existing risk factors may be selected for treatment with an anti-Aβ proficiency antibody (e.g., BAN2401).

[0454] In some embodiments, subjects who are carriers of the ApoE4 allele may have an increased risk of ARIA during treatment with an anti-Aβ protoplasmic antibody (e.g., BAN2401). Therefore, in some embodiments, a subject's ApoE4 status is assessed by DNA testing of a bodily sample (such as blood or a buccal swab) prior to treatment (e.g., treatment with an anti-Aβ protoplasmic antibody, such as BAN2401). In some embodiments, subjects who are carriers of the ApoE4 allele (e.g., for heterozygous or homozygous ApoE4 alleles) may not receive treatment with an anti-Aβ protoplasmic antibody (such as BAN2401). In some embodiments, subjects who are carriers of the ApoE4 allele (e.g., for heterozygous or homozygous ApoE4 alleles) may begin treatment with an anti-Aβ protoplasmic antibody (e.g., BAN2401) but may be monitored for ARIA more frequently during treatment than subjects who are not carriers of the ApoE4 allele. In some embodiments, treatment may be discontinued if a subject who is a carrier of the ApoE4 allele (e.g., for heterozygous or homozygous ApoE4 alleles) is found to develop ARIA. In some embodiments, subjects who are not carriers of the ApoE4 allele (e.g., heterozygous or homozygous ApoE4 alleles) are selected to be treated with an anti-Aβ protofibrillary antibody (e.g., BAN2401).

[0455] In some embodiments, subjects with higher hypertension (also referred to as higher mean arterial pressure) compared to controls (e.g., blood pressure of healthy subjects or threshold blood pressure measurements based on population averages) (e.g., before and / or during treatment) may have an increased risk of ARIA when receiving treatment with anti-Aβ proximal fibrillation antibodies (e.g., with BAN2401). In some embodiments, the subject's mean arterial blood pressure is assessed prior to treatment (e.g., treatment with anti-Aβ proximal fibrillation antibodies, such as with BAN2401), for example, by auscultation, by measuring blood flow oscillations and calculating blood flow, or by measuring blood pressure with an invasive probe inserted directly into the lumen of the artery. In some embodiments, subjects with higher mean arterial pressure compared to controls (e.g., healthy subjects) may not receive treatment with anti-Aβ proximal fibrillation antibodies (such as BAN2401). In some embodiments, high mean arterial pressure may be 130-139 mmHg / 80-89 mmHg or higher. In some embodiments, high mean arterial pressure may be 140 mmHg / 90 mmHg or higher. In some embodiments, a high mean arterial pressure (MAP) may be 180 mmHg / 120 mmHg or higher. In some embodiments, subjects with a higher MAP compared to controls may begin treatment with an anti-Aβ primary fibrillary antibody (e.g., BAN2401), but may be monitored for ARIA more frequently during treatment than subjects without a higher MAP compared to controls. In some embodiments, treatment may be discontinued if a subject experiences an increase in blood pressure during treatment and / or if a subject with a higher MAP is found to develop ARIA. In some embodiments, subjects with a normal MAP are selected to receive anti-Aβ primary fibrillary antibody (e.g., BAN2401) treatment.

[0456] In some embodiments, subjects with a higher amyloid load compared to controls (e.g., healthy subjects) (e.g., as determined by amyloid PET or by fluid biomarkers such as the Aβ 42 / 40 ratio, measured before and / or during treatment) may have an increased risk of ARIA when treated with anti-Aβ protofibrillary antibodies (e.g., with BAN2401). In some embodiments, the subject's amyloid load is assessed prior to treatment (e.g., treatment with anti-Aβ protofibrillary antibodies, such as with BAN2401), for example, by PET imaging against amyloid PET or by detecting fluid biomarkers such as the Aβ 42 / 40 ratio. In some embodiments, subjects with a higher amyloid load compared to controls (e.g., healthy subjects) may not require treatment with anti-Aβ protofibrillary antibodies (such as BAN2401). In some embodiments, subjects with a higher amyloid burden compared to controls may initiate treatment with an anti-Aβ primary fibrillary antibody (e.g., BAN2401), but may be monitored for ARIA more frequently during treatment than subjects without a higher amyloid burden compared to controls. In some embodiments, treatment may be discontinued if a subject develops a higher amyloid burden and / or if a subject with a higher amyloid burden is found to develop ARIA. In some embodiments, subjects with a low amyloid burden are selected to receive anti-Aβ primary fibrillary antibody (e.g., BAN2401) treatment.

[0457] In some embodiments, subjects with cortical surface iron deposition (e.g., before and / or during treatment) may have an increased risk of ARIA-E when treated with anti-Aβ protofibrillary antibodies (e.g., with BAN2401). In some embodiments, the subject's brain may be scanned, for example, by imaging (e.g., by MRI), to assess surface iron deposition before treatment (e.g., treatment with anti-Aβ protofibrillary antibodies, such as BAN2401). In some embodiments, subjects with cortical surface iron deposition may not be treated with anti-Aβ protofibrillary antibodies (e.g., BAN2401). In some embodiments, subjects with cortical surface iron deposition may begin treatment with anti-Aβ protofibrillary antibodies (e.g., BAN2401) but may be monitored for ARIA more frequently during treatment than subjects without cortical surface iron deposition. In some embodiments, treatment may be discontinued if a subject develops cortical surface iron deposition and / or if a subject with cortical surface iron deposition is found to develop ARIA-E. In some embodiments, subjects without cortical surface iron deposition are selected to be treated with an anti-Aβ protofibrillary antibody (e.g., BAN2401).

[0458] 7. The use of steroids in the treatment of severe ARIA In some embodiments, patients at increased risk of intracerebral hemorrhage or microbleeding events and / or ARIA are given steroids before and / or during treatment with an anti-Aβ proximal fibrillary antibody (such as BAN2401). In some embodiments, steroids are administered to patients who exhibit severe ARIA during treatment with an anti-Aβ proximal fibrillary antibody (e.g., BAN2401). Steroid treatment can be administered via any known route, such as intravenous and / or oral. Steroid dosage and regimen can be performed according to methods known in the art. In some embodiments, patients with severe radiographic or symptomatic ARIA-E are given steroids at doses and / or frequencies consistent with standards of care known to those skilled in the art.

[0459] 8. Use with anticoagulants, antiplatelet agents, and thrombolytic agents. Unbound by conventional wisdom, it has been unexpectedly found that patients concurrently administered certain anticoagulants or thrombolytic agents may have an equal or reduced risk of ARIA events, cerebral hemorrhage, or microbleeds compared to subjects administered only anti-Aβ protofibrillary antibodies (such as BAN2401). Similarly, unbound by conventional wisdom, some patients using certain anticoagulants or thrombolytic agents may experience improved treatment outcomes when administered anti-Aβ protofibrillary antibodies (such as BAN2401).

[0460] In some embodiments, subjects with Alzheimer's disease (AD) or early AD are treated with an anticoagulant or thrombolytic agent (e.g., aspirin, antiplatelet, anticoagulant, fibrinolytic, tissue plasminogen activator). As used herein, thrombolytic agents and antithrombotic agents are used interchangeably. In some embodiments, the thrombolytic agent is aspirin. In some embodiments, the thrombolytic agent is an antiplatelet drug. In some embodiments, the thrombolytic agent is an anticoagulant. In some embodiments, the thrombolytic agent is fibrinolytic. In some embodiments, the thrombolytic agent is a tissue plasminogen activator. In some embodiments, subjects treated with anticoagulants are given an anti-Aβ profibrinolytic antibody (e.g., BAN2401). In some embodiments, subjects treated with anticoagulants and given an anti-Aβ profibrinolytic antibody (e.g., BAN2401) have an equal or reduced risk of ARIA events or intracerebral hemorrhage compared to subjects given only an anti-Aβ profibrinolytic antibody (e.g., BAN2401). In some embodiments, an anti-Aβ protoplasmic antibody (e.g., BAN2401) is administered to a subject treated with an antiplatelet drug. In some embodiments, subjects treated with an antiplatelet drug and administered an anti-Aβ protoplasmic antibody (e.g., BAN2401) have an equal or reduced risk of ARIA events or intracerebral hemorrhage compared to subjects administered only an anti-Aβ protoplasmic antibody (e.g., BAN2401). In some embodiments, an anti-Aβ protoplasmic antibody (e.g., BAN2401) is administered to a subject treated with aspirin. In some embodiments, subjects treated with aspirin and administered an anti-Aβ protoplasmic antibody (e.g., BAN2401) have an equal or reduced risk of ARIA events or intracerebral hemorrhage compared to subjects administered only an anti-Aβ protoplasmic antibody (e.g., BAN2401). In some embodiments, no anticoagulant or thrombolytic agent is administered to a subject receiving an anti-Aβ protoplasmic antibody (e.g., BAN2401). In some embodiments, subjects treated with anticoagulants or thrombolytic agents are not selected for treatment with anti-Aβ profibrillary antibodies (e.g., BAN2401). In some embodiments, patients receiving anti-Aβ profibrillary antibodies (e.g., BAN2401) are not given tissue plasminogen activator. In some embodiments, subjects treated with tissue plasminogen activator are not selected for treatment with anti-Aβ profibrillary antibodies (e.g., BAN2401). In some embodiments, anti-Aβ profibrillary antibodies (e.g., BAN2401) are administered to patients treated with tissue plasminogen activator, with additional monitoring for ARIA. In some embodiments, ARIA events are monitored in patients receiving anti-Aβ profibrillary antibodies (e.g., BAN2401) and also receiving anticoagulants or thrombolytic agents.In some embodiments, patients receiving anti-Aβ protoplasmic antibodies (such as BAN2401) and also receiving anticoagulants or thrombolytic agents will discontinue anti-Aβ protoplasmic antibodies until treatment with anticoagulants or thrombolytic agents is discontinued.

[0461] In some embodiments, the subject's brain may be monitored (e.g., via MRI) at any time during treatment with an anti-Aβ protofibrillary antibody (e.g., BAN2401). For example, additional monitoring may be performed when the subject has factors indicating an increased risk of cerebral hemorrhage, such as a subject receiving anticoagulant therapy. In some embodiments, subjects administering steroids may be further monitored, for example, via MRI.

[0462] 9. Select patients based on biomarkers and monitor changes in the treatment protocol. a. Measurement of Tau PET The disclosures and methods discussed herein partially reveal the finding that biomarkers, such as tau PET levels, can be used to select patients for treatment to allow for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ primary fibrillary antibodies, alone or in combination with other biomarkers. Treatment containing anti-Aβ primary fibrillary antibodies, such as BAN2401, can reduce the rate of tau accumulation in brain regions, such as the temporal region, as measured by tau PET levels (e.g., as measured by tau PET imaging), compared to control patients. In some embodiments, this is associated with reduced amyloid load in the subject's brain and improved cognitive outcomes. Without being bound by theory, tau PET levels (e.g., the tau PET standard uptake ratio (SUVr)) can be used in various embodiments as a less invasive and / or supplemental biomarker to improve the measurement of treatment efficacy and / or to allow for monitoring and treatment decisions. Such decisions may include whether to increase or decrease the amount of anti-Aβ protofibrillary antibody administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, and / or whether to discontinue treatment with anti-Aβ protofibrillary antibody.

[0463] As used herein, the term “tau PET” refers to tau positron emission tomography imaging. In some embodiments, tau PET imaging (also known as PET scans) is performed to evaluate tau pathology. In some embodiments, tau PET is evaluated with a PET tracer and the same tracer is used in subsequent evaluations. In some embodiments, PET imaging uses the [18F]MK-6240 tracer.

[0464] Tau positron emission tomography (PET) imaging can be used to confirm the presence of tau pathology in the brains of early-stage AD subjects during the screening phase of a study, and / or to evaluate the effect of at least one anti-Aβ protofibrillary antibody on amyloid levels in the brain, both through whole-brain analysis (e.g., average of 5-6 cortical regions) and brain region analysis (e.g., in the temporal region). In some embodiments, PET scans use [18F]MK-6240 (florquinitau) tracer. In some embodiments, tau load can be determined by visual readings of PET imaging uptake (e.g., by a trained radiologist). In embodiments, brain regions are assessed for uptake of the imaging agent. In some embodiments, tau PET levels in the temporal region are assessed. In some embodiments, tau PET levels in the frontal region are assessed. In some embodiments, tau PET levels in the parietal region are assessed. In some embodiments, tau PET levels in the occipital region are assessed. In some embodiments, tau PET levels in the cingulate gyrus are assessed. In some embodiments, the temporal region includes the medial temporal region. In some embodiments, the medial temporal region includes the hippocampus, entorhinal cortex, parahippocampal gyrus, and / or anteromedial / lateral temporal lobe. In some embodiments, the temporal region includes the posterior temporal region. In some embodiments, the posterior temporal region includes the amygdala, entorhinal cortex, parahippocampal gyrus, middle / medial and posterior temporal lobes, and / or the fusiform cortex. In some embodiments, the temporal region includes the temporal lobe. In some embodiments, the temporal lobe includes the superior anterior / posterior temporal lobe, middle / inferior temporal lobe, posterior temporal lobe, and / or the fusiform cortex. In some embodiments, tau PET levels of the entire cortical gray matter are assessed. In some embodiments, the reference region for assessing tau PET levels is the ventral cerebellum (Cb).

[0465] In some embodiments, “tau PET level” can be identified by the standard uptake ratio (SUVr) compared to a reference region measured by tau PET imaging. As used herein, “tau PET level,” “tau level in the brain,” and “tau load” are used interchangeably. As used herein, tau PET level refers to a measurement of tau levels in a brain region (e.g., the temporal region) via PET. Methods for calculating tau PET SUVr are known in the art and may include those described herein. In some embodiments, the standard uptake ratio quantification analysis of amyloid levels is performed using PMOD PNEURO BiomedicalImage Quantification software (PMOD Technologies, Zurich, Switzerland). In some embodiments, object motion in the PET images in the X, Y, and Z planes is first assessed, and motion correction is performed, if necessary, before averaging individual images (e.g., 5-minute radiographic frames) using, for example, the PMOD averaging function (averaging PET frames to increase the signal-to-noise ratio). In some embodiments, a corresponding MRI from the subject is prepared (e.g., using matrix size reduction processing, cropping the MRI to include only the brain, segmenting the image into binary maps of gray matter, white matter, and CSF, and stripping the skull image to leave only the brain mask). In some embodiments, the averaged PET image and the prepared MRI are matched using a PMOD matching function to place the images in the same orientation. In some embodiments, an averaged PET is generated using, for example, a brain normalization function provided by PMOD software, along with a brain normalization and rigid matching transformation matrix. In some embodiments, this averaged PET is normalized to the MNInst space (Senjem et al., 2005), which is the same orientation as the segmented MRI of the subject, for quantitative analysis. In some embodiments, a PMOD masking function is used to mask the brain and zero out the image outside the mask to create normalized gray matter PET and normalized white matter PET. Standard uptake values ​​(SUVs) for all gray matter mapping regions and three white matter regions (pons, cerebellar white matter, and subcortical white matter) can be calculated using PMOD software, using normalized PET, subject weight, and the injected dose of tracer to achieve units of SUV. In some embodiments, SUVr is the ratio of the overall cortical mean to a selected reference region. In some embodiments, the whole cerebellar mask is used as the reference region. In some embodiments, the reference region is the subcortical white matter, the ventral cerebellum, the derived whole cerebellum, the whole cerebellum modified by the subcortical white matter, the cerebellar gray matter, and a composite reference region consisting of the cerebellar cortex, the pontine subcortical white matter, and the cerebellar white matter.

[0466] In some embodiments, the adjusted mean change relative to baseline is measured at least once before treatment and after treatment initiation (e.g., over a period of at least 6 months after the initial dose of treatment). In some embodiments, the adjusted mean change relative to baseline is measured over a period of at least 12 months after the initial dose of treatment. In some embodiments, the adjusted mean change relative to baseline is measured over a period of at least 13 months after the initial dose of treatment. In some embodiments, the adjusted mean change relative to baseline is measured over a period of at least 18 months after the initial dose of treatment. In some embodiments, the adjusted mean change of the subject's tau PET SUVr value relative to baseline is less than 0.15 after administration of the first dose of the composition. In some embodiments, the adjusted mean change of the subject's tau PET SUVr value relative to baseline is less than 0.10 after administration of the first dose of the composition. In some embodiments, the adjusted mean change of the subject's tau PET SUVr value relative to baseline is less than 0.05 after administration of the first dose of the composition. In some embodiments, the adjusted mean change of the subject's tau PET SUVr value relative to baseline is less than 0.15 after 13 months following the initial dose of treatment. In some embodiments, after administration of the first dose of the composition, the adjusted mean change in the subject's tau PET SUVr value relative to baseline is less than 0.05. In some embodiments, 18 months after the initial dose of treatment, the adjusted mean change in the subject's tau PET SUVr value relative to baseline is less than 0.15.

[0467] Other methods for measuring tau via positron emission tomography (PET) are known in the art. These methods may include tau measurement. IQ Algorithm (see, for example, Whittington et al., J. Nucl Med. [Journal of Nuclear Medicine] 2021 Sep 1;62(9):1292-1300 for understanding quantitative measurements of tau PET radiotracers).

[0468] Measurements of tau PET levels can be used alone or in conjunction with one or more additional criteria, such as one or more measurements in biological fluids (e.g., the ratio of tau181 and / or Aβ1-42 to Aβ1-40), PET measurements of Aβ (e.g., via radiotracer uptake), MRI assessment of Aβ plaques, and / or behavioral measurements, as discussed herein, to evaluate treatment efficacy. Such measurements can also be used to diagnose patients eligible for treatment (e.g., by measuring tau PET levels alone or in conjunction with one or more additional AD pathological markers in the subject, and determining the subject's suitability for treatment due to higher tau PET levels than observed in healthy control subjects). In some embodiments, a subject is selected for treatment due to high tau PET levels in a brain region (where tau PET levels are higher than in subjects without AD). In some embodiments, a subject is selected for treatment due to high tau PET levels in the temporal region of the brain, where tau PET levels are greater than 1.4 as measured by amyloid PET SUVr. In some embodiments, a subject is selected for treatment due to a high tau PET level in the temporal region of the brain, wherein the tau PET level is greater than 1.5 as measured by amyloid PET SUVr. In some embodiments, the measurement of tau PET level may be used in place of another method for measuring brain tau level and / or another biomarker in place of Aβ. In some embodiments, the measurement of tau PET level may be used in conjunction with the measurement of one or more additional biomarkers. In some embodiments, patients may be monitored by one or more additional biomarkers, such as, but not limited to: (a) tau detected by PET scan from visual readings or semi-qualitative thresholds (SUVr or percentage units); (b) total tau (t-tau) in cerebrospinal fluid (CSF); and / or (c) blood biomarkers such as total plasma tau (T-tau) and / or phosphorylated tau (P-tau) (e.g., p-tau181)). In some embodiments, a patient's tau PET level can be monitored in combination with one or more of the ratio of Aβ1-42 to Aβ1-40 in a fluid sample (e.g., a blood sample) and / or a p-tau181 measurement. In some embodiments, this combination includes serum or plasma GFAP measurements. In some embodiments, measurements of tau PET levels can be used instead of another method for measuring brain tau levels to determine treatment efficacy and / or make treatment decisions, such as whether to continue treatment, switch to a maintenance dose, etc.

[0469] In some embodiments, tau PET levels can be used to calculate the relative change with respect to a baseline measurement (e.g., a measurement of tau PET levels before the start of treatment). In some embodiments, tau PET level measurements can be repeated after the start of a treatment regimen to monitor treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05-0.1 in a brain region over a 13-month period indicates treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05-0.1 in a brain region over an 18-month period indicates treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05-0.1 in the temporal region of the brain over a 13-month period indicates treatment efficacy. In some embodiments, an increase in tau PET levels of no more than 0.05-0.1 in the temporal region of the brain over an 18-month period indicates treatment efficacy.

[0470] In some embodiments, the rate of change of tau PET levels is calculated based on two measurements of the subject. In some embodiments, the rate of change of tau PET levels is calculated based on more than two measurements of the subject. In some embodiments, the rate of change of tau PET levels indicates the rate of tau accumulation in the subject's brain.

[0471] In some embodiments, the rate of change of tau PET levels is calculated based on at least two measurements of the subject, wherein one measurement is performed from the subject before treatment and the second measurement is performed after treatment, wherein treatment continues for at least 13 or 18 months after the initial dose of treatment. In some embodiments, the rate of change of tau PET levels is compared to the rate of change of tau PET levels in untreated control subjects with AD who have not received treatment. In some embodiments, a lower rate of increase in tau PET relative to untreated control subjects indicates treatment efficacy. In some embodiments, a lower rate of increase in tau PET relative to untreated control subjects over a 6-month time period indicates treatment efficacy. In some embodiments, a lower rate of increase in tau PET relative to untreated control subjects over a 12-month time period indicates treatment efficacy. In some embodiments, a lower rate of increase in tau PET relative to untreated control subjects over a 13-month time period indicates treatment efficacy. In some embodiments, a lower rate of increase in tau PET relative to untreated control subjects over an 18-month time period indicates treatment efficacy.

[0472] Methods for measuring clinical efficacy or monitoring treatment may employ a set threshold to determine changes in brain tau levels, for example, to identify patients suitable for treatment, such as with anti-Aβ primary fibrillary antibodies, or to determine whether to continue treatment, switch to a maintenance dose, or conclude that a patient is amyloid-negative. In some embodiments, the tauPET level threshold may be evaluated in conjunction with another measurement of brain amyloid load, such as amyloid PET scans, CSF, or serum or plasma biomarkers, to help determine whether a subject is suitable for treatment or to continue treatment. In some embodiments, tauPET levels may be used instead of another method for measuring brain tau levels. In some embodiments, tau PET levels greater than a threshold level are used to determine whether a patient is suitable for treatment. In some embodiments, the tau PET level threshold is about 1.4. In some embodiments, the tau PET level threshold is about 1.5. In some embodiments, subjects are selected for treatment with anti-amyloid β (Aβ) primary fibrillary antibodies, wherein the subject has a tau PET level greater than about 1.4 in the brain region. In some embodiments, the selected subject is treated with an anti-amyloid beta (Aβ) primary fibrillary antibody, wherein the subject has a tau PET level greater than about 1.5 in the brain region. In some embodiments, the brain region is the temporal region. In some embodiments, the brain region is the temporal lobe. In some embodiments, the brain region is the posterior temporal lobe. In some embodiments, the brain region is the medial temporal lobe.

[0473] b. Measurement of the Aβ42 / 40 ratio The disclosures and methods discussed in this article are partly based on the findings that biomarkers (e.g., the Aβ42 / 40 ratio) can be used to select patients for treatment to allow for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ primary fibrillary antibodies, alone or in combination with other biomarkers. Aβ42 and 40 are measured to calculate the ratio in blood samples, as disclosed in PCT / US2022 / 073576, which is incorporated herein by reference. Treatment containing anti-Aβ primary fibrillary antibodies such as BAN2401 can increase the Aβ42 / 40 ratio in subjects associated with reduced brain amyloid load and improved cognitive outcomes.

[0474] Methods for measuring the Aβ42 / 40 ratio are known in the art, such as determinations using LC MS / MS. Methods may include measuring Aβ42 and Aβ40 in a sample to calculate the ratio using PrecivityAD. TMAssay methods (see, for example, Kirmess et al., J. Clinica Chimica Acta [Journal of Clinical Chemistry] 519: 267-275 (2021)) and Sysmex assay (https: / / www.eisai.com / news / 2019 / news201990.html).

[0475] Measurements of the Aβ42 / 40 ratio can be used alone or in combination with one or more additional criteria, such as tau PET levels, PET measurements of Aβ radiotracer uptake, MRI evaluation of Aβ plaques, and / or behavioral measurements, to evaluate treatment efficacy, as discussed herein. Such determinations can also be used to diagnose patients eligible for treatment (e.g., determining a subject's suitability for treatment by measuring the Aβ42 / 40 ratio and finding it to be lower than that observed in healthy controls, alone or in combination with measurements of one or more other AD pathological markers). In some embodiments, measurements of the Aβ42 / 40 ratio can be used instead of other methods of measuring brain amyloid levels, such as PET scans used to determine a subject's suitability for treatment. In some embodiments, measurements of the Aβ42 / 40 ratio can be used instead of other methods of measuring brain amyloid levels, such as PET scans used to determine treatment efficacy and / or make treatment decisions (such as whether to continue treatment, switch to a maintenance dose, etc.).

[0476] In some embodiments, the Aβ42 / 40 ratio measurement may employ a relative change relative to a baseline measurement. In some embodiments, the Aβ42 / 40 ratio measurement may employ a set threshold to determine changes in brain amyloid levels, for example, to identify patients suitable for treatment, such as with anti-Aβ protofibrillary antibodies, or to determine whether to continue treatment, or to determine whether to switch to a maintenance dose, or to conclude that the patient is amyloid-negative. In some embodiments, the threshold may be evaluated in conjunction with another measurement of brain amyloid load, such as a PET scan, to help determine whether a subject is suitable for treatment or to continue treatment. In some embodiments, the Aβ42 / 40 ratio threshold may be used instead of another method of measuring brain amyloid levels, such as a PET scan, to determine amyloid positivity. In some embodiments, the Aβ42 / 40 ratio threshold is equal to or about 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.099, or 0.1. In some embodiments, the threshold is about 0.092. In some embodiments, the threshold is 0.092. In some embodiments, the threshold is approximately 0.094. In some embodiments, a decrease in the Aβ42 / 40 ratio below the threshold may indicate the need to continue treatment or to choose an increased dosing regimen. In some embodiments, an increase in the Aβ42 / 40 ratio above the threshold may be used to indicate that treatment may be terminated (e.g., terminated to support a maintenance regimen) and / or otherwise determine a reduction or discontinuation of the dosing regimen. In some embodiments, a decrease in the Aβ42 / 40 ratio below the threshold may be used to determine, for example, whether to discontinue a maintenance dosing regimen and revert to a previous treatment regimen.

[0477] c. Measurement of p-tau levels The disclosures and methods discussed herein depend in part on the finding that biomarkers (such as p-tau levels) can be used to select patients for treatment to allow for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody being administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ protofibrillary antibodies in combination with other biomarkers (such as phosphorylated tau (p-tau) levels, including tau phosphorylated at 181 (P-tau181), tau phosphorylated at 217 (P-tau217), and / or tau phosphorylated at 231 (P-tau231), and / or the P-tau181 / NP-tau181 ratio, and / or the P-tau217 / NP-tau217 ratio). p-tau levels can be measured in CSF, serum, or plasma, as disclosed in PCT / US2022 / 079571, which is incorporated herein by reference. Treatment containing anti-Aβ protofibrillary antibodies such as BAN2401 resulted in reduced p-tau181 levels in subjects, which are associated with reduced brain amyloid burden and improved cognitive outcomes.

[0478] Methods for measuring the p-tau ratio are known in the art, such as immunoassay-based methods (e.g., Quanterix™ Simoa). ® The techniques used include p-tau assays and / or mass spectrometry (IP / LC-MS / MS). As determined by the Braak stage (I-II), plasma p-tau181 is elevated in the early stages of AD and continues to rise as the disease progresses to Braak stages V-VI (Janelidze et al., “Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia”). Nat. Med.[Nature Medicine], 26(3):379-386 (2020). This biomarker is highly correlated with amyloid PET and TauPET and has been shown to be 3.5-fold higher in AD compared to controls, with a moderate increase in the MCI group, and also appears to differentiate patients clinically diagnosed with AD from other tau protein lesions (Thijssen et al., “Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobardegeneration”). Nat. Med [Natural Medicine], 26(3):387-397 (2020); Janelidze et al.).

[0479] Measurements of p-tau levels (e.g., p-tau181, p-tau217, and / or p-tau231, and / or the p-tau181 / np-tau181 ratio, and / or the p-tau217 / np-tau217 ratio) may be used alone or in combination with one or more additional criteria (such as tau PET levels, PET measurements of Aβ radiotracer uptake, MRI evaluation of Aβ plaques, and / or behavioral measurements) to evaluate treatment efficacy, as discussed herein. Such assays can also be used to diagnose patients who meet treatment criteria (e.g., by measuring p-tau levels (e.g., p-tau181 levels, p-tau217 levels, and / or p-tau231 levels, and / or the p-tau181 / np-tau181 ratio, and / or the p-tau217 / np-tau217 ratio) and determining whether a subject is suitable for treatment, either alone or in combination with measurements of one or more additional AD pathological markers, because the levels are higher than those observed in healthy control subjects). In some embodiments, measurements of p-tau levels (e.g., p-tau181 levels, p-tau217 levels, and / or p-tau231 levels, and / or the p-tau181 / np-tau181 ratio, and / or the p-tau217 / np-tau217 ratio) can be used instead of another method for measuring brain amyloid levels (such as PET scans used to determine whether a subject is suitable for treatment). In some embodiments, measurements of p-tau levels (e.g., p-tau181 levels, p-tau217 levels, and / or p-tau231 levels, and / or the p-tau181 / np-tau181 ratio, and / or the p-tau217 / np-tau217 ratio) can be used instead of another method for measuring brain amyloid levels, such as PET scans used to determine treatment efficacy and / or make treatment decisions (e.g., whether to continue treatment, switch to maintenance dose, etc.).

[0480] In some embodiments, plasma or serum p-tau181 level measurements may employ relative changes compared to a baseline measurement. In some embodiments, changes in p-tau181 levels may be used to evaluate treatment efficacy. In some embodiments, a decrease in p-tau181 levels indicates treatment efficacy, such as a decrease in brain amyloid levels. In some embodiments, p-tau181 level measurements may employ a set threshold to determine changes in brain amyloid levels, for example, to identify and / or select patients suitable for treatment, such as with anti-Aβ primary fibrillary antibodies, or to determine whether to continue treatment, or to determine whether to switch to a maintenance dose, or to conclude that the patient is amyloid-negative. In some embodiments, the threshold may be evaluated in conjunction with another measurement of brain amyloid load, such as a PET scan, to help determine whether a subject is suitable for treatment or to continue treatment. In some embodiments, a p-tau181 level threshold may be used instead of another method for measuring brain amyloid levels, such as a PET scan. In some embodiments, a p-tau181 level threshold of about 2.2 to 2.3 pg / mL or higher is used to identify and / or select patients suitable for treatment, such as with anti-Aβ primary fibrillary antibodies. In some embodiments, a p-tau181 level threshold of about 2.2 pg / mL or higher is used to identify and / or select patients suitable for treatment, for example, with anti-Aβ protofibrillary antibodies. In some embodiments, a p-tau181 level threshold of about 2.3 pg / mL or higher is used to identify and / or select patients suitable for treatment, for example, with anti-Aβ protofibrillary antibodies. In some such embodiments, Quanterix™ Simoa is used. ® p-tau assay measures p-tau181 levels. In some embodiments, the threshold is approximately 2.3 pg / mL. In some embodiments, the threshold is approximately 2.2 pg / mL. In some embodiments, an increase in p-tau181 levels above the threshold may indicate the need to continue treatment or to select for an increased dosing regimen. In some embodiments, a decrease in p-tau181 levels below the threshold may be used to indicate that treatment can be terminated (e.g., terminated to support a maintenance regimen) and / or otherwise determine a reduction or discontinuation of the dosing regimen.

[0481] In some embodiments, the level of p-tau 181 in the blood can be measured, for example, where blood-based tests are faster, easier, and / or more cost-effective than cerebrospinal fluid (CSF) measurements or imaging methods. Specifically, p-tau 181 has been shown to be associated with brain amyloid burden, tau accumulation, and clinical progression in preclinical and early AD individuals (Wang YL et al., Plasma p-tau181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study. Front Neurol. 4382021;12:695696.; Jack CR et al., Predicting amyloid PET and tau PET stages with plasma biomarkers. Brain. 2023; 146:2029-44). In some embodiments, higher tau PET levels (e.g., p-tau 181) in subjects compared to healthy controls indicate that subjects with pre-AD, at risk of AD, or with early AD will progress within the next 18 months and / or may be predicted to progress from Aβ+ mild cognitive impairment to AD within 36 months.

[0482] d. Plasma or serum levels of GFAP In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of glial fibrillary acidic protein (GFAP) in the subject's plasma or serum. Without being bound by theory, GFAP levels can be used as a biomarker for astrocyte activation. GFAP levels can be measured using techniques known in the art, such as immunoassay-based methods (e.g., Quanterix™ Simoa® assay) and / or mass spectrometry (IP / LC-MS / MS). In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of GFAP levels in the subject's plasma or serum. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of GFAP levels in the subject's plasma or serum by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% relative to baseline.

[0483] In some embodiments, serum GFAP levels can be used to select patients for treatment, allowing for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ primary fibrillary antibodies. In some embodiments, additional biomarkers combined with decreased GFAP levels over the same period can indicate effective treatment. In some embodiments, improvements in other biomarkers combined with decreased GFAP levels over the same period can indicate effective treatment. In some embodiments, improvements in other biomarkers combined with decreased GFAP levels relative to an untreated control can indicate effective treatment. In some embodiments, indications of treatment efficacy can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0484] e. Cerebrospinal fluid neurogranulin levels In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in the subject's cerebrospinal fluid neurogranulin levels. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in cerebrospinal fluid neurogranulin levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% relative to baseline.

[0485] In some embodiments, administration of the composition disclosed herein containing at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody to a subject 18 months after administration of the composition results in a reduction in cerebrospinal fluid neurogranulin levels. In some embodiments, administration of the composition disclosed herein containing at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody to a subject 18 months after administration of the composition results in a reduction in cerebrospinal fluid neurogranulin levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% relative to baseline.

[0486] In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of cerebrospinal fluid neurogranulin levels of at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL relative to baseline. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of cerebrospinal fluid neurogranulin levels of at least about 65 pg / mL relative to baseline.

[0487] In some embodiments, after 18 months of administration of a composition comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody, administration of the composition disclosed herein comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody to a subject results in a reduction of cerebrospinal fluid neurogranulin levels of at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL relative to baseline. In some embodiments, after 18 months of administration of the composition, administration of the composition disclosed herein comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody to a subject results in a reduction of cerebrospinal fluid neurogranulin levels of at least 65 pg / mL relative to baseline.

[0488] In some embodiments, at least one anti-Aβ primary fibrillary antibody is BAN2401.

[0489] In some embodiments, the therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody is 10 mg / kg. In some embodiments, the composition disclosed herein containing at least one anti-Aβ primary fibrillation antibody in a therapeutically effective amount is administered every two weeks or monthly. In some embodiments, the composition containing 10 mg / kg BAN2401 is administered every two weeks. In some embodiments, the composition containing 10 mg / kg BAN2401 is administered monthly.

[0490] In some embodiments, neurogranulin levels in cerebrospinal fluid (CSF) can be used to select patients for treatment, allowing for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ protofibrillary antibodies. In some embodiments, improvements in additional biomarkers combined with decreases in CSF neurogranulin levels over the same period can indicate effective treatment. In some embodiments, improvements in additional biomarkers combined with decreases in CSF neurogranulin levels over the same period can indicate effective treatment. In some embodiments, improvements in additional biomarkers combined with decreases in CSF neurogranulin levels relative to an untreated control can indicate effective treatment. In some embodiments, indications of treatment efficacy can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0491] f. Level of neurofilament light chains In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chains relative to placebo. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chains relative to placebo of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0492] In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chains relative to placebo after 18 months of composition administration. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in cerebrospinal fluid levels and / or plasma or serum levels of neurofilament light chains relative to baseline after 18 months of composition administration, relative to placebo, by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%.

[0493] In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in cerebrospinal fluid neurofilament light chain protein levels exceeding about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, and about 75 pg / mL, relative to baseline. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in cerebrospinal fluid neurofilament light chain protein levels not exceeding about 75 pg / mL, relative to baseline.

[0494] In some embodiments, 18 months after administration of the composition, administering the subject with the composition disclosed herein containing at least one therapeutically effective amount of an anti-Aβ primary fibrillary antibody results in cerebrospinal fluid neurofilament light chain protein levels exceeding about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, and about 75 pg / mL, relative to baseline. In some embodiments, 18 months after administration of the composition, administering the subject with the composition disclosed herein containing at least one therapeutically effective amount of an anti-Aβ primary fibrillary antibody results in cerebrospinal fluid neurofilament light chain protein levels not exceeding about 75 pg / mL, relative to baseline.

[0495] In some embodiments, at least one anti-Aβ primary fibrillary antibody is BAN2401.

[0496] In some embodiments, the therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody disclosed herein is 10 mg / kg. In some embodiments, the composition comprising at least one anti-Aβ primary fibrillation antibody disclosed herein, containing a therapeutically effective amount, is administered every two weeks or monthly. In some embodiments, the composition comprising 10 mg / kg BAN2401 is administered every two weeks. In some embodiments, the composition comprising 10 mg / kg BAN2401 is administered monthly.

[0497] In some embodiments, additional biomarkers and plasma or serum levels of neurofilament light chains can be used to select patients for treatment, allowing for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ protofibrillary antibodies. In some embodiments, improvements in additional biomarkers in combination with decreased plasma or serum levels of neurofilament light chains over the same period can indicate effective treatment. In some embodiments, improvements in additional biomarkers in combination with decreased plasma or serum levels of neurofilament light chains over the same period can indicate effective treatment. In some embodiments, improvements in additional biomarkers in combination with decreased plasma or serum levels of neurofilament light chains compared to an untreated control can indicate effective treatment. In some embodiments, indications of treatment efficacy can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0498] g. Cerebrospinal fluid phosphorylated Tau level In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction in the subject's cerebrospinal fluid phosphorylated Tau (p-tau) level. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of cerebrospinal fluid phosphorylated Tau level of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% relative to baseline.

[0499] In some embodiments, administration of the composition disclosed herein, comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillary antibody, to a subject 18 months after administration of the composition results in a reduction in cerebrospinal fluid phosphorylated Tau levels. In some embodiments, administration of the composition disclosed herein, comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillary antibody, to a subject 18 months after administration of the composition comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillary antibody, to a subject results in a reduction in cerebrospinal fluid phosphorylated Tau levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% relative to baseline.

[0500] In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of cerebrospinal fluid phosphorylated Tau levels of at least about 65 pg / mL, at least about 70 pg / mL, at least about 75 pg / mL, at least about 80 pg / mL, at least about 85 pg / mL, at least about 90 pg / mL, or at least about 95 pg / mL relative to baseline. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject results in a reduction of cerebrospinal fluid phosphorylated Tau levels of at least about 95 pg / mL relative to baseline.

[0501] In some embodiments, after 18 months of administration of a composition comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody, administration of the composition disclosed herein comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody to a subject results in a reduction of cerebrospinal fluid phosphorylated Tau levels by at least about 65 pg / mL, at least about 70 pg / mL, at least about 75 pg / mL, at least about 80 pg / mL, at least about 85 pg / mL, at least about 90 pg / mL, or at least about 95 pg / mL relative to baseline. In some embodiments, after 18 months of administration of a composition comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody, administration of the composition disclosed herein comprising at least one therapeutically effective amount of an anti-Aβ primary fibrillation antibody to a subject results in a reduction of cerebrospinal fluid phosphorylated Tau levels by at least 95 pg / mL relative to baseline.

[0502] In some embodiments, at least one anti-Aβ primary fibrillary antibody is BAN2401.

[0503] In some embodiments, the therapeutically effective amount of at least one anti-Aβ primary fibrillation antibody is 10 mg / kg. In some embodiments, the composition disclosed herein containing at least one anti-Aβ primary fibrillation antibody in a therapeutically effective amount is administered every two weeks or monthly. In some embodiments, the composition containing 10 mg / kg BAN2401 is administered every two weeks. In some embodiments, the composition containing 10 mg / kg BAN2401 is administered monthly.

[0504] In some embodiments, additional biomarkers and cerebrospinal fluid (CSF) levels of phosphorylated Tau can be used to select patients for treatment, allowing for monitoring and treatment decisions, such as whether to increase or decrease the amount of antibody administered, whether to increase or decrease the frequency of administration, whether to introduce additional therapeutic agents, whether to switch to a maintenance dose, and / or whether to discontinue treatment with anti-Aβ protofibrillary antibodies. In some embodiments, an improvement in additional biomarkers combined with a decrease in phosphorylated Tau levels in CSF during the same period can indicate effective treatment. In some embodiments, an improvement in additional biomarkers combined with a decrease in phosphorylated Tau levels in CSF during the same period can indicate effective treatment. In some embodiments, an improvement in additional biomarkers combined with a decrease in phosphorylated Tau levels in CSF relative to an untreated control can indicate effective treatment. In some embodiments, indications of treatment efficacy can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0505] h. Brain volume In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject resulted in an improvement in total hippocampal atrophy relative to placebo, as measured by volumetric MRI (vMRI). In some embodiments, the subject's brain volume (e.g., total ventricular volume, left and / or right ventricular volume, total volume, right and / or left hippocampal volume, cortical thickness) was measured prior to treatment. In some embodiments, the subject's brain volume (e.g., total ventricular volume, left and / or right ventricular volume, total volume, right and / or left hippocampal volume, cortical thickness) was measured at 6, 12, and / or 18 months after treatment. In some embodiments, administration of the composition disclosed herein, comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody, to a subject resulted in an improvement in brain volume atrophy relative to placebo, as measured by vMRI.

[0506] 10. Subjects who have AD, are suspected of having AD, or are at risk of developing AD. Subjects treated in this study include those with or suspected of having Alzheimer's disease (AD). In some embodiments, subjects exhibit changes in one or more biomarkers associated with AD pathology (e.g., the biomarkers described above) compared to a reference measurement (e.g., changes in increase, decrease, rate and / or extent of increase, or rate and / or extent of decrease). In some embodiments, the reference measurement may be a measurement obtained from the same subject (e.g., at an earlier time point) or a measurement of a portion of the body, tissue, or fluid of a subject whose biomarker levels do not change in response to AD pathology. In some embodiments, the reference measurement may be a measurement obtained from another subject (such as a healthy control subject) or may be the average of measurements obtained from more than one reference subject.

[0507] In some embodiments, subjects may exhibit changes and / or differences in measurements of one or more biomarkers associated with AD pathology compared to reference measurements (e.g., measurements from healthy controls) prior to treatment, such as one or more of the following: (a) increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., a measurement of about 20-40 percentiles, e.g., a measurement of about 20-32 percentiles), (b) increased tau in the brain, e.g., as measured by positron emission tomography (PET), (c) Decreased cerebrospinal fluid levels of Aβ1-42 (e.g., decreased Aβ1-42 / 1-40 ratio) and / or increased total tau, phosphorylated tau isoforms (e.g., p-tau181, p-tau217 and / or p-tau231, p-tau181 / np-tau181 ratio and / or p-tau217 / np-tau217 ratio), neurogranulin and / or neurofilament light chains (NfL), and (d) Decreased serum or plasma levels of Aβ1-42 (e.g., a decreased Aβ1-42 / 1-40 ratio in serum or plasma) and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231), P-tau181 / NP-tau181 ratio and / or P-tau217 / NP-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL). In some embodiments, subjects may exhibit changes in the ratio of phosphorylated to non-phosphorylated Tau217 in plasma or serum (P-Tau217 / NP-Tau217 ratio, also referred to as P-Tau217R or pTau217R), for example, this ratio may be increased in subjects with AD, suspected of having AD, or at risk of developing AD. Unbound by theory, the biomarkers disclosed in this paper can effectively predict amyloid PET status (Rissman et al., 2024, Alzheimers & Dementia, 20(2): 1214-1224; Janelidze et al., 2022, Alzhimer's & Dementia, 18:283-293) and are used for the detection and diagnosis of AD (Hampel et al., 2023, Neuron, 111(18):2781-2799). In some embodiments, at least one of p-tau217 / np-tau217, Aβ42 / Aβ40, and p-tau181 / np-tau181 can be used to predict amyloid PET status.In some embodiments, measurements of p-tau217 and / or Aβ42 / Aβ40 can be used to predict amyloid PET status. In some embodiments, a combination of p-tau217 and Aβ42 / Aβ40 can be used to predict amyloid PET status. In some embodiments, the ratio of p-tau217 / np-tau217 and Aβ42 / Aβ40 can be used in combination to predict amyloid PET status.

[0508] In some embodiments, the subject is amyloid-positive, for example, as indicated by PET assessment, CSF assessment of Aβ(1-42), MRI, and / or retinal amyloid accumulation.

[0509] In some embodiments, the subject has AD, for example, has been diagnosed with AD. For example, a subject may have been diagnosed with (a) mild cognitive impairment of moderate probability due to Alzheimer's disease and / or has been diagnosed with mild Alzheimer's dementia; (b) mild cognitive impairment of moderate probability due to Alzheimer's disease according to the National Institute on Aging and Alzheimer's Association (NIA-AA) Core Clinical Guidelines; (c) mild cognitive impairment of moderate probability due to Alzheimer's disease according to a CDR total score of 0.5 and a memory box score of 0.5 or higher before treatment; (d) mild cognitive impairment of moderate probability due to Alzheimer's disease according to, for example, a history of subjective memory decline and gradual onset and slow progression within the most recent year before treatment, as confirmed by an informed person; (e) mild Alzheimer's dementia according to the NIA-AA Core Clinical Guidelines for probable Alzheimer's dementia; or (f) mild Alzheimer's dementia according to a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher before treatment.

[0510] In some embodiments, the subject has early-stage Alzheimer's disease (AD). Subjects with early-stage AD may experience symptoms of varying severity, ranging from mild cognitive impairment due to moderate likelihood of AD to mild Alzheimer's dementia. In some embodiments, subjects with early-stage AD have an MMSE score of 22 to 30 and a total Clinical Dementia Rating Scale (CDR) score of 0.5 to 1.0.

[0511] In some embodiments, such as based on one or more biomarkers of dementia and / or cognitive symptoms, the subject is suspected of having AD.

[0512] In some embodiments, the subject is at risk of developing Alzheimer's disease (AD) but has not yet exhibited cognitive symptoms of dementia. For example, the subject may have risk factors associated with age or genetic mutations. In some embodiments, the subject is ApoE4 positive. In some embodiments, the subject is at least 65 years old, for example, 65 to 80 years old. In some embodiments, the subject is 55 to 64 years old and has at least one risk factor selected from: (i) a first-degree relative diagnosed with dementia before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid protein as determined by PET or cerebrospinal fluid (CSF) testing. In some embodiments, the subject at risk of AD has elevated brain amyloid protein, for example, as measured and / or confirmed by PET assessment, but does not exhibit any detectable cognitive symptoms. In some embodiments, biomarkers (e.g., amyloid PET) in subjects at risk of developing AD change; tau in the brain, for example, cerebrospinal fluid levels of one or more of the following, as measured by positron emission tomography (PET): Aβ1-42 (or the Aβ1-42 / 1-40 ratio in cerebrospinal fluid), total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217 and / or P-tau231), P-tau181 / NP-tau181 ratio, P-tau217 / NP-tau231. Changes in serum or plasma levels relative to control subjects or populations in terms of the 17 ratio, neurogranulin and neurofilament light chain (NfL), and / or one or more of the following: Aβ1-42 (or Aβ1-42 / 1-40 ratio), total tau, phosphorylated tau (P-tau) isotypes (e.g., P-tau181, P-tau217 and / or P-tau231), P-tau181 / NP-tau181 ratio and / or P-tau217 / NP-tau217 ratio, glial fibrillary acidic protein (GFAP) and / or neurofilament light chain (NfL).

[0513] In some embodiments, subjects at risk of developing AD may have pre-AD (also known as preclinical AD, where the subject's cognition is not impaired, but there is elevated amyloid protein in the brain, for example based on changes in one or more biomarkers associated with AD pathology). For example, subjects may exhibit changes in one or more biomarkers associated with AD pathology, but without cognitive impairment, for example, as measured by clinical symptoms of AD. In some embodiments, the subject's overall Clinical Dementia Rating Scale (CDR) score is 0. In some embodiments, the subject has a Mini-Mental State Examination (MMSE) score greater than or equal to 27, with educational adjustments. In some embodiments, the subjects’ Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII) scores were one standard deviation lower than the age-adjusted mean in the WMS-IV LMII; that is, scores greater than 15 for subjects aged 50 to 64, scores greater than 12 for subjects aged 65 to 69, scores greater than 11 for subjects aged 70 to 74, scores greater than 9 for subjects aged 75 to 79, and scores greater than 7 for subjects aged 80 to 90.

[0514] 11. Anti-Aβ primary fibrillary antibody In some embodiments, the antibody that binds to Aβ (also referred to as an anti-Aβ antibody) is an antibody that binds to any form (e.g., conformation) of Aβ, such as Aβ monomers, oligomers (e.g., different forms of Aβ oligomers, such as dimers, trimers, tetramers, pentamers, hexamers, nonamers, dodecamers), paranuclear cells (e.g., monomers that partially fold to form the nucleus for protofibrillation), primary protofibrils, or mature protofibrils. In some embodiments, the anti-Aβ antibody may bind to more than one form of Aβ. For example, an exemplary anti-Aβ antibody may be a pan-Aβ antibody, such as a pan-AβpE3 antibody that reacts with Aβ in the form of high molecular weight oligomers, primary protofibrils, and protofibrils found to be in different plaque types. In some embodiments, the anti-Aβ antibody may preferentially bind to a specific form of Aβ. For example, an exemplary Aβ antibody may be an anti-Aβ primary protofibril antibody that at least binds to primary protofibrils. In some embodiments, the anti-Aβ primary protofibril antibody may preferentially bind to primary protofibrils and may also bind to other forms of Aβ. In some embodiments, anti-Aβ primary fibrillary antibodies may preferentially bind to primary fibrils compared to other forms of Aβ. In some embodiments, anti-Aβ primary fibrillary antibodies may preferentially bind to primary fibrils rather than to other forms of Aβ.

[0515] In some embodiments, any anti-Aβ primary fibrillary antibody may be used in the methods disclosed herein. In some embodiments, the antibody comprises one or more of the sequences listed in Tables 1-4, such as the complete set of six complementarity-determining regions (CDRs) and / or the complete set of variable regions and / or the complete set of heavy and light chain sequences from each table. In some embodiments, the anti-Aβ primary fibrillary antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). In some embodiments, the anti-Aβ primary fibrillary antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-Aβ protoplasmic antibody comprises a human heavy chain and light chain variable region framework. In some embodiments, the anti-Aβ protoplasmic antibody comprises a human IgG1 heavy chain constant region and a human Igκ light chain constant region. In some embodiments, the anti-Aβ protoplasmic antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. As used herein in the context of antibody sequence or structure, “CDR” refers to the complementary determinant region that provides the major determinant for antigen binding. Typically, there are six CDRs at the antigen binding site: three of the VH (HCDR1, HCDR2, HCDR3) and three of the VL (LCDR1, LCDR2, LCDR3). CDRs are determined according to the Kabat numbering scheme. These CDRs can be determined according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Maryland, 1991, hereinafter referred to as the “Kabat Report”).

[0516] In some embodiments, the at least one anti-Aβ primary fibrillary antibody comprises a human constant region. In some embodiments, the human constant region of the at least one anti-Aβ primary fibrillary antibody comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allele variant thereof as disclosed in the Kabat report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the heavy chain constant region is selected from IgG1 and its allele variants. The amino acid sequence of the human IgG1 constant region is known in the art and is shown in SEQ ID NO: 11.

[0517] In some embodiments, the human constant region of the at least one anti-Aβ antibody comprises a light chain constant region selected from the κ-λ chain constant region and any allelic variant thereof as discussed in the Kabat report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the light chain constant region is selected from κ and its allelic variants. The amino acid sequence of the human κ chain constant region is known in the art and is shown in SEQ ID NO: 12.

[0518] In some embodiments, the at least one anti-Aβ primary fibrillary antibody is BAN2401, also known as lencanezumab. The terms “BAN2401” and “lencanezumab” are used interchangeably and refer to the humanized IgG1 monoclonal form of mAb158, a murine monoclonal antibody produced to target primary fibrillary fibrillation and disclosed in WO 2007 / 108756 and Journal of Alzheimer's Disease 43: 575-588 (2015). BAN2401 comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), and is described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 comprises (i) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 7 and (ii) a light chain variable region containing the amino acid sequence of SEQ ID NO: 8. The full-length sequences of the heavy and light chains of BAN2401 are listed in SEQ ID NO: 9 and 10, and described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015).

[0519] In some embodiments, the isolated anti-Aβ protoplasmic antibody to be used for treatment is present at a concentration of at least 80 mg / mL. In some embodiments, the isolated anti-Aβ protoplasmic antibody is present at a concentration of at least 100 mg / mL. In some embodiments, the isolated anti-Aβ protoplasmic antibody is present at a concentration of at least 200 mg / mL. In some embodiments, the isolated anti-Aβ protoplasmic antibody is present at a concentration of at least 250 mg / mL. In some embodiments, the isolated antibody or a fragment thereof is present at a concentration ranging from 80 mg / mL to 300 mg / mL. In some embodiments, the isolated anti-Aβ protoplasmic antibody is present at a concentration ranging from 85 mg / mL to 275 mg / mL. In some embodiments, the isolated anti-Aβ protoplasmic antibody is present at a concentration ranging from 90 mg / mL to 250 mg / mL. In some embodiments, the isolated anti-Aβ protoplasmic antibody is present at a concentration ranging from 95 mg / mL to 225 mg / mL. In some embodiments, the isolated anti-Aβ protofibrillary antibody is present at a concentration ranging from 100 mg / mL to 200 mg / mL. In some embodiments, the isolated antibody or its fragment is present at concentrations of 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, or 300 mg / mL. In some embodiments, the isolated antibody or its fragment is present at a concentration of 100 mg / mL. In some embodiments, the isolated antibody or its fragment is present at a concentration of 200 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 300 mg / mL. In some embodiments, the isolated antibody or fragment thereof is BAN2401. As used herein, an "antibody fragment" comprises a portion of the antibody, such as containing an antigen-binding region or a variable region thereof. Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, biantibodies, linear antibodies, and single-chain antibody molecules.

[0520] 12. A therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody In various embodiments, the method of the present invention includes administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ primary fibrillary antibody. As used herein, the term "therapeuticly effective amount" refers to an amount of compound or pharmaceutical composition sufficient to produce the desired therapeutic effect.

[0521] Those skilled in the art will understand that the therapeutically effective amount of at least one anti-Aβ protofibrillary antibody administered to a subject can be determined based on a variety of factors, including pharmacodynamic characteristics, route of administration, frequency of treatment, and the health status, age, and weight of the subject to be treated, and with the information disclosed herein, the appropriate amount for each subject can be determined.

[0522] In some embodiments, the therapeutically effective dose is a dose selected to improve efficacy and / or maintain efficacy and improve at least one of safety and tolerability. In some embodiments, the therapeutically effective dose is selected to reduce at least one side effect while simultaneously improving efficacy and / or maintaining efficacy. Therapeuticly effective doses of anti-Aβ protofibrillary antibodies and methods for measuring therapeutic efficacy are disclosed in PCT / US2022 / 073576; PCT / US2022 / 079571; and PCT / US2022 / 041926 and are incorporated herein by reference.

[0523] In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg relative to the subject's body weight.

[0524] In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg relative to the subject's body weight.

[0525] In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg relative to the subject's body weight.

[0526] In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg relative to the subject's body weight.

[0527] In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject relative to the subject's body weight, starting at 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg. In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of up to 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg relative to the subject's body weight.

[0528] In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 0.5 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 1 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 2 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 2.5 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 3 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 4 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 5 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 6 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 7 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ profibrillary antibody is administered to the subject at a dose of 7.5 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 8 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 9 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 10 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 11 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 12 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 12.5 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 13 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 14 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 15 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protoplasmic antibody is administered to the subject at a dose of 16, 17, 18, 19, or 20 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of 21, 22, 23, 24, or 25 mg / kg relative to the subject's body weight.

[0529] In some embodiments, at least one anti-Aβ primary fibrillary antibody is administered to the subject at a dose of 27.5 mg / kg, 30 mg / kg, 32.5 mg / kg, 35 mg / kg, 37.5 mg / kg, 40 mg / kg, 42.5 mg / kg, 45 mg / kg, 47.5 mg / kg, or 50 mg / kg relative to the subject's body weight.

[0530] As mentioned, in some embodiments, the at least one anti-Aβ protofibrillary antibody is BAN2401. Therefore, in some embodiments, BAN2401 is administered to the subject at doses of 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg relative to the subject's body weight.

[0531] In some embodiments, BAN2401 is administered to the subject at doses of 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg relative to the subject's body weight.

[0532] In some embodiments, BAN2401 is administered to the subject at doses of 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg relative to the subject's body weight.

[0533] In some embodiments, BAN2401 is administered to the subject at doses of 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg relative to the subject's body weight.

[0534] In some embodiments, BAN2401 is administered to the subject in doses starting at 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of up to 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg relative to the subject's body weight.

[0535] In some embodiments, BAN2401 is administered to the subject at a dose of 0.5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 1 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 2 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 2.5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 3 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 4 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 6 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 7 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 7.5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 8 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 9 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 10 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 11 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 12 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 12.5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 13 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 14 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 15 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 16, 17, 18, 19, or 20 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 21, 22, 23, 24, or 25 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at doses of 27.5 mg / kg, 30 mg / kg, 32.5 mg / kg, 35 mg / kg, 37.5 mg / kg, 40 mg / kg, 42.5 mg / kg, 45 mg / kg, 47.5 mg / kg, or 50 mg / kg relative to the subject's body weight.

[0536] In some embodiments, BAN2401 is administered to the subject at a dose of 2.5 mg / kg to 10 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 5 mg / kg to 10 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 2.5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 7.5 mg / kg relative to the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 10 mg / kg relative to the subject's body weight.

[0537] In some embodiments, a first dose of anti-Aβ profibrillary antibody is administered to the subject without an initial titration step for the therapeutic dose (e.g., the subject begins treatment at 10 mg / kg without titration). In some embodiments, a dose of BAN2401 may be used without a prior titration step. In some embodiments, the subject is switched to a maintenance dose without an initial titration step for the maintenance dose. In certain cases, providing a therapeutic dose without a titration step may provide additional therapeutic benefits to the patient, such as a faster conversion of plasma biomarkers to amyloid negativity or facilitating earlier identification of patients who respond to anti-Aβ profibrillary antibody treatment without plasma biomarkers (non-responders) and who will benefit from alternative therapies.

[0538] 13. Dosage regimen and route of administration In various embodiments, this document discloses a method for treating AD, comprising administering an anti-Aβ profibrillary antibody (e.g., BAN2401) to a subject. In some embodiments, the subject has early-stage AD. In some embodiments, an anti-Aβ profibrillary antibody (e.g., BAN2401) is administered to a subject with pre-AD or suspected AD. In some embodiments, the anti-Aβ profibrillary antibody may be administered to the subject according to a dosing regimen (also referred to as a “dosing regimen,” “treatment regimen,” or “treatment”) (e.g., a schedule specifying the dose of anti-Aβ profibrillary antibody administered per unit time, which includes the number of doses over a given time period and the time elapsed between doses). In some embodiments, the dosing regimen includes administering the anti-Aβ profibrillary antibody at a specified dose according to a schedule (e.g., on a repetitive basis). In some embodiments, the anti-Aβ profibrillary antibody may be administered daily, weekly (also referred to as “weekly,” or every other week (also referred to as “every two weeks,” or monthly (also referred to as “every four weeks”). In some embodiments, the anti-Aβ profibrillary antibody may be administered intravenously and / or subcutaneously. In some embodiments, the dosing regimen includes administering at least one starting dose (also referred to as a treatment dose) and at least one maintenance dose. In some embodiments, the dosing regimen includes administering at least one dose of anti-Aβ profibrillary antibody via one route of administration. In some embodiments, the dosing regimen includes administering at least one dose of anti-Aβ profibrillary antibody via more than one route of administration (e.g., initially administering the antibody intravenously and then switching to subcutaneous administration).

[0539] In some embodiments, anti-Aβ primary fibrillary antibodies are administered intravenously, for example, by injection into a peripheral vein. In the upper extremity, the median basilic vein or cephalic vein of the arm or the palmar vein on the back of the hand can be used. In the lower extremity, the dorsal venous plexus of the foot can be used.

[0540] After 18 months, the population model predicted that reducing the frequency of 10 mg / kg to once every 4 weeks would continue to reduce amyloid β plaque levels.

[0541] In some embodiments, anti-Aβ profibrillary antibodies are administered subcutaneously. In a subcutaneous injection, the anti-Aβ profibrillary antibody is injected into a tissue layer between the skin and muscle, such as adipose tissue beneath the skin. In some embodiments, subcutaneous administration is injected into the abdomen (e.g., at or below the level of the navel), the thigh (e.g., the front of the thigh), or the upper arm (e.g., the back or side of the upper arm). In some embodiments, the volume of the subcutaneous injection is less than 2 mL.

[0542] In some embodiments, anti-Aβ profibrillary antibodies are administered subcutaneously using a vial and syringe (also referred to as a "vial / syringe," "syringe / vial," or "SC vial"). For example, anti-Aβ profibrillary antibodies in a subcutaneous preparation can be transferred from a vial into a syringe and then injected into the subject.

[0543] In some embodiments, an autoinjector (also referred to as an "autoinjector," "AI," "AI device," or "SCAI") is used to administer anti-Aβ primary fibrillation antibodies. An exemplary autoinjector is the YpsoMate™ 2.25 mL AI device, which has been approved in the United States and Europe as a demonstration of Ajovy® (fremanezumabv-frm). In some embodiments, the autoinjector may include a plastic PLAJEX™ syringe, a conical needle (24G-29G), a V-shaped spring, spring force, and component color. It may be a disposable injection device consisting of a housing with a contents viewing window, a spring-loaded mechanism, and integrated needle safety features. In some embodiments, the 2.25 mL PLAJEX™ syringe may be pre-filled with anti-Aβ primary fibrillation antibodies. At least one AI device may be required to administer a dose of anti-Aβ primary fibrillation antibodies.

[0544] In some embodiments, at least one dose of anti-Aβ primary fibrillation antibody is administered intravenously and at least one dose is administered subcutaneously. For example, anti-Aβ primary fibrillation antibody (e.g., BAN2401) may be administered intravenously to the subject for a period of time (e.g., 2 months, 4 months, 6 months, 8 months, 10 months, 12 months, 14 months, 16 months, 18 months, 20 months, 22 months, or 24 months), after which the antibody may be administered subcutaneously. In some embodiments, anti-Aβ primary fibrillation antibody may be administered subcutaneously using a vial-syringe followed by subcutaneous administration using an AI. In some embodiments, anti-Aβ primary fibrillation antibody may be administered subcutaneously using a vial-syringe or an AI followed by intravenous administration.

[0545] In some embodiments, the treatment method includes switching between intravenous and subcutaneous doses or from a starting dose to a maintenance dose at a predetermined time point (e.g., after 18 months or after 24 months). In some embodiments, the treatment method includes using biomarker levels to determine the switching between intravenous and subcutaneous doses or from a starting dose to a maintenance dose, for example, when measured at or after a predetermined time point (e.g., after 18 months or after 24 months). In some embodiments, the maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections).

[0546] In some embodiments, BAN2401 (also known as LEQEMBI, lencanemab, or lencanemab-irmb) is provided as a solution for intravenous use and is a preservative-free, sterile, clear to milky white and colorless to pale yellow solution for intravenous use after dilution. In some embodiments, LEQEMBI may be provided in single-dose vials at a concentration of 500 mg / 5 mL (100 mg / mL) or 200 mg / 2 mL (100 mg / mL). In some embodiments, each mL of the solution contains 100 mg of lencanemab-irmb and arginine hydrochloride (42.13 mg), histidine (0.18 mg), histidine hydrochloride monohydrate (4.99 mg), polysorbate 80 (0.50 mg), and water for injection at a pH of approximately 5.0. In some embodiments, LEQEMBI is diluted in 250 mL of 0.9% sodium chloride injection (USP). In some embodiments, the dose of LEQEMBI is 10 mg / kg relative to the subject's body weight.

[0547] a. Starting dose In some embodiments, anti-Aβ protofibrillary antibodies may be administered to subjects (e.g., subjects with AD, suspected of having AD, or at risk of developing AD) according to a dosage regimen (also referred to as a dosing regimen), wherein the dose (e.g., a therapeutically effective dose) is repeated at regular dosing intervals. In some embodiments, the dose may be referred to as a starting dose, a therapeutic dose, or a first dose. A starting dose may be administered to subjects according to a dosage regimen (e.g., a starting dose regimen, also referred to as a starting dosing regimen), wherein the starting dose of anti-Aβ protofibrillary antibodies may be administered at certain intervals (e.g., daily, weekly, bi-weekly, or monthly) for a period of time, e.g., until the subject demonstrates evidence of improved AD pathology and / or slowed AD progression. In some embodiments, this period of time is at least 18 months or at least 24 months. In some embodiments, the period of time is 18 months. In some embodiments, the period of time is 24 months. In some embodiments, the period of time is about 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, or 60 months. In some embodiments, the starting dose may be administered until the subject is amyloid-negative.

[0548] In some embodiments, at least one starting dose of anti-Aβ profibrillary antibody is administered intravenously to the subject. Exemplary dosing regimens may include intravenous administration of anti-Aβ profibrillary antibody (e.g., BAN2401) at a dose of 10 mg / kg. In some embodiments, BAN2401 is administered intravenously at a dose of 10 mg / kg once weekly, for example, for at least 18 months or at least 24 months, or for example, until the subject becomes amyloid-negative or until one or more other biomarker levels are reached (e.g., changes in biomarkers discussed herein). In some embodiments, BAN2401 is administered intravenously at a dose of 10 mg / kg every two weeks, for example, for at least 18 months or at least 24 months, or for example, until the subject becomes amyloid-negative or until one or more other biomarker levels are reached (e.g., changes in biomarkers discussed herein).

[0549] In some embodiments, at least one starting dose of anti-Aβ profibrillary antibody (e.g., BAN2401) is administered subcutaneously, for example via viavial-syringe or via self-injector. Exemplary dosing regimens may include: subcutaneous administration of anti-Aβ profibrillary antibody (e.g., BAN2401) at a dose of 720 mg. In some embodiments, this dose may be administered in a single 720 mg injection. In some embodiments, the 720 mg dose may be administered in two simultaneous (e.g., successive) 360 mg injections (e.g., 400 mg / 2 mL of 2 x 1.8 mL or 200 mg / mL of 2 x 1.8 mL). In some embodiments, BAN2401 is administered subcutaneously at a dose of 720 mg once weekly, for example, for 18 months. In some embodiments, BAN2401 is administered subcutaneously at a dose of 720 mg once weekly, for example, for 24 months. In some embodiments, BAN2401 is administered subcutaneously at a dose of 720 mg once weekly, for example, for at least 18 months or at least 24 months, or for example, until the subject becomes amyloid-negative or until one or more other biomarkers are reached (e.g., changes in biomarkers discussed herein). In some embodiments, BAN2401 is administered subcutaneously at a dose of 720 mg every two weeks, for example, for at least 18 months or at least 24 months, or for example, until the subject becomes amyloid-negative or until one or more other biomarkers are reached (e.g., changes in biomarkers discussed herein). The 720 mg dose can be administered in two simultaneous (e.g., successive) 360 mg injections (e.g., 400 mg / 2 mL x 1.8 mL or 200 mg / mL x 1.8 mL).

[0550] In some embodiments, different starting doses of anti-Aβ profibrillary antibodies (e.g., BAN2401) may be administered. In some embodiments, subcutaneous doses of anti-Aβ profibrillary antibodies (e.g., BAN2401) may be administered in more than one dose. For example, a subject may be switched from a first dose of the antibody for a first duration to a second dose of the antibody for a second duration. For example, a 720 mg dose may be administered subcutaneously once weekly for a first duration, followed by a 500 mg dose administered subcutaneously once weekly for a second duration. In some embodiments, a 720 mg dose (2 x 1.8 mg of 200 mg / mL subcutaneous formulation) may be administered in two consecutive 360 ​​mg injections for a first duration, and then a 500 mg dose (2 x 1.25 mL of 200 mg / mL subcutaneous formulation) may be administered in two consecutive 250 mg injections for a second duration. In some embodiments, the first time period is less than about 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or 24 months, or less than the period until the subject is amyloid-negative or reaches one or more biomarker levels as discussed herein. In some embodiments, the first time period is less than 18 months. In some embodiments, the second time period includes the first time period plus the remaining 18 months, such that the total of the first and second time periods is about 18 months. In some embodiments, the subject may continue the first time period by receiving a subcutaneous dose of 720 mg anti-Aβ primary fibrillation antibody (e.g., BAN2401) weekly via self-injection, and then continue the second time period by receiving a subcutaneous dose of 500 mg anti-Aβ primary fibrillation antibody (e.g., BAN2401) weekly via self-injection.

[0551] In some embodiments, the initial dosing regimen of Aβ protofibrillary antibody (e.g., BAN2401) may include administering the antibody at more than one dose and / or via more than one administration modality. In some embodiments, a subject may be switched from a first intravenous dose of the antibody for a first duration to a second intravenous or subcutaneous dose of the antibody for a second duration. In some embodiments, a subject may be switched from a first intravenous dose of the antibody for a first duration to a second subcutaneous dose of the antibody for a second duration. For example, a first dose of 10 mg / kg may be administered intravenously to the subject every two weeks for a first duration (e.g., 6 months or 12 months), followed by a second dose of 720 mg or less (e.g., 500 mg) for a second duration (e.g., 6 months or 12 months). In some embodiments, a maintenance dosing regimen may follow the initial dosing regimen (including intravenous administration of a first dose of Aβ proficiency antibody (e.g., BAN2401) for a first time period and subcutaneous administration of a second dose of Aβ proficiency antibody for a second time period), such as a maintenance dosing regimen including subcutaneous administration of the antibody at a dose of 360 mg every two weeks or subcutaneous administration of the antibody at a dose of 250 mg every two weeks. In some embodiments, the subject's exposure to anti-Aβ proficiency antibody depends on whether the dose is administered using a vial / syringe or an AI. In some embodiments, the exposure to the antibody is greater when using an AI than when using a vial / syringe. Therefore, the dose administered subcutaneously using an AI may be lower than the dose administered subcutaneously using a vial / syringe. In some embodiments, where the target systemic exposure is based on intravenous administration (e.g., 10 mg / kg every two weeks), the exposure from the dose administered subcutaneously using the AI ​​method may be higher than the exposure obtained using the vial / syringe method. Therefore, the dose administered subcutaneously using an AI may be lower than the dose administered subcutaneously using a vial / syringe. In some embodiments, the systemic exposure from a dose administered intravenously at 10 mg / kg every two weeks is approximately equal to a dose administered subcutaneously weekly using the vial / syringe method at 720 mg, or approximately equal to a dose administered subcutaneously weekly using the AI ​​method at 500 mg. For example, the dose of anti-Aβ profibrillary antibody administered subcutaneously using the AI ​​method may be approximately 40%, 45%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the dose administered subcutaneously using the vial / syringe method. In some embodiments, the dose of anti-Aβ profibrillary antibody administered subcutaneously using the AI ​​method is 65%, 6...

Claims

1. A method of treating AD in a subject having Alzheimer’s disease (AD), suspected of having AD, or at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

2. A method of delaying clinical decline in a subject having AD, suspected of having AD, or at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

3. A method of reducing brain amyloid levels in a subject having AD, suspected of having AD, or at risk of developing AD, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg) of an antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

4. A method of converting an amyloid positive subject to amyloid negative, the method comprising subcutaneously administering to the subject 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg) of an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

5. The method of any one of claims 1-4, wherein subcutaneously administering the anti- Aβ protofibril antibody at 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg) reduces biomarkers of AD pathology and / or provides lower systemic exposure (e.g., AUC) to the antibody than for a higher dose, e.g., 720 mg, subcutaneously administered.

6. The method of any one of claims 1-5, wherein subcutaneously administering the anti- Aβ protofibril antibody at 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg) reduces the risk of developing ARIA relative to a higher dose, e.g., 720 mg, of the antibody subcutaneously administered.

7. The method of any one of claims 1-6, wherein the anti-Aβ protofibril antibody is administered at a dose of 150 mg to 200 mg, 200 mg to 250 mg, 250 mg to 300 mg, 350 mg to 400 mg, 450 mg to 500 mg, or 550 mg to 600 mg.

8. The method of any one of claims 1-7, wherein the anti-Aβ protofibril antibody is subcutaneously administered at a dose of 500 mg.

9. The method of any one of claims 1-8, wherein the dose is administered in two portions, e.g., consecutively.

10. The method of any one of claims 1-9, wherein the anti-Aβ protofibril antibody is administered once a week.

11. The method of any one of claims 1-9, wherein the anti-Aβ protofibril antibody is administered once every two weeks.

12. The method of any one of claims 1-9, wherein the anti-Aβ protofibril antibody is administered once a month.

13. The method of any one of claims 1-12, wherein the anti-Aβ protofibril antibody is administered at a starting dose for a first period of time, e.g., according to a starting dosing regimen, and at a maintenance dose for a second period of time, e.g., according to a maintenance dosing regimen.

14. The method of claim 13, wherein the initial dosing regimen comprises intravenous administration of each initial dose or subcutaneous administration of each initial dose.

15. The method of claim 13 or claim 14, wherein the maintenance dosing regimen comprises subcutaneous administration of each maintenance dose or intravenous administration of each maintenance dose.

16. The method of claim 13 or claim 15, wherein the initial dosing regimen comprises at least one intravenous administered initial dose and at least one subcutaneously administered initial dose.

17. The method of any one of claims 13, 14, or 16, wherein the maintenance dosing regimen comprises at least one intravenous administered maintenance dose and at least one subcutaneously administered maintenance dose.

18. The method of any one of claims 13-17, wherein the initial dose is greater than the maintenance dose.

19. The method of claim 13, wherein the initial dose of the anti-Aβ protofibril antibody is 150 mg to 600 mg, e.g., 200 mg to 550 mg, preferably 500 mg, administered subcutaneously.

20. The method of claim 13, wherein the maintenance dose of the anti-Aβ protofibril antibody is 150 mg to 500 mg, e.g., 360 mg, administered subcutaneously.

21. The method of claim 20, wherein the maintenance dose of the anti-Aβ protofibril antibody is 250 mg, administered subcutaneously.

22. The method of any one of claims 13-21, wherein the initial dose is administered weekly.

23. The method of any one of claims 13-22, wherein the maintenance dose is administered weekly.

24. The method of any one of claims 13-22, wherein the maintenance dose is administered biweekly.

25. The method of any one of claims 13-24, wherein the first period of time is at least about 6 months, about 12 months, about 18 months, about 24 months, or about 30 months.

26. The method of claim 25, wherein the first period of time is at least 18 months.

27. The method of claim 25 or claim 26, wherein the first period of time is at least 24 months.

28. The method of any one of claims 13-27, wherein the first period of time continues until the subject is amyloid negative.

29. The method of claim 13, wherein the anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously at a starting dose of 500 mg weekly for at least 18 months, and then administered subcutaneously at a maintenance dose of 250 mg weekly for the second period of time.

30. The method of claim 13, wherein the anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously at a starting dose of 500 mg weekly for at least 24 months, and then administered subcutaneously at a maintenance dose of 250 mg biweekly for the second period of time.

31. The method of any of claims 13-30, wherein the second time period begins when one or more biomarkers of the subject indicate a reduction or slowing of AD progression.

32. The method of any of claims 13-31, wherein the second time period is at least about 6 months, about 12 months, about 18 months, about 24 months, about 36 months, about 42 months, about 48 months, about 54 months, about 60 months, or for the lifetime of the subject.

33. The method of any of claims 13-32, wherein the maintenance dose is administered subcutaneously with an autoinjector (AI).

34. The method of any of claims 13-17, wherein the anti-Ab protofibril antibody is administered intravenously at a dose of 10 mg / kg relative to the subject’s body weight every two weeks.

35. The method of any of claims 1-34, wherein the anti-Ab protofibril antibody is comprised in a pharmaceutical composition in the form of a pre-filled syringe.

36. The method of any of claims 1-34, wherein the anti-Ab protofibril antibody is comprised in a pharmaceutical composition via an autoinjector.

37. The method of any of claims 1-36, wherein the anti-Ab protofibril antibody comprises a heavy chain complementarity determining region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

38. The method of any of claims 1-37, wherein the anti-Ab protofibril antibody is BAN2401 (loncastimab).

39. The method of any of claims 1-38, wherein the subject exhibits a change and / or difference in the measurement of one or more biomarkers associated with AD pathology prior to treatment.

40. The method of claim 39, wherein the change and / or difference in the measurement is selected from: a. increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., about 20-40 percent unit measure, e.g., about 20-32 percent unit measure), b. increased tau in the brain, e.g., as measured by positron emission tomography (PET), c. decreased cerebrospinal fluid levels of the Ab1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio), neurogranin, and / or neurofilament light chain (NfL), and d. increased levels of the Ab1-40 / 1-42 ratio in the brain, e.g., as measured by amyloid PET. d. decreased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

41. The method of any one of claims 1-38, wherein the subject exhibits a change and / or difference in a measure of one or more biomarkers associated with AD pathology during and / or after treatment.

42. The method of claim 40, wherein the change and / or difference in the measure is selected from: a. reduction in amyloid in the brain, e.g., as measured by amyloid PET (e.g., about 20-40 percent unit measure, e.g., about 20-32 percent unit measure), b. reduction in tau in the brain, e.g., as measured by positron emission tomography (PET), c. increased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or decreased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231, p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio), neurogranin, and / or neurofilament light chain (NfL), and d. decreased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

43. The method of any one of claims 1-42, wherein the subject is amyloid positive prior to administration, e.g., as indicated by PET assessment, CSF assessment for Aβ(1-42), CSF assessment for total tau, CSF assessment for p-tau (e.g., p-tau181, p-tau217, and / or p-tau231, p-tau181 / np-tau181 ratio, and / or p-tau217 / np-tau217 ratio), MRI, retinal amyloid accumulation, and / or blood biomarker assessment (e.g., plasma Aβ1-42 / 1-40 ratio, plasma p-tau181, plasma p-tau217, plasma p-tau 231 levels, p-tau181 / np-tau181 ratio, and / or p-tau217 / np-tau217 ratio).

44. The method of any one of claims 1-43, wherein the subject is ApoE4 positive.

45. The method of any one of claims 1-44, wherein the subject is monitored for ARIA development.

46. The method of any one of claims 1-45, wherein the subject is 65 to 80 years of age.

47. The method of any one of claims 1-45, wherein the subject is 55 to 64 years of age and has at least one risk factor selected from: (i) a first degree relative diagnosed with a dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to the administration.

48. The method of any one of claims 1-47, wherein the subject has Alzheimer’s disease.

49. The method of any one of claims 1-48, wherein the subject has early Alzheimer’s disease.

50. The method of any one of claims 1-49, wherein the subject has been diagnosed with a. mild cognitive impairment due to moderate likelihood of Alzheimer’s disease and / or has been diagnosed with mild Alzheimer’s disease dementia; b. mild cognitive impairment due to moderate likelihood of Alzheimer’s disease according to the National Institute on Aging and Alzheimer’s Association (NIA-AA) core clinical criteria; c. mild cognitive impairment due to moderate likelihood of Alzheimer’s disease according to a CDR Sum of Boxes score of 0.5 prior to treatment and a Memory Box score of 0.5 or higher; d. mild cognitive impairment due to moderate likelihood of Alzheimer’s disease according to a history of subjective memory decline and gradual onset and slow progression in the year prior to treatment as evidenced by, for example, informant confirmation; e. mild Alzheimer’s disease dementia according to the NIA-AA core clinical criteria for possible Alzheimer’s disease dementia; or f. mild Alzheimer’s disease dementia according to a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or higher prior to treatment.

51. The method of any one of claims 1-47, wherein the subject is suspected of having AD.

52. The method of any one of claims 1-47, wherein the subject is a subject at risk of developing AD.

53. The method of claim 52, wherein the subject at risk of developing AD has prodromal AD.

54. The method of claim 52 or claim 53, wherein the subject does not have cognitive impairment.

55. The method of any one of claims 52-54, wherein the subject has a total Clinical Dementia Rating (CDR) score of 0 prior to the administration.

56. The method of any one of claims 52-55, wherein the subject has a Mini-Mental State Examination (MMSE) score greater than or equal to 27 by education adjustment prior to the administration.

57. The method of any of claims 52-56, wherein prior to the administration, the subject has a Wechsler Memory Scale-Revised Logical Memory II (WMS-R LM II) score that is at least one standard deviation below the age-corrected mean in the WMS-IV LM II, the score is less than or equal to 15 for subjects in the age range of 50 to 64, the score is less than or equal to 12 for subjects in the age range of 65 to 69, the score is less than or equal to 11 for subjects in the age range of 70 to 74, the score is less than or equal to 9 for subjects in the age range of 75 to 79, and the score is less than or equal to 7 for subjects in the age range of 80 to 90.

58. A method of treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for having AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the antibody at a starting dose of 10 mg / kg relative to body weight of the subject every two weeks; and for example, subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks after the starting dose for 18 or 24 months.

59. A method of delaying clinical decline in a subject having, suspected of having, or at risk for having AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the antibody at a starting dose of 10 mg / kg relative to body weight of the subject every two weeks; and for example, subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks after the starting dose for 18 months.

60. A method of reducing brain amyloid levels in a subject having AD, suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the antibody at a starting dose of 10 mg / kg relative to body weight of the subject every two weeks; and for example, subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks after 18 or 24 months of the starting dose.

61. A method of converting an amyloid positive subject to amyloid negative, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the antibody at a starting dose of 10 mg / kg relative to body weight of the subject every two weeks; and for example, subcutaneous administration of the antibody at a maintenance dose of 250 mg weekly or every two weeks after 18 or 24 months of the starting dose.

62. The method of any one of claims 58-61, wherein the starting dose of the antibody is intravenously administered for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

63. The method of any one of claims 58-62, wherein the starting dose of the antibody is intravenously administered for at least 18 months.

64. The method of any one of claims 58-63, wherein the starting dose of the antibody is intravenously administered for at least 24 months.

65. The method of any one of claims 58-64, wherein the maintenance dose of the antibody is administered weekly.

66. The method of any one of claims 58-64, wherein the maintenance dose of the antibody is administered every two weeks.

67. The method of any of claims 58-66, wherein the maintenance dose of the antibody is administered using a vial-syringe.

68. The method of any of claims 58-66, wherein the maintenance dose of the antibody is administered using an AI.

69. A method of treating Alzheimer’s disease (AD) in a subject having, suspected of having, or at risk for having AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: subcutaneously administering the antibody at a starting dose of 500 mg weekly; and for example, subcutaneously administering the antibody at a maintenance dose of 250 mg weekly or every other week after 18 or 24 months of the starting dose.

70. A method of delaying clinical decline in a subject having, suspected of having, or at risk for having AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: subcutaneously administering the antibody at a starting dose of 500 mg weekly; and for example, subcutaneously administering the antibody at a maintenance dose of 250 mg weekly or every other week after 18 or 24 months of the starting dose.

71. A method of reducing brain amyloid levels in a subject having AD, suspected of having AD, or at risk of developing AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: subcutaneously administering the antibody at a starting dose of 500 mg weekly; and for example, subcutaneously administering the antibody at a maintenance dose of 250 mg weekly or every other week after 18 or 24 months of the starting dose.

72. A method of converting an amyloid positive subject to amyloid negative, the method comprising administering to the subject an antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: subcutaneously administering the antibody at a starting dose of 500 mg weekly; and for example, subcutaneously administering the antibody at a maintenance dose of 250 mg weekly or every other week after 18 or 24 months of the starting dose.

73. The method of any of claims 69-72, wherein the starting dose of the antibody is administered subcutaneously for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.

74. The method of any of claims 69-73, wherein the starting dose of the antibody is administered subcutaneously for at least 18 months.

75. The method of any of claims 69-73, wherein the starting dose of the antibody is administered subcutaneously for at least 24 months.

76. The method of any of claims 69-75, wherein the starting dose of the antibody is administered using a vial-syringe.

77. The method of any of claims 69-76, wherein the starting dose of the antibody is administered using an Al.

78. The method of any of claims 69-77, wherein the maintenance dose of the antibody is administered weekly.

79. The method of any one of claims 69-77, wherein the maintenance dose of the antibody is administered every two weeks.

80. The method of any one of claims 69-79, wherein the maintenance dose of the antibody is administered using a vial-syringe.

81. The method of any one of claims 69-79, wherein the maintenance dose of the antibody is administered using an AI.

82. The method of any one of claims 69-81, wherein the anti-Aβ protofibril antibody comprises a heavy chain complementarity determining region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

83. The method of any one of claims 69-82, wherein the anti-Aβ protofibril antibody is BAN2401 (loncastimab).

84. The method of any one of claims 69-83, wherein the subject exhibits a change in a measure of one or more biomarkers associated with AD pathology prior to treatment.

85. The method of claim 84, wherein the change in the measure is selected from: a. increased amyloid in the brain, e.g., as measured by amyloid PET (e.g., about 20-40 percent unit measure, e.g., about 20-32 percent unit measure), b. increased tau in the brain, e.g., as measured by positron emission tomography (PET), c. decreased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, neurogranin, and / or neurofilament light chain (NfL), and d. decreased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or increased total tau, phospho-tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231, p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

86. The method of any one of claims 69-84, wherein the subject exhibits a change and / or difference in a measure of one or more biomarkers associated with AD pathology during and / or after treatment.

87. The method of claim 86, wherein the change and / or difference in the measure is selected from: a. decreased amyloid in the brain, e.g., as measured by amyloid PET (e.g., about 20-40 percent unit measure, e.g., about 20-32 percent unit measure), b. decreased tau in the brain, e.g., as measured by positron emission tomography (PET), c. increased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or decreased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, neurogranin, and / or neurofilament light chain (NfL), and d. increased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or decreased total tau, phospho-tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231, p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). c. Increased cerebrospinal fluid levels of the Aβ1-42 / 1-40 ratio and / or decreased total tau, p-tau (e.g., p-tau181, p-tau217, and / or p-tau231, p-tau181 / np-tau181 ratio, and / or p-tau217 / np-tau217 ratio), neurogranin, and / or neurofilament light chain (NfL), and d. Increased serum or plasma levels of the Aβ1-42 / 1-40 ratio and / or decreased total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau181, P-tau217, and / or P-tau231), p-tau181 / np-tau181 ratio, p-tau217 / np-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL).

88. The method of any one of claims 58-87, wherein the subject is amyloid positive prior to administration, e.g., as indicated by PET assessment, CSF assessment of Aβ(1-42), MRI, retinal amyloid accumulation.

89. The method of any one of claims 58-88, wherein the subject is ApoE4 positive.

90. The method of any one of claims 58-89, wherein the subject is monitored for development of ARIA.

91. The method of any one of claims 58-90, wherein the subject is 65 to 80 years of age.

92. The method of any one of claims 58-90, wherein the subject is 55 to 64 years of age and has at least one risk factor selected from: (i) a first-degree relative diagnosed with a dementia onset before age 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid according to PET or cerebrospinal fluid (CSF) testing prior to the administration.

93. The method of any one of claims 58-93, wherein the subject has Alzheimer’s disease.

94. The method of any one of claims 58-93, wherein the subject has early Alzheimer’s disease.

95. The method of any one of claims 58-94, wherein the subject has been diagnosed with a. mild cognitive impairment due to probable Alzheimer’s disease and / or has been diagnosed with mild Alzheimer’s disease dementia; b. mild cognitive impairment due to probable Alzheimer’s disease according to the National Institute on Aging and Alzheimer’s Association (NIA-AA) Core Clinical Criteria; c. mild cognitive impairment due to probable Alzheimer’s disease according to a CDR Sum of Boxes score of 0.5 prior to treatment and a Memory Box score of 0.5 or higher; d. mild cognitive impairment due to moderate likelihood of Alzheimer's disease according to, for example, subjective memory decline and a history of gradual onset and slow progression confirmed by an informant within the last year prior to treatment; e. mild Alzheimer's disease dementia according to the NIA-AA Core Clinical Criteria for possible Alzheimer's disease dementia; or f. mild Alzheimer's disease dementia according to a CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher prior to treatment.

96. The method of any one of claims 58-92, wherein the subject is suspected of having AD.

97. The method of any one of claims 58-92, wherein the subject is a subject at risk of developing AD.

98. The method of claim 97, wherein the subject at risk of developing AD has prodromal AD.

99. The method of claim 97 or claim 98, wherein the subject does not have cognitive impairment.

100. The method of any one of claims 97-99, wherein the subject has a Clinical Dementia Rating (CDR) score of 0 prior to the administration.

101. The method of any one of claims 97-100, wherein the subject has a Mini-Mental State Examination (MMSE) score greater than or equal to 27 by education adjustment prior to the administration.

102. The method of any one of claims 97-101, wherein the subject has a Wechsler Memory Scale-Revised Logical Memory Memory Subscale II (WMS-R LM II) score that is at least one standard deviation below the age-corrected mean in the WMS-IV LM II of less than or equal to 15 for subjects in the age range of 50 to 64, less than or equal to 12 for subjects in the age range of 65 to 69, less than or equal to 11 for subjects in the age range of 70 to 74, less than or equal to 9 for subjects in the age range of 75 to 79, and less than or equal to 7 for subjects in the age range of 80 to 90 prior to the administration.

103. A method of treating a subject having, suspected of having, or at risk of having early AD, and who has received a first anti-Abeta antibody, the method comprising: administering to the subject a second anti-Abeta antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenously administering the second antibody at a maintenance dose of 10 mg / kg relative to the body weight of the subject every two weeks or every month; or subcutaneously administering the second antibody at a maintenance dose of 250 mg every week or every two weeks.

104. A method of delaying clinical decline in a subject who has received a first anti- Aβ antibody, the method comprising: administering to the subject a second anti-Abeta antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenously administering the second antibody at a maintenance dose of 10 mg / kg relative to the body weight of the subject every two weeks or every month; or subcutaneously administering the second antibody at a maintenance dose of 250 mg every week or every two weeks.

105. A method of reducing brain amyloid levels in a subject who has received a first anti-Abeta antibody, the method comprising: administering to the subject a second anti-Abeta antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenously administering the second antibody at a maintenance dose of 10 mg / kg relative to the body weight of the subject every two weeks or every month; or subcutaneously administering the second antibody at a maintenance dose of 250 mg every week or every two weeks.

106. A method of maintaining amyloid levels in a subject who has received a first anti-Abeta antibody, the method comprising: administering to the subject a second anti-Abeta antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the second antibody at a maintenance dose of 10 mg / kg relative to body weight of the subject every two weeks or every month; or subcutaneous administration of the second antibody at a maintenance dose of 250 mg every week or every two weeks.

107. A method of treating a subject having early AD, suspected of having early AD, or at risk of having early AD, the method comprising: administering to the subject a first anti-Abeta antibody, administering to the subject a second anti-Abeta antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the second antibody at a maintenance dose of 10 mg / kg relative to body weight of the subject every two weeks or every month; or subcutaneous administration of the second antibody at a maintenance dose of 250 mg every week or every two weeks.

108. The method of any one of claims 103-107, wherein the maintenance dose of the subcutaneous administration of the antibody is administered using a vial-syringe.

109. The method of any one of claims 103-107, wherein the maintenance dose of the subcutaneous administration of the antibody is administered using an Al.

110. The method of any one of claims 103-109, wherein the first anti-Abeta antibody is selected from aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lanabezumab, or solanezumab.

111. The method of claim 110, wherein the first anti-Abeta antibody is donanemab.

112. A method of treating a subject having early AD, suspected of having early AD, or at risk of having early AD, the method comprising administering to the subject an anti-Aβ protofibril antibody comprising three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), according to a dosage regimen comprising: intravenous administration of the antibody at a first starting dose of 10 mg / kg relative to the body weight of the subject every two weeks; subcutaneous administration of the antibody at a second starting dose of 720 or 500 mg weekly; and for example, subcutaneous administration of the antibody at a dose of 250 mg weekly after 18 or 24 months of treatment with the starting dose.

113. The method of any one of claims 1-112, wherein the subject is being treated with a thrombolytic agent or an anti-platelet agent, but not with an anti-coagulant.

114. The method of claim 113, wherein the subject is receiving an anti-platelet drug.

115. The method of claim 113, wherein the subject is receiving a thrombolytic agent.

116. The method of claim 115, wherein the thrombolytic agent is selected from the group of aspirin or a fibrinolytic agent.

117. The method of claim 116, wherein the subject is receiving aspirin.

118. The method of claim 116, wherein the subject is receiving a fibrinolytic agent.

119. The method of any one of claims 1-118, wherein the subject has had or has an increased risk of having a cerebral hemorrhagic event, such as microbleeds or intracerebral hemorrhage, or an ARIA event prior to treatment.

120. The method of any one of claims 1-118, wherein the subject has not had a cerebral hemorrhagic event, such as microbleeds or intracerebral hemorrhage, or an ARIA event prior to treatment.

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