Treatment methods using anti-Aβ protofibril antibodies

Abstract

Methods for selecting, monitoring, and treating subjects who have AD or are suspected of having AD, or who have or are suspected of having another disorder related to amyloid accumulation in the brain based on the risk of ARIA events or intracerebral hemorrhage are disclosed. [Solution] One aspect of the present disclosure relates to a method for treating AD in subjects who have AD, are suspected of having AD, or are at risk of having AD, comprising subcutaneous administration of an anti-Aβ protofibril antibody at a dose of 150 mg to 600 mg to the subject, the antibody having three heavy chain complementation-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 complementation-determining regions (LCDR1, LCDR1, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

Description

[Technical Field]

[0001] [Related applications] [1] This application claims priority to U.S. Provisional Patent Application No. 63 / 507,400 filed on 9 June 2023, U.S. Provisional Patent Application No. 63 / 572,110 filed on 29 March 2024, and U.S. Provisional Patent Application No. 63 / 648,077 filed on 15 May 2024, the contents of each of these, respectively, are incorporated herein by reference in their entirety.

[0002] [Field] [2] Methods and administration protocols for treating target Alzheimer's disease (AD) using anti-Aβ protofibril antibodies are disclosed herein, as well as methods relating to amyloid-related imaging abnormalities (ARIA). [Background technology]

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

[0004] [4] The disease generally progresses slowly, with a general decline in cognitive function, and terminal patients become bedridden. Patients with AD typically survive only 3 to 10 years after the onset of symptoms, although extreme cases of survival for 2 and 20 years have been reported (Hebert, LE et al., Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003; 60:1119-1122). Although the number of deaths from AD is greatly underestimated because AD is rarely listed as the cause of death on death certificates, AD is the 7th leading cause of death overall in the United States and the 5th leading cause of death among Americans aged 65 and over (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010; 6:158-94).

[0005] [5] AD has a significant economic burden on developed countries as a whole, and has a profound impact on healthcare systems and public funds, as well as on patients and their families. In the United States alone, total payments were estimated at $172 billion in 2010, of which $123 billion was for Medicare and Medicaid.

[0006] [6] Histologically, the disease is characterized by senile plaques found primarily in the association cortex, limbic system, and basal ganglia. The main component of these plaques is amyloid-beta peptide (Aβ). Aβ exists in various structural states (monomers, oligomers, protofibrils, and insoluble fibers). The detailed mechanistic relationship between the onset of Alzheimer's disease and Aβ production is unknown. However, some anti-Aβ antibodies are currently being clinically studied as promising treatments for Alzheimer's disease.

[0007] [7] Despite recent developments in AD treatments, such as Aβ-targeting therapies, there is still a need for better treatments, including more sophisticated methods for selecting patients suitable for treatment and methods for adjusting responses to treatment-related events such as ARIA.

[0008] [8] Accordingly, this specification discloses improved methods for selecting, monitoring and treating patients with AD to treat patients who are less likely to present with ARIA and / or to address responses to ARIA occurrence during treatment. [Overview of the project]

[0009] [overview] [9] One aspect of the present disclosure relates to a method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having Alzheimer's disease (AD), comprising subcutaneous administration to the subject at a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), of an anti-Aβ protofibril antibody having three heavy chain complementation-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 complementation-determining regions (LCDR1, LCDR1, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0010]

[10] Another aspect of the present disclosure relates to a method for delaying the clinical progression of a subject who has, is suspected of having, or is at risk of having AD, comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an anti-Aβ protofibril antibody having three heavy chain complementary 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 complementary 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).

[0011]

[11] Further aspects of the present disclosure relate to a method for reducing brain amyloid levels in subjects who have, are suspected of having, or are at risk of having AD, comprising subcutaneously administering to a subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementarizing 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 complementarizing 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).

[0012]

[12] Another aspect of the present disclosure relates to a method for converting an amyloid-positive subject to amyloid-negative, comprising subcutaneously administering to a subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an anti-Aβ protofibril antibody having three heavy chain complementary 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 complementary determining regions (LCDR1, LCDR1, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3).

[0013]

[13] In some embodiments, when anti-Aβ protofibril antibodies are administered subcutaneously at doses of 150 mg to 600 mg, e.g., 200 mg to 550 mg (e.g., 500 mg), they reduce biomarkers of AD pathology and / or lower systemic exposure (e.g., AUC) to the antibody compared to when administered subcutaneously at higher doses, e.g., 720 mg.

[0014]

[14] In some embodiments, when anti-Aβ protofibril antibodies are administered subcutaneously at doses of 150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg), the risk of developing ARIA is reduced compared to when administered subcutaneously at higher doses, for example, 720 mg.

[0015]

[15] In some embodiments, the anti-Aβ protofibril antibody is administered in 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, the anti-Aβ protofibril antibody is administered subcutaneously in a dose of 500 mg.

[0016]

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

[0017]

[17] In some embodiments, the anti-Aβ protofibril antibody is administered once a week.

[0018]

[18] In some embodiments, the anti-Aβ protofibril antibody is administered every other week.

[0019]

[19] In some embodiments, the anti-Aβ protofibril antibody is administered once a month.

[0020]

[20] In some embodiments, the anti-Aβ protofibril antibody is administered in an initial dose during a first period, for example, according to an initiation dose plan, and then in a maintenance dose during a second period, for example, according to a maintenance dose plan.

[0021]

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

[0022]

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

[0023]

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

[0024]

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

[0025]

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

[0026]

[26] In some embodiments, the initial dose of the anti-Aβ protofibril antibody is 150 mg to 600 mg, such as 200 mg to 550 mg, preferably 500 mg, and is administered subcutaneously.

[0027]

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

[0028]

[28] In some embodiments, the maintenance dose of the anti-Aβ protofibril is 250 mg and is administered subcutaneously.

[0029]

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

[0030]

[30] In some embodiments, the maintenance dose is administered weekly.

[0031]

[31] In some embodiments, the maintenance dose is administered every other week.

[0032]

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

[0033]

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

[0034]

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

[0035]

[35] In some embodiments, the first period is continued until the subject becomes amyloid-negative.

[0036]

[36] In some embodiments, an anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously once weekly at an initial dose of 500 mg for at least 18 months, followed by a maintenance dose of 250 mg once weekly for a second period.

[0037]

[37] In some embodiments, an anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously once weekly at an initial dose of 500 mg for at least 24 months, followed by a second period at a maintenance dose of 250 mg every other week.

[0038]

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

[0039]

[39] In some embodiments, the second 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 the lifetime of the subject.

[0040]

[40] In some embodiments, the maintenance dose is administered subcutaneously using an auto-injector (AI).

[0041]

[41] In some embodiments, the anti-Aβ protofibril antibody is administered intravenously every other week at a dose of 10 mg / kg of the subject's body weight.

[0042]

[42] In some embodiments, the anti-Aβ protofibril antibody is included in the pharmaceutical composition in the form of a pre-filled syringe.

[0043]

[43] In some embodiments, the anti-Aβ protofibril antibody is included in a pharmaceutical composition delivered via an autoinjector.

[0044]

[44] In some embodiments, the anti-Aβ protofibril antibody comprises a heavy chain complementary 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.

[0045]

[45] In some embodiments, the anti-Aβ protofibril antibody is BAN2401 (lecanemab).

[0046]

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

[0047]

[47] In some embodiments, the change and / or difference in the measured values ​​is selected from: a. an increase in brain amyloid (e.g., a centroid value of about 20-40, e.g., a centroid value of about 20-32), measured by amyloid PET, b. an increase in brain tau, measured by positron emission tomography (PET), c. a decrease in cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 Increased levels of the ratio (p-tau 217 / np-tau 217 ratio), neurogranin, and / or neurofilament light chains (NfL), and decreased serum or plasma levels of the d.Aβ1-42 / 1-40 ratio and / or increased levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL).

[0048]

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

[0049]

[49] In some embodiments, the change and / or difference in the measured values ​​is selected from: a. a decrease in brain amyloid (e.g., centroid value of about 20-40, e.g., centroid value of about 20-32), measured by amyloid PET, b. a decrease in brain tau, measured by positron emission tomography (PET), c. an increase in cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231, p-tau 181 / np-tau 181) Decreased levels of the ratio (p-tau 217 / np-tau 217 ratio), neurogranin, and / or neurofilament light chains (NfL), and increased serum or plasma levels of the d.Aβ1-42 / 1-40 ratio and / or decreased levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL).

[0050]

[50] In some embodiments, subjects are amyloid-positive before administration, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), CSF evaluation of total tau, CSF evaluation of p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio), MRI, retinal amyloid accumulation, and / or blood biomarker evaluation (e.g., plasma Aβ1-42 / 1-40 ratio, plasma p-tau 181, plasma p-tau 217, plasma p-tau 231 levels, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio).

[0051]

[51] In some embodiments, the subjects are ApoE4 positive.

[0052]

[52] In some embodiments, subjects are monitored for the onset of ARIA.

[0053]

[53] In some embodiments, the subjects are between 65 and 80 years of age.

[0054]

[54] In some embodiments, subjects are aged 55 to 64 years and have at least one risk factor selected from: (i) a first-degree relative diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration.

[0055]

[55] In some embodiments, the subjects have Alzheimer's disease.

[0056]

[56] In some embodiments, the subjects have early Alzheimer's disease.

[0057]

[57] In some embodiments, subjects have been diagnosed with: a. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) and / or mild Alzheimer's dementia; b. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute of Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a pre-treatment CDR global score of 0.5 and a Memory Box score of 0.5 or higher; d. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a history of subjective memory impairment with slow onset and slow progression in the year prior to treatment (e.g., corroborated by an informant); e. mild Alzheimer's dementia based on the NIA-AA core clinical criteria for probable Alzheimer's dementia; or f. pre-treatment CDR score of 0.5 to 1.0 and Memory Box score Mild Alzheimer's disease based on a Box score of 0.5 or higher.

[0058]

[58] In some embodiments, the subject is suspected of being AD.

[0059]

[59] In some embodiments, the subjects are those at risk of developing AD.

[0060]

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

[0061]

[61] In some embodiments, the subjects do not have cognitive impairment.

[0062]

[62] In some embodiments, subjects have a Global Clinical Dementia Rating (CDR) score of 0 prior to administration.

[0063]

[63] In some embodiments, subjects have a Mini-Mental State Examination (MMSE) score of 27 or higher, including the pre-administration educational adjustments.

[0064]

[64] In some embodiments, subjects have a WMS-IV LMII score that is at least one standard deviation lower than the age-adjusted mean of the Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) prior to the administration, and is ≤15 for subjects aged 50–64, ≤12 for subjects aged 65–69, ≤11 for subjects aged 70–74, ≤9 for subjects aged 75–79, and ≤7 for subjects aged 80–90.

[0065]

[65] One aspect of the present disclosure relates to a method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, the method comprising administering an anti-Aβ protofibril antibody to a subject having 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 dosing plan comprising: administering the antibody intravenously every other week at an initial dose of 10 mg / kg of the subject's body weight; and, for example, administering the antibody subcutaneously every week or every other week at a maintenance dose of 250 mg after 18 or 24 months of administration at the initial dose.

[0066]

[66] One aspect of the present disclosure relates to a method for delaying the clinical progression of a subject having AD, suspected AD, or at risk of AD, the method comprising administering an anti-Aβ protofibril antibody to a subject having 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 dosing plan comprising: administering the antibody intravenously every other week at an initial dose of 10 mg / kg of the subject's body weight; and, for example, administering the antibody subcutaneously every week or every other week at a maintenance dose of 250 mg after 18 months of administration at the initial dose.

[0067]

[67] Another aspect of the present disclosure relates to a method for reducing brain amyloid levels in subjects who have, are suspected of having, or are at risk of having AD, the method comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementary 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 complementary 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 dosing plan comprising: administering the antibody intravenously every other week at an initial dose of 10 mg / kg of the subject's body weight; and, for example, administering the antibody subcutaneously every week or every other week at a maintenance dose of 250 mg after 18 or 24 months of administration at the initial dose.

[0068]

[68] Further aspects of the present disclosure relate to a method for converting an amyloid-positive subject to amyloid-negative, the method comprising administering an anti-Aβ protofibril antibody to a subject having 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 dosing plan comprising: administering the antibody intravenously every other week at an initial dose of 10 mg / kg of the subject's body weight; and, for example, administering the antibody subcutaneously every week or every other week at a maintenance dose of 250 mg after 18 or 24 months of administration at the initial dose.

[0069]

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

[0070]

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

[0071]

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

[0072]

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

[0073]

[73] In some embodiments, the maintenance dose of the antibody is administered every other week.

[0074]

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

[0075]

[75] In some embodiments, the maintenance dose of the antibody is administered using AI.

[0076]

[76] One aspect of the present disclosure relates to a method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, the method comprising administering an anti-Aβ protofibril antibody to a subject having 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: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3), according to a dosing plan comprising: weekly subcutaneous administration of the antibody at an initial dose of 500 mg; and weekly or bi-weekly subcutaneous administration of the antibody at a maintenance dose of 250 mg after, for example, 18 or 24 months of administration at the initial dose.

[0077]

[77] Another aspect of the present disclosure relates to a method for delaying the clinical progression of a subject having AD, suspected AD, or at risk of AD, the method comprising administering an anti-Aβ protofibril antibody to a subject having 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 dosing plan comprising: weekly subcutaneous administration of the antibody at an initial dose of 500 mg; and weekly or bi-weekly subcutaneous administration of the antibody at a maintenance dose of 250 mg after, for example, 18 or 24 months of administration at the initial dose.

[0078]

[78] Further aspects of the present disclosure relate to a method for reducing brain amyloid levels in subjects having, suspected of having, or at risk of having AD, the method comprising administering an anti-Aβ protofibril antibody to a subject having 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, LCDR1, 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 dosing plan comprising: weekly subcutaneous administration of the antibody at an initial dose of 500 mg; and weekly or bi-weekly subcutaneous administration of the antibody at a maintenance dose of 250 mg after, for example, 18 or 24 months of administration at the initial dose.

[0079]

[79] Another aspect of the present disclosure relates to a method for converting an amyloid-positive subject to amyloid-negative, the method comprising administering an antibody to a subject having 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), which is carried out according to a dosing plan comprising: administering the antibody subcutaneously weekly at an initial dose of 500 mg; and administering the antibody subcutaneously weekly or bi-weekly at a maintenance dose of 250 mg after, for example, 18 or 24 months of administration at the initial dose.

[0080]

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

[0081]

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

[0082]

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

[0083]

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

[0084]

[84] In some embodiments, the initial dose of antibody is administered using AI.

[0085]

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

[0086]

[86] In some embodiments, the maintenance dose of the antibody is administered every other week.

[0087]

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

[0088]

[88] In some embodiments, the maintenance dose of the antibody is administered using AI.

[0089]

[89] In some embodiments, the anti-Aβ protofibril antibody comprises a heavy chain complementary 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.

[0090]

[90] In some embodiments, the anti-Aβ protofibril antibody is BAN2401 (lecanemab).

[0091]

[91] In some embodiments, subjects show changes in measurements of one or more biomarkers related to AD pathology prior to treatment.

[0092]

[92] In some embodiments, the change in the measured value is selected from: a. an increase in brain amyloid (e.g., centroid value of about 20-40, e.g., centroid value of about 20-32) measured by amyloid PET, b. an increase in brain tau measured by positron emission tomography (PET), c. a decrease in cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, p Increased levels of tau-217 / np-tau-217 ratio, neurogranin, and / or neurofilament light chains (NfL), and decreased serum or plasma levels of d.Aβ1-42 / 1-40 ratio and / or increased levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau-181, P-tau-217, and / or P-tau-231), p-tau-181 / np-tau-181 ratio, p-tau-217 / np-tau-217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL).

[0093]

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

[0094]

[94] In some embodiments, the change and / or difference in the measured values ​​is selected from: a. a decrease in brain amyloid (e.g., centroid value of about 20-40, e.g., centroid value of about 20-32), measured by amyloid PET, for example; b. a decrease in brain tau, measured by positron emission tomography (PET), for example; c. an increase in cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 18 Decreased levels of 1 ratio, p-tau-217 / np-tau-217 ratio, neurogranin, and / or neurofilament light chains (NfL), and increased serum or plasma levels of d.Aβ1-42 / 1-40 ratio and / or decreased levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau-181, P-tau-217, and / or P-tau-231), p-tau-181 / np-tau-181 ratio, p-tau-217 / np-tau-217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL).

[0095]

[95] In some embodiments, subjects are amyloid-positive before administration, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), MRI, and retinal amyloid accumulation.

[0096]

[96] In some embodiments, the subjects are ApoE4 positive.

[0097]

[97] In some embodiments, subjects are monitored for the onset of ARIA.

[0098]

[98] In some embodiments, the subjects are between 65 and 80 years old.

[0099]

[99] In some embodiments, subjects are aged 55–64 years and have at least one risk factor selected from: (i) a first-degree relative diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid levels based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration.

[0100]

[0100] In some embodiments, the subject has Alzheimer's disease.

[0101]

[0101] In some embodiments, the subject has early Alzheimer's disease.

[0102]

[0102] In some embodiments, the subject has been diagnosed with any of the following: a. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) and / or mild Alzheimer's dementia; b. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a pre-treatment CDR global score of 0.5 and a Memory Box score of 0.5 or higher; d. mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a medical history (e.g., corroborated by an informant) of subjective memory impairment with slow onset and slow progression in the year prior to treatment; e. mild Alzheimer's dementia based on the NIA-AA core clinical criteria for Alzheimer's dementia; or f. mild Alzheimer's dementia based on a pre-treatment CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or higher.

[0103]

[0103] In some embodiments, the subject is suspected of being AD.

[0104]

[0104] In some embodiments, the subject is at risk of developing Alzheimer's disease (AD).

[0105]

[0105] In some embodiments, subjects at risk of developing AD have pre-AD.

[0106]

[0106] In some embodiments, the subjects do not have cognitive impairment.

[0107]

[0107] In some embodiments, the subject has a Global Clinical Dementia Scale (CDR) score of 0 prior to administration.

[0108]

[0108] In some embodiments, the subjects have a Mini-Mental State Examination (MMSE) score of 27 or higher, including the pre-administration educational adjustments.

[0109]

[0109] In some embodiments, the subjects have a WMS-IV LMII score that is at least one standard deviation lower than the age-adjusted mean of the Revised Logical Memory Subscale II (WMS-R LM II) prior to the administration, and is 15 or less for subjects aged 50-64, 12 or less for subjects aged 65-69, 11 or less for subjects aged 70-74, 9 or less for subjects aged 75-79, and 7 or less for subjects aged 80-90.

[0110]

[0110] Further aspects of the present disclosure relate to a method for treating a subject who has, is suspected of having, or is at risk of having early AD and has received a first anti-Aβ antibody, the method comprising administering a second anti-Aβ protofibril antibody to the subject, which has three heavy chain complementation-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 complementation-determining regions (LCDR1, LCDR1, 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 dosing schedule comprising administering the second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg of the subject's body weight; or administering the second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg.

[0111]

[0111] Another aspect of the present disclosure relates to a method for delaying the clinical deterioration of a subject who has received a first anti-Aβ antibody, the method comprising administering a second anti-Aβ protofibril antibody to a subject, the second having three heavy chain complementation-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 complementation-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 dosing schedule comprising administering the second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg of the subject's body weight; or administering the second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg.

[0112]

[0112] One aspect of the present 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 a second anti-Aβ protofibril antibody to a subject, the second having 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 dosing schedule comprising administering the second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg of the subject's body weight; or administering the second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg.

[0113]

[0113] Further aspects of the present disclosure relate to a method for maintaining amyloid levels in a subject who has received a first anti-Aβ antibody, the method comprising administering a second anti-Aβ protofibril antibody to a subject, the second having three heavy chain complementation-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 complementation-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 dosing schedule comprising administering the second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg of the subject's body weight; or administering the second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg.

[0114]

[0114] One aspect of the present disclosure relates to a method for treating a subject who has, is suspected of having, or is at risk of having early AD, the method comprising administering a first anti-Aβ protofibril antibody to the subject, and administering a second anti-Aβ protofibril antibody to the subject having 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 carried out according to a dosing plan comprising administering the second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg of the subject's body weight; or administering the second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg.

[0115]

[0115] In some embodiments, the maintenance dose of antibody to be administered subcutaneously is administered using a vial-syringe.

[0116]

[0116] In some embodiments, the maintenance dose of antibody administered subcutaneously is administered using AI.

[0117]

[0117] In some embodiments, the first anti-Aβ antibody is selected from aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, or soranezumab.

[0118]

[0118] In some embodiments, the first anti-Aβ antibody is donanemab.

[0119]

[0119] Another aspect of the present disclosure relates to a method for treating a subject who has, is suspected of having, or is at risk of having early AD, the method comprising administering an anti-Aβ protofibril antibody to the subject, which has 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, LCDR1, 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 method being carried out according to a dosing plan comprising the steps of: intravenously administering the antibody every other week at an initial dose of 10 mg / kg of the subject's body weight; subcutaneously administering the antibody weekly at a second initial dose of 720 or 500 mg; and subcutaneously administering the antibody weekly at a dose of 250 mg after, for example, 18 or 24 months of treatment at the initial dose.

[0120]

[0120] In some embodiments, the subject receives a thrombolytic agent or antiplatelet agent instead of an anticoagulant.

[0121]

[0121] In some embodiments, the subject is receiving an antiplatelet drug.

[0122]

[0122] In some embodiments, the subject is receiving a thrombolytic agent.

[0123]

[0123] In some embodiments, the thrombolytic agent is selected from aspirin or a fibrinolytic agent.

[0124]

[0124] In some embodiments, the subject is receiving aspirin.

[0125]

[0125] In some embodiments, the subject is subjected to a fibrin-solving agent.

[0126]

[0126] In some embodiments, the subjects have experienced or are at high risk of experiencing a cerebral hemorrhage event, such as a microhemorrhage or intracerebral hemorrhage, or an ARIA event, prior to treatment.

[0127]

[0127] In some embodiments, the subjects have not experienced a cerebral hemorrhage event, such as a microhemorrhage or intracerebral hemorrhage, or an ARIA event prior to treatment.

[0128] [Enumerated embodiments] 1. A method for treating Alzheimer's disease (AD) in subjects who have AD, are suspected of having AD, or are at risk of having AD, comprising administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subject, wherein the subject has not experienced a cerebral hemorrhage event (e.g., microbleed or intracerebral hemorrhage) prior to treatment and / or has not shown any changes such as a decrease in cerebral white matter as measured by brain imaging prior to treatment. 2. A method for selecting subjects with AD, suspected AD, or at risk of AD for treatment with anti-amyloid-beta (Aβ) protofibril antibodies, the following: a. A step in determining that the subject has not experienced any intracerebral hemorrhage events (e.g., microbleeds or intracerebral hemorrhage) prior to treatment, and / or has not experienced any such events currently, and / or has not shown any changes in the brain white matter, such as a decrease, as measured by brain imaging; b. A step to select patients for treatment with a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody. Methods that include... 3. A method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, comprising administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subject, wherein the subject is receiving a thrombolytic agent or antiplatelet agent, rather than an anticoagulant. 4. The method according to Embodiment 3, wherein the subject is receiving an antiplatelet drug. 5. The method according to Embodiment 3, wherein the subject is receiving a thrombolytic agent. 6. The method according to Embodiment 5, wherein the thrombolytic agent is selected from aspirin or a fibrinolytic agent. 7. The method according to Embodiment 6, wherein the subject is receiving aspirin. 8. The method according to Embodiment 6, wherein the subject is receiving a fibrin-solving agent. 9. A method for treating Alzheimer's disease (AD) in subjects who have AD, are suspected of having AD, or are at risk of having AD, comprising administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subject, wherein the subject is not receiving treatment with anticoagulants. 10. A method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, comprising administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subject, wherein the subject is at high risk of an ARIA event or a hemorrhagic event (e.g., microbleed or intracerebral hemorrhage), and the method further comprises administering a steroid and / or monitoring the subject's brain (e.g., by MRI). 11. The method according to Embodiment 10, wherein the subject has previously experienced a cerebral hemorrhage event (e.g., microhemorrhage or intracerebral hemorrhage) or an ARIA event prior to treatment. 12. A method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, comprising the steps of administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subject, detecting an ARIA event (e.g., a severe ARIA event, ARIA-H, ARIA-E), and administering a steroid. 13. The method according to any one of Embodiments 1 to 12, wherein the method reduces brain amyloid. 14. A method for treating severe ARIA in a subject receiving anti-amyloid-beta (Aβ) protofibril antibody therapy, comprising the steps of administering a steroid and / or monitoring the subject's brain (e.g., by MRI). 15. The method according to any one of Embodiments 1 to 14, wherein the anti-Aβ protofibril antibody comprises three heavy chain complementation 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 complementation 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). 16. The method according to any one of Embodiments 1 to 15, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 8. 17. The method according to any one of Embodiments 1 to 16, wherein the anti-Aβ protofibril antibody comprises BAN2401 (lecanemab). 18. The method according to any one of Embodiments 1 to 17, comprising intravenous infusion of a therapeutically effective dose of anti-Aβ protofibril antibody at a dose of 10 mg / kg relative to the subject's body weight. 19. The method according to any one of Embodiments 1 to 17, comprising subcutaneous administration of approximately 250 to 720 mg of an effective therapeutic dose of anti-Aβ protofibril antibody. 20. The method according to any one of Embodiments 1 to 17, comprising a subcutaneous administration of 250 mg of a therapeutically effective dose of anti-Aβ protofibril antibody. 21. The method according to any one of Embodiments 1 to 17, comprising a subcutaneous administration of 360 mg of a therapeutically effective dose of anti-Aβ protofibril antibody. 22. The method according to any one of Embodiments 1 to 17, comprising a subcutaneous administration of 500 mg of a therapeutically effective dose of anti-Aβ protofibril antibody. 23. The method according to any one of Embodiments 1 to 17, comprising a subcutaneous administration of 720 mg of a therapeutically effective dose of anti-Aβ protofibril antibody. 24. The method according to any one of Embodiments 1 to 19, wherein the therapeutically effective dose is administered subcutaneously by an auto-injector. 25. The method according to any one of Embodiments 1 to 18, wherein the therapeutically effective dose is administered once a week. 26. The method according to any one of embodiments 1 to 17 and 19 to 24, wherein the therapeutically effective dose is administered every two weeks. The method according to any one of Embodiments 1 to 26, wherein the frequency of administration is reduced to, for example, every 2, 4, 6, 8, 10, or 12 weeks after 27.18 months of treatment. 28. A method in which, after 18 months of treatment, the effective therapeutic dose is reduced to, for example, a subcutaneous dose of 360 mg or 250 mg, or maintained at an intravenous dose of 10 mg / kg. 29. The method according to Embodiment 22 or any one of Embodiments 24-28, wherein the therapeutically effective dose is reduced from a subcutaneous dose of 500 mg per week to a subcutaneous dose of 360 mg per week or 250 mg per week. 30. The method according to any one of the implementations 24-28, 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 according to any one of Embodiments 1 to 30, wherein the second therapeutic agent is administered to the subject sequentially or simultaneously. 32. The method according to Embodiment 31, wherein the second therapeutic agent is an anti-tau antibody. 33. The method according to Embodiment 32, wherein the anti-tau antibody comprises three heavy chain complementation 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 complementation 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). 34. The method according to Embodiment 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. 35. The method according to any one of Embodiments 1 to 34, further comprising monitoring of ARIA, e.g., ARIA-E and / or ARIA-H, as observed by MRI, for example. 36. The method according to any one of Embodiments 1 to 35, wherein a titration step is not required before administering a first therapeutically effective dose of anti-Aβ protofibril antibody to the target. 37. The method, compared to a pre-treatment and / or untreated control, is as follows: a. One or more cerebrospinal fluid biomarkers, e.g., Aβ1-42, Aβ1-40 (including the Aβ1-42:Aβ1-40 ratio), total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, neurogranin, neurofilament light chain (NfL) peptide, improvement or slowing of the deterioration of phosphorylated tau; and / or b. Decrease in plasma or serum biomarkers, e.g., Aβ1-42, Aβ1-40 (including the Aβ1-42:Aβ1-40 ratio), total tau, phosphorylated tau (P-tau) (tau phosphorylated at position 181 (P-tau181), 217 (P-tau217), 231 (P-tau231)), P-tau181 / NP-tau181 ratio, and / or P-tau217 / NP-tau217 ratio, glial fibrillary acidic protein (GFAP), and / or slowing of the decrease or increase of neurofilamentous light chains (NfL). A method according to any one of embodiments 1 to 36, which brings about the following: 38. Treatment, a. Determine clinical progression using ADCOMS; b. Determine clinical deterioration using ADAS MCI-ADL; c. Determine the clinical progression using the modified iADRS; d. To measure by CDR-SB, to slow clinical progression; or e.Measured by ADAS-Cog, it slows clinical progression. The method according to any one of Embodiments 1 to 37. 39. The method according to Embodiment 37 or Embodiment 38, wherein the results are measured at least 6 months after administration of the first therapeutically effective dose. 40. The method according to any one of embodiments 37 to 39, wherein the results are measured at least 12 months after administration of the first therapeutically effective dose. 41. The method according to any one of embodiments 37 to 39, wherein the results are measured at least 13 months after administration of the first therapeutically effective dose. 42. The method according to any one of embodiments 37 to 39, wherein the results are measured at least 18 months after administration of the first therapeutically effective dose. 43. The method according to any one of embodiments 37 to 42, wherein the subject is switched from an initial administration plan to a maintenance administration plan. 44. The method according to Embodiment 43, wherein the switch to the maintenance dose is performed at least 6 months (e.g., 6 months, 13 months, or 18 months) after the start of the initial administration plan, or after the subject has converted to an amyloid-negative state, as determined by, for example, improvement of biomarkers. 45. The method according to Embodiment 43 or Embodiment 44, wherein the initial administration plan includes intravenous infusion of a therapeutically effective dose of 10 mg / kg of the subject's body weight every two weeks. 46. ​​The method according to Embodiment 43 or Embodiment 44, wherein the initial administration plan includes subcutaneous administration of an effective therapeutic dose of 720 mg of anti-Aβ protofibril antibody. 47. The method according to Embodiment 43 or Embodiment 44, wherein the initial administration plan includes subcutaneous administration of an effective therapeutic dose of 500 mg of anti-Aβ protofibril antibody. 48. The method according to any one of Embodiments 43 to 47, wherein the maintenance administration plan includes monthly intravenous infusion of a therapeutically effective dose of 10 mg / kg relative to the subject's body weight. 49. The method according to any one of Embodiments 43 to 47, wherein the maintenance administration plan includes subcutaneous administration of an effective therapeutic dose of 360 mg of anti-Aβ protofibril antibody. 50. The method according to any one of Embodiments 43 to 47, wherein the maintenance administration plan includes subcutaneous administration of an effective therapeutic dose of 250 mg of anti-Aβ protofibril antibody weekly. 51. The method according to any one of Embodiments 43 to 45, wherein the maintenance administration plan includes the same administration plan as the initial administration plan. 52. A method for treating Alzheimer's disease (AD) in subjects who have, are suspected of having, or are at risk of having AD, comprising the steps of selecting patients who are not receiving anticoagulants, and administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subjects. 53. A method for treating Alzheimer's disease (AD) in subjects who have, are suspected of having, or are at risk of having AD, comprising the steps of selecting patients who have not received thrombolytic agents, and administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subjects. Methods that include... 54. A method for treating Alzheimer's disease (AD) in a person who has, is suspected of having, or is at risk of having AD, the method comprising the steps of: selecting a patient receiving an anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent); administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the patient; and monitoring the patient for ARIA. 55. A method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, comprising the steps of administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the subject, administering an anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent, antiplatelet agent) as needed, and monitoring the subject for ARIA. 56. A method for treating Alzheimer's disease (AD) in a person who has, is suspected of having, or is at risk of having AD, the following: a. A step of administering a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody to the target; b. If the subject is administered an anticoagulant or thrombolytic agent (e.g., aspirin, fibrinolytic agent, antiplatelet agent), discontinue administration of anti-amyloid-beta (Aβ) protofibril antibody to the subject; c. The step of resuming administration of anti-amyloid-beta (Aβ) protofibril antibodies to the subject at or after the subject has stopped receiving anticoagulants or thrombolytic agents (e.g., aspirin, fibrinolytic agents, antiplatelet agents); and d. Steps to monitor the subject regarding ARIA Methods that include... 57. A method for treating Alzheimer's disease (AD) in a subject who has, is suspected of having, or is at risk of having AD, comprising the steps of: selecting patients who are receiving anticoagulants or thrombolytic agents (e.g., aspirin, fibrinolytic agents, antiplatelet agents); and delaying the administration of an anti-amyloid-beta (Aβ) protofibril antibody to the subject until the treatment with the anticoagulant or thrombolytic agent is completed. 58. The method according to any one of Embodiments 1 to 57, wherein a subject shows a change and / or difference in a measurement of one or more biomarkers related to pre-treatment AD pathology compared to a reference measurement (e.g., a measurement from a healthy control). 59. The changes in the measured values ​​are as follows: a. For example, by measuring with amyloid PET, an increase in brain amyloid (e.g., a centiloid value of approximately 20-40, e.g., a centiloid value of approximately 20-32), b. For example, by measuring the increase in brain tau using positron emission tomography (PET), c. Decreased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or increased total tau, p-tau (e.g., p-tau 181, p-tau 217, p-tau 231, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 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 levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau 181, P-tau 217, P-tau 231, P-tau 181 / NP-tau 181 ratio, and / or P-tau 217 / NP-tau 217 ratio), glial fibrillary acidic protein (GFAP), and / or neurofilamentous light chain (NfL). The method according to embodiment 58, selected from the above. 60. The method according to any one of Embodiments 1 to 59, wherein the subject is amyloid-positive before treatment, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), MRI, retinal amyloid accumulation, and / or blood biomarker evaluation (e.g., Aβ1-42 / 1-40 ratio, plasma p-tau 181, plasma p-tau 217, plasma p-tau 231 levels, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio). 61. The method according to any one of Embodiments 1 to 60, wherein the subject is ApoE4 positive. 62. The method according to any one of Embodiments 1 to 61, wherein the subject is monitored for the onset of ARIA. 63. The method according to any one of Embodiments 1 to 62, wherein the subject is 65 to 80 years old. 64. The subjects are aged 55-64 and meet the following criteria: (i) A first-degree relative diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Elevated brain amyloid levels based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration. The method according to any one of embodiments 1 to 62, having at least one risk factor selected from the following. 65. The method according to any one of Embodiments 1 to 64, wherein the subject has Alzheimer's disease. 66. The method according to any one of Embodiments 1 to 65, wherein the subject has early-stage Alzheimer's disease. 67. The target is as follows: a. Diagnosed with mild cognitive impairment due to Alzheimer's disease (moderate likelihood) and / or mild Alzheimer's dementia; b. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. Mild cognitive impairment due to Alzheimer's disease based on a pre-treatment CDR global score of 0.5 and a Memory Box score of 0.5 or higher (moderate likelihood); d. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a medical history of subjective memory impairment with slow onset and slow progression within the year prior to treatment (e.g., corroborated by an informant); e. Mild Alzheimer's disease based on the NIA-AA core clinical criteria for Alzheimer's disease; or f. Mild Alzheimer's disease based on a pre-treatment CDR score of 0.5-1.0 and a Memory Box score of 0.5 or higher. The method according to any one of embodiments 1 to 66, which is diagnosed as having any of the following: 68. The method according to any one of Embodiments 1 to 67, wherein the subject is suspected to have AD. 69. The method according to any one of Embodiments 1 to 68, wherein the subject is a subject at risk of developing Alzheimer's disease (AD). 70. The method according to Embodiment 69, wherein the subject at risk of developing AD has pre-Alzheimer's disease (pre-AD). 71. The method according to Embodiment 70, wherein the subject does not have cognitive impairment. 72. The method according to any one of Embodiments 69 to 71, wherein the subject has a Global Clinical Dementia Scale (CDR) score of 0. 73. The method according to any one of Embodiments 69 to 72, wherein the subject has a Mini-Mental State Examination (MMSE) score of 27 or higher (including educational adjustments) prior to the administration. 74. The method according to any one of embodiments 69 to 73, wherein, prior to the administration, the subject has a WMS-IV LMII score that is at least one standard deviation lower than the age-adjusted mean of the Revised Logical Memory Subscale II (WMS-R LM II), and the score is 15 or less for subjects aged 50 to 64 years, 12 or less for subjects aged 65 to 69 years, 11 or less for subjects aged 70 to 74 years, and 9 or less for subjects aged 75 to 79 years. 75. A method for treating Alzheimer's disease (AD) in a subject who has AD, is suspected of having AD, or is at risk of having AD, comprising subcutaneously administering an anti-Aβ protofibril antibody to the subject at a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), comprising three heavy chain complementary 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 complementary determining regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 76. A method for delaying the clinical progression of a subject who has AD, is suspected of having AD, or is at risk of having AD, comprising subcutaneously administering an anti-Aβ protofibril antibody to the subject at a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), comprising three heavy chain complementary 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 complementary determining regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 77. A method for reducing brain amyloid levels in a subject who has AD, is suspected of having AD, or is at risk of having AD, comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementary 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 complementary determining regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). 78. A method for converting an amyloid-positive subject to an amyloid-negative state, comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementation-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 complementation-determining regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). The method according to any one of Embodiments 75 to 78, wherein the antibody is administered subcutaneously at a dose of 79.150 mg to 600 mg, for example, 200 mg to 550 mg (e.g., 500 mg), thereby reducing the biomarkers of AD pathology and / or lowering systemic exposure (e.g., AUC) to the antibody compared to administration at a higher dose, for example, 720 mg. The method according to any one of embodiments 75 to 79, wherein an antibody administered subcutaneously in a dose of 80.150 mg to 600 mg, for example 200 mg to 550 mg (for example 500 mg), reduces the risk of ARIA compared to a higher dose, for example 720 mg of the antibody administered subcutaneously. 81. The method according to any one of Embodiments 75 to 80, wherein the anti-Aβ protofibril antibody is administered in 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. 82. The method according to any one of Embodiments 75 to 81, wherein an anti-Aβ protofibril antibody is administered subcutaneously at a dose of 500 mg. 83. The method according to any one of embodiments 75 to 82, wherein the dose is administered in two parts, for example, consecutively. 84. The method according to any one of embodiments 75 to 83, wherein an anti-Aβ protofibril antibody is administered once a week. 85. The method according to any one of embodiments 75 to 83, wherein an anti-Aβ protofibril antibody is administered once every two weeks. 86. The method according to any one of embodiments 75 to 83, wherein an anti-Aβ protofibril antibody is administered once a month. 87. The method according to any one of embodiments 75 to 86, wherein the anti-Aβ protofibril antibody is administered, for example, in an initial dose during a first period according to an initiation dose plan, and then, for example, in a maintenance dose during a second period according to a maintenance dose plan. 88. The method according to Embodiment 87, wherein the starting dose is 500 mg. 89. The method according to Embodiment 87 or Embodiment 88, wherein the starting dose is greater than the maintenance dose. 90. The method according to any one of embodiments 87 to 89, wherein the maintenance dose is 360 mg. 91. The method according to any one of Embodiments 87 to 90, wherein the maintenance dose is 250 mg. 92. The method according to any one of embodiments 87 to 91, wherein the starting dose is administered weekly. 93. The method according to any one of embodiments 87 to 92, wherein the maintenance dose is administered weekly. 94. The method according to any one of embodiments 87 to 92, wherein the maintenance dose is administered every other week. 95. The method according to any one of embodiments 87 to 94, wherein the first period is at least about 6 months, about 12 months, about 18 months, about 24 months, or about 30 months. 96. The method according to Embodiment 95, wherein the first period is at least 18 months. 97. The method according to Embodiment 95 or Embodiment 96, wherein the first period is at least 24 months. 98. The method according to any one of embodiments 87 to 97, wherein the first period is continued until the subject becomes amyloid-negative. 99. The method according to any one of Embodiments 87 to 98, wherein an anti-protofibril antibody (e.g., BAN2401) is administered subcutaneously at an initial dose of 500 mg once weekly for at least 18 months, followed by a maintenance dose of 250 mg once weekly for a second period. 100. The method according to any one of Embodiments 87 to 98, wherein an anti-protofibril antibody (e.g., BAN2401) is administered subcutaneously at a starting dose of 500 mg once weekly for at least 18 months, followed by a maintenance dose of 360 mg every other week for a second period. 101. The method according to any one of embodiments 87 to 100, wherein a second period is initiated when one or more biomarkers in the subject show a reduction or delay in the progression of AD. 102. The method according to any one of Embodiments 87 to 101, wherein the second 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 over the lifetime of the subject. 103. The method according to any one of embodiments 87 to 102, wherein the maintenance dose is administered subcutaneously using an auto-injector (AI). 104. The method according to any one of Embodiments 75 to 103, wherein the anti-Aβ protofibril antibody is administered subcutaneously to the subject after intravenous administration of the antibody. 105. The method according to any one of Embodiments 75 to 103, wherein an anti-Aβ protofibril antibody is administered subcutaneously to the subject before intravenous administration of the antibody. 106. The method according to Embodiment 104 or Embodiment 105, wherein intravenous infusion is administered every other week at a dose of 10 mg / kg relative to the subject's body weight. 107. The method according to any one of Embodiments 75 to 106, wherein the anti-Aβ protofibril antibody is contained in the pharmaceutical composition in the form of a pre-filled syringe. 108. The method according to any one of Embodiments 75 to 106, wherein an anti-Aβ protofibril antibody is contained in a pharmaceutical composition in an auto-injector. 109. The method according to any one of Embodiments 75 to 108, wherein the anti-Aβ protofibril antibody comprises a heavy chain complementary 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. 110. The method according to any one of Embodiments 75 to 108, wherein the anti-Aβ protofibril antibody is BAN2401 (lecanemab). 111. The method according to any one of Embodiments 75 to 110, wherein the subject shows a change in the measurement value of one or more biomarkers related to AD pathology before treatment. 112. The changes in the measured values ​​are as follows: a. For example, by measuring with amyloid PET, an increase in brain amyloid (e.g., a centiloid value of approximately 20-40, e.g., a centiloid value of approximately 20-32), b. For example, by measuring the increase in brain tau using positron emission tomography (PET), c. Decreased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or increased total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 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-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilamentous light chain (NfL). A method according to embodiment 111, selected from the above. 113. The method according to any one of Embodiments 75 to 112, wherein the subject is amyloid-positive before administration, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), MRI, retinal amyloid accumulation, and / or blood biomarker evaluation (e.g., Aβ1-42 / 1-40 ratio, plasma p-tau 181, plasma p-tau 217, plasma p-tau 231 levels, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio). 114. The method according to any one of embodiments 75 to 113, wherein the subject is ApoE4 positive. 115. The method according to any one of embodiments 75 to 114, wherein the subject is monitored for the onset of ARIA. 116. The method according to any one of embodiments 75 to 115, wherein the subject is 65 to 80 years old. 117. The subjects are aged 55-64 years and have at least one risk factor, and the risk factor is as follows: (i) A first-degree relative diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Elevated brain amyloid levels based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration. A method according to any one of embodiments 75 to 115, selected from the above. 118. The method according to any one of embodiments 75 to 117, wherein the subject has Alzheimer's disease. 119. The method according to any one of embodiments 75 to 118, wherein the subject has early-stage Alzheimer's disease. 120. The target is as follows: a. Diagnosed with mild cognitive impairment due to Alzheimer's disease (moderate likelihood) and / or mild Alzheimer's dementia; b. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. Mild cognitive impairment due to Alzheimer's disease based on a pre-treatment CDR global score of 0.5 and a Memory Box score of 0.5 or higher (moderate likelihood); d. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a medical history of subjective memory impairment with slow onset and slow progression within the year prior to treatment (e.g., corroborated by an informant); e. Mild Alzheimer's disease based on the NIA-AA core clinical criteria for Alzheimer's disease; or f. Mild Alzheimer's disease based on a pre-treatment CDR score of 0.5-1.0 and a Memory Box score of 0.5 or higher. The method according to any one of embodiments 75 to 119, which has been diagnosed as having any of the following: 121. The method according to any one of embodiments 75 to 117, wherein the subject is suspected to have AD. 122. The method according to any one of embodiments 75 to 117, wherein the subject is a subject at risk of developing Alzheimer's disease (AD). 123. The method according to Embodiment 122, wherein the subject at risk of developing AD has pre-AD. 124. The method according to Embodiment 123 or Embodiment 124, wherein the subject does not have cognitive impairment. 125. The method according to any one of Embodiments 122 to 124, wherein the subject has a Global Clinical Dementia Scale (CDR) score of 0 prior to the administration. 126. The method according to any one of Embodiments 122 to 125, wherein the subject has a Mini-Mental State Examination (MMSE) score (including educational adjustments) of 27 or higher prior to the administration of the above-mentioned treatment. 127. The method according to any one of embodiments 122 to 126, wherein, prior to the administration, the subject has a WMS-IV LMII score that is at least one standard deviation lower than the age-adjusted mean of the Revised Logical Memory Subscale II (WMS-R LM II), and is 15 or less for subjects aged 50 to 64 years, 12 or less for subjects aged 65 to 69 years, 11 or less for subjects aged 70 to 74 years, 9 or less for subjects aged 75 to 79 years, and 7 or less for subjects aged 80 to 90 years. 128. A method for treating Alzheimer's disease (AD) in subjects who have AD, are suspected of having AD, or are at risk of having AD, comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementation-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 complementation-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), which is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, after administering the initial dose for 18 months, the antibody is administered subcutaneously weekly or bi-weekly at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 129. A method for delaying the clinical progression of a subject with AD, suspected AD, or at risk of AD, comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementary 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 complementary 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), which is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, after administering the initial dose for 18 months, the antibody is administered subcutaneously weekly or bi-weekly at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 130. A method for reducing brain amyloid levels in subjects with AD, suspected AD, or at risk of AD, comprising administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementary 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 complementary regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), which is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, after administering the initial dose for 18 months, the antibody is administered subcutaneously weekly or bi-weekly at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 131. A method for converting an amyloid-positive subject to an amyloid-negative subject, comprising administering an antibody to a subject having three heavy chain complementation-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 complementation-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), wherein the antibody is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, after administering the initial dose for 18 months, the antibody is administered subcutaneously weekly or bi-weekly at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 132. The method according to any one of Embodiments 128 to 131, wherein the maintenance dose is 500 mg. 133. The method according to any one of Embodiments 128 to 131, wherein the maintenance dose is 360 mg. 134. The method according to any one of Embodiments 128 to 131, wherein the maintenance dose is 250 mg. 135. The method according to any one of Embodiments 128 to 134, wherein the starting 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. 136. The method according to any one of embodiments 128 to 135, wherein the starting dose of the antibody is administered intravenously for at least 18 months. 137. The method according to any one of embodiments 128 to 136, wherein the starting dose of the antibody is administered intravenously for at least 24 months. 138. The method according to any one of embodiments 128 to 137, wherein a maintenance dose of antibody is administered weekly. 139. The method according to any one of embodiments 128 to 137, wherein a maintenance dose of antibody is administered every other week. 140. The method according to any one of Embodiments 128 to 139, wherein a maintenance dose of antibody is administered using a vial-syringe. 141. The method according to any one of Embodiments 128 to 139, wherein a maintenance dose of antibody is administered using AI. 142. A method for treating Alzheimer's disease (AD) in subjects who have AD, are suspected of having AD, or are at risk of having AD, comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementation-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 complementation-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), which is as follows: A step of administering the antibody subcutaneously weekly at a starting dose of 500 mg; and For example, a step in which, after administering the initial dose for 18 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following. 143. A method for delaying the clinical progression of a subject who has AD, is suspected of having AD, or is at risk of having AD, comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementary 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 complementary 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), which is as follows: A step of administering the antibody subcutaneously weekly at a starting dose of 500 mg; and For example, a step in which, after administering the initial dose for 18 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following. 144. A method for reducing brain amyloid levels in subjects with AD, suspected AD, or at risk of AD, comprising administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementary 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 complementary regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), which is as follows: A step of administering the antibody subcutaneously weekly at a starting dose of 500 mg; and For example, a step in which, after administering the initial dose for 18 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following. 145. A method for converting an amyloid-positive subject to an amyloid-negative subject, comprising administering an antibody to a subject having three heavy chain complementation-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 complementation-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), wherein the antibody is as follows: A step of administering the antibody subcutaneously weekly at a starting dose of 500 mg; and For example, a step in which, after administering the initial dose for 18 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following. 146. The method according to any one of Embodiments 142 to 145, wherein the starting dose of antibody is administered subcutaneously for at least 6 months, at least 12 months, at least 18 months, or at least 24 months. 147. The method according to any one of embodiments 142 to 146, wherein the starting dose of the antibody is administered subcutaneously for at least 18 months. 148. The method according to any one of embodiments 142 to 147, wherein the starting dose of the antibody is administered subcutaneously for at least 24 months. 149. The method according to any one of Embodiments 142 to 148, wherein the starting dose of antibody is administered using a vial-syringe. 150. The method according to any one of Embodiments 142 to 148, wherein the starting dose of antibody is administered using AI. 151. The method according to any one of Embodiments 142 to 150, wherein a maintenance dose of antibody is administered weekly. The method according to any one of Embodiments 142 to 150, wherein a maintenance dose of 152 antibodies is administered every other week. 153. The method according to any one of Embodiments 142 to 152, wherein a maintenance dose of antibody is administered using a vial-syringe. 154. The method according to any one of Embodiments 142 to 152, wherein a maintenance dose of antibody is administered using AI. 155. The method according to any one of Embodiments 128 to 154, wherein the anti-Aβ protofibril antibody comprises a heavy chain complementary 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. 156. The method according to any one of Embodiments 128 to 155, wherein the anti-Aβ protofibril antibody is BAN2401 (lecanemab). 157. The method according to any one of Embodiments 128 to 156, wherein the subject shows changes in the measurement value of one or more biomarkers related to AD pathology before treatment. 158. The changes in the measured values ​​are as follows: a. For example, by measuring with amyloid PET, an increase in brain amyloid (e.g., a centiloid value of approximately 20-40, e.g., a centiloid value of approximately 20-32), b. For example, by measuring the increase in brain tau using positron emission tomography (PET), c. Decreased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or increased total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 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 levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilamentous light chain (NfL). A method according to embodiment 157, selected from the above. 159. The method according to any one of Embodiments 128 to 158, wherein the subject is amyloid-positive before administration, for example, as indicated by PET evaluation, CSF evaluation of Aβ(1-42), MRI, and retinal amyloid accumulation. 160. The method according to any one of embodiments 128 to 159, wherein the subject is ApoE4 positive. 161. The method according to any one of embodiments 128 to 160, wherein the subject is monitored for the onset of ARIA. 162. The method according to any one of embodiments 128 to 161, wherein the subject is 65 to 80 years old. 163. The subjects are aged 55-64 and meet the following criteria: (i) A first-degree relative diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Elevated brain amyloid levels based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration. The method according to any one of embodiments 128 to 161, having at least one risk factor selected from the following. 164. The method according to any one of embodiments 128 to 163, wherein the subject has Alzheimer's disease. 165. The method according to any one of embodiments 128 to 164, wherein the subject has early-stage Alzheimer's disease. 166. The subjects are as follows: a. Diagnosed with mild cognitive impairment due to Alzheimer's disease (moderate likelihood) and / or mild Alzheimer's dementia; b. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. Mild cognitive impairment due to Alzheimer's disease based on a pre-treatment CDR global score of 0.5 and a Memory Box score of 0.5 or higher (moderate likelihood); d. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a medical history of subjective memory impairment with slow onset and slow progression within the year prior to treatment (e.g., corroborated by an informant); e. Mild Alzheimer's disease based on the NIA-AA core clinical criteria for Alzheimer's disease; or f. Mild Alzheimer's disease based on a pre-treatment CDR score of 0.5-1.0 and a Memory Box score of 0.5 or higher. The method according to any one of embodiments 128 to 165, which is diagnosed as having any of the following: 167. The method according to any one of embodiments 128 to 166, wherein the subject is suspected to have AD. 168. The method according to any one of embodiments 128 to 163, wherein the subject is a subject at risk of developing Alzheimer's disease (AD). 169. The method according to embodiment 168, wherein the subject at risk of developing AD has pre-AD. 170. The method according to either Embodiment 168 or Embodiment 169, wherein the subject does not have cognitive impairment. 171. The method according to any one of Embodiments 168 to 170, wherein the subject has a Global Clinical Dementia Scale (CDR) score of 0 prior to the administration. 172. The method according to any one of Embodiments 168 to 171, wherein the subject has a Mini-Mental State Examination (MMSE) score of 27 or higher (including educational adjustments) prior to the administration. 173. The method according to any one of embodiments 168 to 172, wherein, prior to the administration, the subject has a WMS-IV LMII score that is at least one standard deviation lower than the age-adjusted mean of the Revised Logical Memory Subscale II (WMS-R LM II), and the score is 15 or less for subjects aged 50 to 64 years, 12 or less for subjects aged 65 to 69 years, 11 or less for subjects aged 70 to 74 years, 9 or less for subjects aged 75 to 79 years, and 7 or less for subjects aged 80 to 90 years. 174. A method for treating Alzheimer's disease (AD) in subjects who have AD, are suspected of having AD, or are at risk of having AD, comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementation-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 complementation-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), which is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, a step in which, after administering the initial dose for 18 or 24 months, the antibody is subcutaneously administered monthly at a dose of 10 mg / kg relative to the subject's body weight. A method carried out in accordance with a dosage plan that includes the following. 175. A method for delaying the clinical progression of a subject with AD, suspected AD, or at risk of AD, comprising administering an anti-Aβ protofibril antibody to a subject having three heavy chain complementary 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 complementary 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), which is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, a step in which, after administering the initial dose for 18 or 24 months, the antibody is subcutaneously administered monthly at a dose of 10 mg / kg relative to the subject's body weight. A method carried out in accordance with a dosage plan that includes the following. 176. A method for reducing brain amyloid levels in subjects with AD, suspected AD, or at risk of AD, comprising administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementary 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 complementary regions (LCDR1, LCDR1, and LCDR3) containing the amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), which is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, a step in which, after administering the initial dose for 18 or 24 months, the antibody is subcutaneously administered monthly at a dose of 10 mg / kg relative to the subject's body weight. A method carried out in accordance with a dosage plan that includes the following. 177. A method for converting an amyloid-positive subject to an amyloid-negative subject, comprising administering an antibody to a subject having three heavy chain complementation-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 complementation-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), wherein the antibody is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the subject's body weight; and For example, after administering the initial dose for 18 months, the antibody is administered subcutaneously monthly at a dose of 10 mg / kg relative to the subject's body weight. A method carried out in accordance with a dosage plan that includes the following. 178. A method for treating subjects who have early AD, are suspected of having early AD, or are at risk of early AD, and who have previously received a first anti-Aβ antibody, the following: The treatment involves administering a second anti-Aβ antibody having three heavy chain complementation 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 complementation 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), which is as follows: A step of administering a second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or A step of administering a second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 179. A method for delaying the clinical deterioration of a subject who has received a first anti-Aβ antibody, the following: The treatment involves administering a second anti-Aβ antibody having three heavy chain complementation 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 complementation 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), which is as follows: A step of administering a second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or A step of administering a second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 180. A method for reducing brain amyloid levels in a subject who has received a first anti-Aβ antibody, the following: The treatment involves administering a second anti-Aβ antibody to a subject at a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), which includes three heavy chain complementary 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 complementary 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). This treatment is as follows: A step of administering a second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or A step of administering a second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 181. A method for maintaining amyloid levels in a subject who has received a first anti-Aβ antibody, the following: The treatment involves administering a second anti-Aβ antibody having three heavy chain complementation 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 complementation 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), which is as follows: A step of administering a second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or A step of administering a second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 182. A method for treating a patient who has, is suspected of having, or is at risk of having early-stage AD, the following: The primary anti-Aβ antibody should be targeted for administration. The treatment involves administering a second anti-Aβ antibody having three heavy chain complementation 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 complementation 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), which is as follows: A step of administering a second antibody intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the subject's body weight; or A step of administering a second antibody subcutaneously every week or every other week at a maintenance dose of 250 mg, 360 mg, or 500 mg. A method carried out in accordance with a dosage plan that includes the following. 183. The method according to any one of Embodiments 178 to 182, wherein the maintenance dose administered subcutaneously is 500 mg. 184. The method according to any one of Embodiments 178 to 182, wherein the maintenance dose administered subcutaneously is 360 mg. 185. The method according to any one of Embodiments 178 to 182, wherein the maintenance dose administered subcutaneously is 250 mg. 186. The method according to any one of Embodiments 178 to 185, wherein a maintenance dose of antibody to be administered subcutaneously is administered using a vial-syringe. 187. The method according to any one of Embodiments 178 to 185, wherein a maintenance dose of antibody administered subcutaneously is administered using AI. 188. The method according to any one of Embodiments 178 to 187, wherein the first anti-Aβ antibody is selected from aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, or soranezumab. 189. The method according to Embodiment 188, wherein the first anti-Aβ antibody is donanemab. 190. A method for treating a subject who has, is suspected of having, or is at risk of having early AD, comprising administering an anti-Aβ protofibril antibody to the subject, which has three heavy chain complementation-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 complementation-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), which is as follows: A step of administering the antibody subcutaneously weekly at a starting dose of 500 mg; and For example, a step in which, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a dose of 360 mg weekly. A method carried out in accordance with a dosage plan that includes the following. 191. A method for treating a subject who has, is suspected of having, or is at risk of having early AD, comprising administering an anti-Aβ protofibril antibody to the subject, which has three heavy chain complementation-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 complementation-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), which is as follows: A step in which the antibody is administered intravenously every other week at a first starting dose of 10 mg / kg relative to the subject's body weight; Subcutaneously administer the antibody weekly at a second starting dose of 720 or 500 mg; and For example, a step in which, after 18 or 24 months of treatment at the initial dose, the antibody is administered subcutaneously weekly at a dose of 360 or 250 mg. A method carried out in accordance with a dosage plan that includes the following. [Brief explanation of the drawing]

[0129] [Figure 1] The results for CDR-SB, ADAS-cog14, and ADCS MCI-ADL in Trial 301 are shown. [Figure 2] This shows the adjusted mean change from baseline in CDR-SB in Trial 301. [Figure 3] This shows the adjusted mean change from baseline in ADAS-Cog14 in trial 301. [Figure 4] This shows the adjusted mean change from baseline in ADCS MCI-ADL in Study 301. [Figure 5] This shows the reduction in brain amyloid-beta plaques in Study 301 (adjusted mean change from baseline in amyloid-beta PET centimeter). [Figure 6] This shows the health-related quality of life index EQ-5D-5L (the health status of the subject today). [Figure 7]This shows the health-related quality of life index, QOL-AD (total score for each subject). [Figure 8] This shows the health-related quality of life index (QOL-AD) (as measured by the subject's representative). [Figure 9] This shows the Zarit Caregiver Burden Scale - Test Partner Burden (total score), a health-related quality of life index. [Figure 10] This indicates the time until the global CDR score deteriorates. [Figure 11] Gradient analysis using CDR-SB: Observational data and extrapolation to 2 years are shown. [Figure 12] This shows the changes in plasma GFAP by treatment group. [Figure 13] This shows the incidence of ARIA and antithrombotic drug use during the core period of the Clarity AD double-blind study. [Figure 14A] This shows the incidence of ARIA by genotype and the use of antithrombotic drugs during the Clarity AD double-blind core period. [Figure 14B] This shows the incidence of ARIA by genotype and the use of antithrombotic drugs during the Clarity AD double-blind core period. [Figure 15] This shows the incidence of ARIA and antithrombotic drug use in the Clarity AD core and OLE. [Figure 16A] This shows the incidence of ARIA and the use of antithrombotic drugs by genotype in the Clarity AD core and OLE. [Figure 16B] This shows the incidence of ARIA and the use of antithrombotic drugs by genotype in the Clarity AD core and OLE. [Figure 17] The expected incidence of ARIA-E for self-injectors and IVs is shown. [Figure 18] The average steady-state concentrations for each route of administration are shown. [Figure 19] The baseline clinical characteristics of trial 301 are shown. [Figure 20] The results for the primary and important secondary endpoints from Trial 301 are shown below. [Figure 21]The overall safety profile from Trial 301 is shown. [Figure 22] This shows the difference between placebo and ARIA and infusion-related reactions in Study 301. [Figure 23] This shows the severity and timing of infusion-related reactions during treatment in Study 301. [Figure 24] This shows ARIA-E events in 897 subjects who received placebo and 898 subjects who received rarecanemab. [Figure 25A] This shows that approximately 90% of ARIA-E cases occurred after treatment initiation ≤ 6 months and resolved within 4 months of detection. It also shows the probability of ARIA-E occurrence between weeks 0 and 76. [Figure 25B] This shows that approximately 90% of ARIA-E cases occurred after treatment initiation ≤ 6 months and resolved within 4 months of detection. It also shows the probability of ARIA-E occurrence between weeks 0 and 120. [Figure 26] Study 301 shows that isolated ARIA-H (without ARIA-E) occurred at a similar rate in the recanemab and placebo groups. [Figure 27] Study 301 shows that most ARIA-H events were microbleeds and cerebral surface hemosiderin deposition associated with ARIA-E. [Figure 28] This study shows that when antiplatelet or anticoagulant drugs were used in combination, the incidence of ARIA did not increase compared to lecanemab monotherapy. [Figure 29] This shows the event incidence rates for ARIA, ARIA-E, and ARIA-H based on the APOE4 carrier status. [Figure 30] This document presents a summary of ARIA cases by baseline microbleed count and APOE4 status. [Figure 31] The concentration-time profiles of lecanemab after single intravenous dose (10 mg / kg; n=30) and subcutaneous dose (700 mg; n=29) administration are shown. [Figure 32] The concentration-time profiles of lecanemab after a single subcutaneous dose (700 mg) in Japanese subjects (n=5) and non-Japanese subjects (n=24) are shown. [Figure 33A] The mean (SD) serum concentration-time curves of lecanemab, comparing subcutaneous administration via vial / syringe with subcutaneous administration via AI device, are shown and presented on linear and semi-logarithmic scales. [Figure 33B] The mean (SD) serum concentration-time curves of lecanemab, comparing subcutaneous administration via vial / syringe with subcutaneous administration via AI device, are shown and presented on linear and semi-logarithmic scales. [Figure 34] The box plots of serum lecanemab Cmax after 720 mg lecanemab subcutaneous injection using vials and syringes (vials / syringes) or 720 mg lecanemab subcutaneous injection using an auto-injector (AI) are shown (PK analysis population). [Figure 35] The box plots show the AUC(0-inf) of serum lecanemab after subcutaneous injection of 720 mg lecanemab using a vial and syringe (vial / syringe) or subcutaneous injection of 720 mg lecanemab using an auto-injector (AI) (PK analysis population). [Figure 36] The box plots of serum AUC(0-t) of lecanemab after subcutaneous injection of 720 mg lecanemab using a vial and syringe (vial / syringe) or 720 mg lecanemab using an auto-injector (AI) are shown (PK analysis population). [Figure 37] This outlines the design of Study 301, which includes the core study, extension phase, and subcutaneous administration substudy. [Figure 38] This study shows the effect of body weight on model-predicted recanemab exposure (and its ratio) after weekly SC administration of a fixed dose of 720 mg (vial / syringe) and bi-weekly IV administration of 10 mg / kg. [Figure 39] This shows a comparison of mean steady-state concentrations after bi-weekly IV administration of 10 mg / kg (Study 301 Core and OLE) or weekly administration of 720 mg of SC AI (Study 301 OLE AI Substudy). [Figure 40]This shows the simulated mean steady-state concentration (Cave,ss) of lecanemab administered using two AI devices for SC 500 mg QW, and the model-predicted (observed) Cave,ss for IV LEC10-BW in the 301 core and OLE phases of the study. [Figure 41] This shows the median model prediction (90% prediction interval) for amyloid PET after administration of recanemab at either 10 mg / kg IV every other week or 500 mg SC AI weekly. [Figure 42] This shows the model-predicted mean (90% prediction interval) of the change in CDR-SB after administration of lecanemab at either 10 mg / kg IV every other week or 500 mg SC AI weekly. [Figure 43] This study shows the predicted changes in amyloid PET in subjects who received 10 mg / kg IV recanemab for 18 or 24 months, followed by weekly 360 mg of SC AI, compared to placebo or continuous 10 mg / kg IV recanemab. [Figure 44] The predicted change in CDR-SB in subjects who received 10 mg / kg IV recanemab for 18 or 24 months, followed by weekly 360 mg SC AI, is shown compared to placebo or continuous 10 mg / kg IV recanemab. [Figure 45] This shows simulated amyloid PET profiles for 4 years of IV LEC10-BW administration compared to the start of SC 360 mg QW (1 × AI device) or LEC10- in subjects with baseline amyloid PET ≥60 and <60 centroids at 18 and 24 months. AI = auto-injector, BW = every other week, CL = centroid, IV = intravenous, PET = positron emission tomography, QW = weekly, Q4W = every 4 weeks. [Figure 46]This shows simulated CDR-SB profiles for IV LEC10-BW administration over 4 years compared to the initiation of SC 360 mg QW (1 × AI device) or LEC10- for maintenance administration at 18 and 24 months in subjects with baseline amyloid PET ≥ 60 and < 60 centroids. AI = auto-injector, BW = every other week, CL = centroid, IV = intravenous, PET = positron emission tomography, QW = weekly, Q4W = every 4 weeks. [Figure 47] The predicted plasma Aβ42 / 40 ratio and p-tau 181 levels after various dosing schedules are shown. AI = auto-injector, BW = every other week, CI = confidence interval, QW = weekly, Q4W = every 4 weeks. The solid line and shaded areas represent the predicted median and 95% CI, respectively. P-tau 181 = human tau protein phosphorylated with threonine at position 181. [Figure 48] SC exposure in healthy volunteers (Study 005) and Study 301 OLE AI device substudy (AD patients) is shown compared to IV LEC10-BW. AD = Alzheimer's disease; HV = healthy volunteers; IV = intravenous; n = 168 (including both IV and AD devices). [Figure 49] This indicates that SC exposure after administration of a 360 mg QW AI maintenance dose remains within the LEC10-BW range. [Figure 50] A Kaplan-Meier (KM) plot is shown, illustrating the actual time elapsed until the event occurred. [Modes for carrying out the invention]

[0130] [Detailed explanation]

[0178] The "amyloid hypothesis" proposes that amyloid-beta (Aβ) peptides play a central role in the pathogenesis of Alzheimer's disease (AD). Specifically, it hypothesizes that neurodegeneration in AD is caused by the deposition of Aβ plaques in brain tissue due to an imbalance between Aβ production and Aβ clearance, which can lead to the formation of neurofibrillary tangles containing tau proteins. Aβ peptides generally exist as a continuum of dynamic structural states, and therefore, species progress from monomeric Aβ to soluble Aβ assemblies containing a wide variety of molecules, from low-molecular-weight oligomers to high-molecular-weight protofibrils, and finally to insoluble fibrils (plaques). Targeting these soluble and insoluble Aβ tangles and plaques may yield therapeutic benefits.

[0131]

[0179] Several immunotherapies have been developed to reduce the amount of insoluble Aβ fibers deposited in the brain. However, a simple correlation has not been found between the amount and progressive accumulation of insoluble amyloid plaques and the clinical course of Alzheimer's disease (AD). While treatment strategies continue to aim at eliminating insoluble amyloid plaques, additional approaches to therapy may include reducing toxic Aβ aggregates, such as protofibrils, which may contribute to the neurodegeneration characteristic of AD (see, for example, the following literature: Dodort, J.-C. and May, P., “Overview on rodent models of Alzheimer's disease.” Curr. Protocols Neurosci. 2005; 9.22-1-9.22-6; Englund, H. et al., “Sensitive ELISA detection of amyloid-β protofibrils in biological samples.” J. Neurochem. 2007; 103:334-45; Gotz, J. et al., “Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior and therapy.” Mol. Psychiat. 2004; 9:664-83).

[0132]

[0180] In various embodiments, anti-Aβ protofibril antibodies, such as BAN2401 and other anti-Aβ protofibril antibodies, can be used to treat subjects in the early stages of the disease, for example, those in whom amyloid has been deposited in the brain, but the downstream neurodegenerative cascade thought to be caused by amyloid deposition is still relatively early in its process (i.e., brain tissue loss is limited and associated clinical deficits are minimal), by slowing the progression of Alzheimer's disease.

[0133]

[0181] In various embodiments, methods are disclosed for selecting patients suitable for treatment with an anti-Aβ protofibril antibody such as BAN2401, wherein the patient has a low risk of developing ARIA, for example, has not experienced a hemorrhagic event (e.g., microbleed or intracerebral hemorrhage) prior to treatment, and / or the patient is not an ApoE4 carrier. In various embodiments, methods are disclosed for selecting patients suitable for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401), wherein the patient has a low risk of developing ARIA, for example, has not shown changes in brain white matter (e.g., reduction) at the time of treatment. In various embodiments, methods are disclosed for selecting patients suitable for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401), wherein the patient has a low risk of developing ARIA, for example, has not received anticoagulants or thrombolytics at the time of treatment, and / or the patient is not an ApoE4 carrier.

[0134]

[0182] In various embodiments, methods for treating patients with Alzheimer's disease or suspected Alzheimer's disease are disclosed herein, where the patient is at low risk of developing ARIA based on brain imaging. In some embodiments, an anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401) is administered to patients who do not have brain hemorrhage (e.g., microbleeds or intracerebral hemorrhage) on baseline imaging. In some embodiments, an anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401) is not administered to patients who have had brain hemorrhage (e.g., microbleeds or intracerebral hemorrhage) on baseline imaging. In some embodiments, an anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401) is administered to patients who do not show changes (e.g., reduction) in brain white matter as measured by pre-treatment brain imaging. In some embodiments, patients who show changes (e.g., a decrease) in the brain white matter as measured by brain imaging are not administered anti-amyloid-beta (Aβ) protofibril antibodies (e.g., BAN2401).

[0135]

[0183] In various embodiments, methods are disclosed for selecting and treating patients with Alzheimer's disease or suspected Alzheimer's disease, where, for example, based on the use of anticoagulants or thrombolytic agents, the patients are at low risk of developing ARIA. In some embodiments, patients receiving aspirin are administered a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401). In some embodiments, patients receiving antiplatelet agents are administered a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401). In some embodiments, patients receiving thrombolytic agents and / or anticoagulants are administered a therapeutically effective dose of anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401). In some embodiments, patients receiving anticoagulants are not selected as candidates for treatment with anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401). In some embodiments, patients receiving thrombolytic agents are not selected as candidates for treatment with anti-amyloid-beta (Aβ) protofibril antibodies (e.g., BAN2401).

[0136]

[0184] In various embodiments, methods for treating patients with Alzheimer's disease or suspected Alzheimer's disease are disclosed herein, in which the patient has an increased risk of ARIA events or cerebral hemorrhage (e.g., microbleeds, intracerebral hemorrhage), in which case the patient is administered an anti-amyloid-beta (Aβ) protofibril antibody (e.g., BAN2401) and further administered steroids. In some embodiments, steroids are administered to patients who have received an anti-amyloid-beta (Aβ) protofibril antibody and have a severe ARIA event.

[0137]

[0185] In some embodiments, additional patient demographics, such as age and whether the subject is a carrier of the apolipoprotein Eε4 gene allele, may be used in combination with baseline status of cerebral hemorrhage (e.g., presence or absence of microbleeds or intracerebral hemorrhage), baseline status of cerebral white matter, and / or treatment with anticoagulants or thrombolytic agents, and / or additional biomarkers indicating amyloid positivity (e.g., West et al, Mol Neurodegen (2021) 16-30, Jansen et al, JAMA (2015) 1924-1938, Ossenkoppele et al, JAMA (2015) 1939-1950) to select patients for treatment.

[0138]

[0186] In some embodiments, one or more additional biomarkers, such as one or more blood biomarkers (e.g., Aβ42:Aβ40 ratio and / or p-tau 181), may be used in combination with brain measurements, such as amyloid or tau PET measurements, to select patients for treatment. In some embodiments, biomarkers related to AD pathology include, but are not limited to, one or more of the following: • Amyloid in the brain (for example, measured by amyloid positron emission tomography (PET)); • Brain tau (for example, measured by tau PET); • Cerebrospinal fluid (CSF) biomarkers, e.g., Aβ42, Aβ40, Aβ42 / Aβ40 ratio, total tau, p-tau (e.g., p-tau-181, p-tau-217, p-tau-231), p-tau-181 / np-tau-181 ratio, p-tau-217 / np-tau-217 ratio; neurogranins; CSF levels of neurofilamentous light chains (NfL), and / or glial fibrillary acidic proteins (GFAP); • Blood biomarkers, e.g., Aβ42, Aβ40, Aβ42 / Aβ40 ratio, total tau, p-tau (e.g., p-tau-181, p-tau-217, p-tau-231), p-tau-181 / np-tau-181 ratio, p-tau-217 / np-tau-217 ratio; neurogranins; plasma and / or serum levels of neurofilamentous light chains (NfL) and / or glial fibrillary acidic proteins (GFAP); • Biomarkers in other bodily fluids (e.g., urine, saliva, tears, sweat, etc.); • Genetic biomarkers (e.g., ApoE4, PSEN1, and / or PSEN2); - Abnormalities of the ocular and / or retinal vascular system (e.g., as measured by optical coherence tomography (OCT) or optical coherence tomography angiography (OCTA)); and / or

[0139]

[0187] Abnormalities in brain structure, function, and / or vascular system (e.g., measured by magnetic resonance imaging (MRI), electroencephalography (EEG), and / or single-photon emission computed tomography (SPECT)). In some embodiments, age and / or apolipoprotein Eε4 gene allele-normalized measurements of tau PET and / or at least one additional biomarker from a subject (e.g., plasma sample) are used to evaluate whether a sample from a subject is suitable for treatment with a protofibril antibody such as BAN2401 and / or to monitor treatment (e.g., if the subject is amyloid-positive). For example, in some embodiments, a carrier of the apolipoprotein Eε4 gene allele may be considered amyloid-positive at biomarker levels lower than those required for a non-carrier subject to be amyloid-positive. In some embodiments, patients who are carriers of the apolipoprotein Eε4 gene allele may be at a higher risk than non-carrier subjects of developing ARIA in response to treatment with anti-amyloid-beta (Aβ) protofibril antibodies (e.g., BAN2401), and may, for example, be cautioned by a physician about the increased risk, monitored for ARIA, and / or advised to refrain from anti-amyloid-beta (Aβ) protofibril antibodies (e.g., BAN2401). Similarly, in another example, older subjects may be considered amyloid-positive at biomarker levels lower than those required to show positivity in younger subjects. In some embodiments, biomarker levels are used in receiver operating characteristic (ROC) analysis to predict amyloid positivity. In some embodiments, amyloid positivity can be predicted by using additional patient demographics, such as age and whether the subject is a carrier of the apolipoprotein Eε4 gene allele, in combination with biomarker levels in the ROC analysis. In some embodiments, predictions of a patient's amyloid positivity are used to determine the dosage or frequency of treatment.

[0140]

[0188] Cognitive and functional decline can be measured by techniques known in this art, including scoring methods such as the CDR-SB, ADCOMS composite clinical score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, modified iADRS, Wechsler Scale for Memory-IV Logical Memory (subscale) I (WMS-IV LMI), and Wechsler Scale for Memory-IV Logical Memory (subscale) II (WMS-IV LMII). In some embodiments, an anti-Aβ protofibril antibody (e.g., BAN2401) is administered in a therapeutically effective dose to mitigate or delay cognitive decline. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered as a therapeutically effective dose including an intravenous infusion of 10 mg / kg of the subject's body weight. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered as a therapeutically effective dose including a subcutaneous infusion of 720 mg. In some embodiments, this method reduces cognitive decline to a milder level compared to untreated subjects, as measured by ADCOMS. In some embodiments, this method reduces cognitive decline to at least 24% (e.g., at least 29%) as measured by ADCOMS, compared to untreated subjects. In some embodiments, this method reduces cognitive decline to a milder level compared to untreated subjects, as measured by CDR-SB. In some embodiments, this method reduces cognitive decline to at least 26% (e.g., at least 27%) as measured by CDR-SB, compared to untreated subjects. In some embodiments, this method reduces cognitive decline to a milder level compared to untreated subjects, as measured by ADAS-Cog14. In some embodiments, this method reduces cognitive decline to at least 26% (e.g., at least 47%) as measured by ADAS-Cog14, compared to untreated subjects. In some embodiments, this method reduces cognitive decline to a milder level compared to untreated subjects, as measured by ADCS MCI-ADL. In some embodiments, this method reduces cognitive decline by at least 37% compared to untreated subjects, as measured by ADCS MCI-ADL.In some embodiments, the method is measured by a CDR global score (for example, a higher score in subsequent evaluations indicates progression to the next stage of AD, while an unchanged score indicates remaining in the same AD stage) to reduce the risk of progression to the next stage of AD. In some embodiments, the results are measured at least 6 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose. In some embodiments, the results are measured at least 12 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose. In some embodiments, the results are measured at least 13 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose. In some embodiments, the results are measured at least 18 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose.

[0141]

[0189] Anti-Aβ protofibril antibodies such as BAN2401 can be formulated into pharmaceutical compositions as disclosed in PCT / IB2021 / 000155 (WO 2021 / 186245 pamphlet), which is incorporated herein by reference. In some embodiments, the composition comprises BAN2401 at 80 mg / mL to 120 mg / mL, arginine at 240 mM to 360 mM, polysorbate 80 at 0.03% w / v to 0.08% w / v, and citrate buffer at 30 mM to 70 mM. 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 of BAN2401, 50 mmol / L of citrate, 350 mmol / L of arginine, and 0.05% polysorbate 80. In some embodiments, the composition comprises BAN2401 at 80 mg / mL to 240 mg / mL, arginine hydrochloride at 140 mM to 260 mM, polysorbate 80 at 0.01% w / v to 0.1% w / v, and histidine buffer at 15 mM to 35 mM. In some embodiments, the composition comprises a liquid dosage form containing 100 mg / mL of BAN2401, 25 mmol / L of histidine, 200 mmol / L of arginine, and 0.05% polysorbate 80.

[0142]

[0190] In some embodiments, BAN2401 is formulated as disclosed in PCT / IB2021 / 000155 (WO 2021 / 186245 pamphlet), which is incorporated herein by reference. In some embodiments, the composition comprises BAN2401 at 80 mg / mL to 240 mg / mL, arginine hydrochloride at 140 mM to 260 mM, polysorbate 80 at 0.01% w / v to 0.1% w / v, and histidine buffer at 15 mM to 35 mM. In some embodiments, the composition comprises a liquid dosage form containing 200 mg / mL of BAN2401, 25 mmol / L of histidine, 200 mmol / L of arginine, and 0.05% polysorbate 80.

[0143]

[0191] In some embodiments, a therapeutic method is provided herein that includes administering a therapeutically effective dose of an anti-Aβ protofibril antibody until a desired improvement is achieved in one or more biomarkers, e.g., until an increase in the Aβ1-42:Aβ1-40 ratio in a liquid sample (e.g., a blood sample) is observed and / or until a decrease in the p-tau181 level in a liquid sample (e.g., a blood sample) is observed. In some embodiments, the treatment is continued until the tau PET level is improved compared to an untreated control subject and / or the treatment is continued until the Aβ1-42:Aβ1-40 ratio in a liquid sample (e.g., a blood sample) is 0.092 or greater. In some embodiments, the treatment is continued until the amyloid PET or tau PET level is improved compared to an untreated control subject. In some embodiments, the treatment is continued until the tau PET level is improved and / or the florbetapir amyloid PET SUVr negativity is less than 1.17 compared to an untreated control subject. In some embodiments, the one or more biomarkers include serum or plasma GFAP measurements. In some embodiments, the treatment is continued until the subject becomes amyloid negative. In some embodiments, after a desired improvement is achieved with one or more biomarkers, the subject transitions to a maintenance dose. In some embodiments, the maintenance dosing regimen can further include one or more additional therapies in addition to the anti-Aβ protofibril antibody, e.g., the maintenance dosing regimen can include administration of E2814.

[0144]

[0192] In some embodiments, the present invention provides a treatment method comprising administering a therapeutically effective dose of anti-Aβ protofibril antibody to a subject (e.g., a subject with Alzheimer's disease, pre-AD, or early Alzheimer's disease) until a desired improvement is achieved in a cognitive outcome or other treatment outcome measure. In some embodiments, the treatment method comprises administering a therapeutically effective dose of anti-Aβ protofibril antibody for at least 18 months, or until a desired improvement is achieved in a cognitive outcome of the subject, for example. Cognitive and functional decline can be measured by techniques known in the art, including scoring methods such as the CDR-SB, ADCOMS composite clinical score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, modified iADRS, Wechsler Scale for Memory-IV Logical Memory (subscale) I (WMS-IV LMI), and Wechsler Scale for Memory-IV Logical Memory (subscale) II (WMS-IV LMII). In some embodiments, the treatment method, which involves administering a therapeutically effective dose of anti-Aβ protofibril antibody, is continued until cognitive decline is less severe compared to untreated subjects, as measured by ADCOMS. In some embodiments, the effectiveness of the treatment method can be evaluated using the CDR Global Score, which can be used to determine whether the patient's AD stage progressed or remained stable during treatment. For example, an increase in the score in the following evaluation indicates progression of AD, while an unchanged score indicates no progression of AD. In some embodiments, the treatment method is continued until cognitive decline is reduced by at least 24% (e.g., at least 29%) compared to untreated subjects, as measured by ADCOMS. In some embodiments, the treatment method is continued until cognitive decline is less severe compared to untreated subjects, as measured by CDR-SB. In some embodiments, the treatment method is continued until cognitive decline is reduced by at least 26% (e.g., at least 27%) compared to untreated subjects, as measured by CDR-SB. In some embodiments, the treatment method is continued until cognitive decline is less severe compared to untreated subjects, as measured by ADAS-Cog14.In some embodiments, the treatment method is continued until cognitive decline is reduced by at least 26% (e.g., at least 47%) compared to untreated subjects, as measured by ADAS-Cog14. In some embodiments, the method further 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 at least one anti-Aβ protofibril antibody in a therapeutically effective dose. In some embodiments, the results are measured at least 12 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose. In some embodiments, the results are measured at least 13 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose. In some embodiments, the results are measured at least 18 months after administration of at least one anti-Aβ protofibril antibody in a therapeutically effective dose.

[0145]

[0193] Methods of treatment (including dosage) by intravenous administration of anti-Aβ protofibril antibodies are disclosed in PCT / U.S. Patent Application Publication No. 2022 / 073576 and No. 2022 / 079571, which are incorporated herein by reference. In some embodiments, treatment comprises intravenous administration of anti-Aβ protofibril antibody at a dose of 10 mg / kg (e.g., BAN2401 at 10 mg / kg) for, for example, at least 18 months, or, for example, until the patient becomes amyloid-negative, every other week. In some embodiments, treatment comprises intravenous administration of anti-Aβ protofibril antibody at a dose of 10 mg / kg (e.g., BAN2401 at 10 mg / kg) for, for example, at least 18 months, or, for example, until the patient becomes amyloid-negative, every other week, followed by switching to a maintenance dose. In some embodiments, the maintenance dose may be the same as the therapeutic dose, or may be a lower dose and / or with a lower frequency of administration.

[0146]

[0194] Methods of treatment with subcutaneously administered anti-Aβ protofibril antibodies (including dosage setting) are disclosed in PCT / U.S. Patent Application Publication No. 2022 / 073576, No. 2022 / 079571, and No. 2022 / 041926, which are incorporated herein by reference. In some embodiments, treatment includes subcutaneous administration of an anti-Aβ protofibril antibody (e.g., 720 mg of BAN2401) weekly, for example, for at least 18 months, or for example, until the patient becomes amyloid-negative. In some embodiments, treatment includes subcutaneous administration of 720 mg of BAN2401 weekly, for example, in two simultaneous (e.g., consecutive) injections of a 360 mg subcutaneous formulation (1.8 mL x 2 at 400 mg / 2m), for example, until the patient becomes amyloid-negative, or for example, for at least 18 months. In some embodiments, treatment involves subcutaneous administration of BAN2401 weekly, for example, 720 mg in two simultaneous (e.g., consecutive) injections of a 360 mg subcutaneous formulation (1.8 mL x 2 at 400 mg / 2m), for example, until the patient becomes amyloid-negative, or for example, for at least 18 months. In some embodiments, treatment involves subcutaneous administration of BAN2401 weekly, for example, 720 mg, for example, for at least 18 months, or for example, until the patient becomes amyloid-negative, followed by switching to a once-weekly subcutaneous maintenance dose, for example, 360 mg. In some embodiments, treatment involves subcutaneous administration of BAN2401 weekly, for example, 720 mg, for example, for at least 18 months, or for example, until the patient becomes amyloid-negative, followed by switching to a bi-weekly subcutaneous maintenance dose, for example, 720 mg. In some embodiments, the treatment method includes subcutaneous administration of BAN2401 weekly, for example, 720 mg per week by two simultaneous (e.g., consecutive) injections of a 360 mg subcutaneous formulation (1.8 mL x 2 at 400 mg / 2m), for example, for at least 18 months. In some embodiments, the treatment method includes subcutaneous administration of BAN2401 weekly, for example, 720 mg per week by two simultaneous (e.g., consecutive) injections of a 360 mg subcutaneous formulation (1.8 mL x 2 at 400 mg / 2m), for example, for at least 18 months, followed by switching to a maintenance dose.In some embodiments, the maintenance dose may be the same as the therapeutic dose, or may involve lower dosing and / or administration frequency. In some embodiments, the treatment method includes using biomarker levels to determine a switch to an intravenous or subcutaneous maintenance dose at a set point in time (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, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg (e.g., BAN2401 at 10 mg / kg) every other week, followed by a switch to a subcutaneous maintenance dose, e.g., 720 mg, e.g., once weekly. In some embodiments, the treatment includes intravenous administration of an anti-Aβ protofibril antibody at 10 mg / kg every other week, followed by a switch to a subcutaneous maintenance dose of 720 mg every other week.

[0147]

[0195] In some embodiments, the treatment method includes determining the switch from subcutaneous treatment to a maintenance dose using biomarker levels. In some embodiments, the treatment includes subcutaneous administration of an anti-Aβ protofibril antibody (e.g., BAN2401) followed by a switch to an intravenous maintenance dose. In some embodiments, the treatment includes subcutaneous administration of BAN2401 weekly, for example, 720 mg in two simultaneous (e.g., consecutive) injections of 360 mg each (1.8 mL x 2 at 400 mg / 2m), followed by a switch to a maintenance dose. In some embodiments, the treatment method includes weekly subcutaneous administration of BAN2401 at a dose of 720 mg, followed by a switch to a maintenance dose. In some embodiments, the treatment includes weekly subcutaneous administration of BAN2401 followed by a switch to an intravenous maintenance dose of 10 mg / kg every other week. In some embodiments, the maintenance dose in question is administered at the same amount and / or frequency as the dose during the treatment period. In some embodiments, the maintenance dose in question is 50% of the dose during the treatment period.

[0148]

[0196] In some embodiments, the patient starts with an intravenous maintenance dose, e.g., 10 mg / kg of BAN2401 as disclosed above, and then switches to a subcutaneous maintenance dose, e.g., 720 mg subcutaneous injection including two simultaneous (e.g., consecutive) injections of 360 mg of the subcutaneous formulation (1.8 mL x 2 at 400 mg / 2m). In some embodiments, the patient starts with a subcutaneous maintenance dose, e.g., 720 mg subcutaneous injection including two simultaneous (e.g., consecutive) injections of 360 mg of the subcutaneous formulation (1.8 mL x 2 at 400 mg / 2m), and then transitions to an intravenous maintenance dose, e.g., 10 mg / kg of BAN2401 as disclosed above.

[0149]

[0197] In some embodiments, if a patient is determined to no longer be amyloid-negative (for example, by evaluation using blood, serum, or CSF biomarkers, and / or by amyloid PET SUVr), the patient is returned from the maintenance dose to the initial treatment dose.

[0150]

[0198] In some embodiments, the maintenance dose is administered at the same amount and / or frequency as the dose during the treatment period. In some embodiments, the maintenance dose is 50% of the dose during the treatment period. In some embodiments, the maintenance dose comprises two or more doses, the first dose being selected from the maintenance doses exemplified above, and the second and / or subsequent doses each comprising a lower amount and / or frequency than the first or previous dose. In some embodiments, the switch to the second or subsequent dose is determined based on one or more biomarkers exemplified above, where the level of the biomarker is different (e.g., improved) from the level used for the switch from the initial dose to the first dose of the maintenance dose.

[0151]

[0199] In some embodiments, treatment for a patient is discontinued if, based on cognitive function assessment, PET SUVr, and / or blood, CSF, or plasma biomarkers, the patient no longer exhibits early AD symptoms.

[0152]

[0200] In some embodiments, a patient's amyloid levels can be monitored for regression after treatment discontinuation by measuring one or more biomarkers, such as tau PET levels and volumetric MRI (vMRI) (including whole brain volume, cortical thickness, and / or total hippocampal volume). In some embodiments, a patient's amyloid levels can be monitored for regression after treatment discontinuation by measuring one or more biomarkers, such as tau PET levels and PET levels (including amyloid PET levels and / or fluorodeoxyglucose (FDG) PET levels). In some embodiments, a patient's amyloid levels can be monitored for regression after discontinuation of treatment by measuring tau PET levels, as well as cerebrospinal fluid levels of one or more biomarkers, e.g., Aβ1-42, Aβ1-40 (e.g., Aβ1-42:Aβ1-40 ratio), total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio), neurogranin, and / or neurofilament light chain (NfL) peptides. In some embodiments, a patient's amyloid levels can be monitored for regression after discontinuation of treatment by measuring tau PET levels, as well as serum or plasma levels of one or more biomarkers, such as Aβ1-42, Aβ1-40 (e.g., Aβ1-42:Aβ1-40 ratio), total tau, phosphorylated tau (P-tau) (tau phosphorylated at position 181 (P-tau181), 217 (P-tau217), and / or 231 (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) biomarkers).

[0153]

[0201] In some embodiments, patient biomarkers are monitored at least once after treatment discontinuation. In some embodiments, patient biomarkers are monitored at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment discontinuation. In some embodiments, treatment is resumed if the patient's biomarker levels become unfavorable (e.g., tau PET levels rise at the same rate as the untreated control group).

[0154]

[0202] In some embodiments, the subject is diagnosed with early-stage AD. In some embodiments, the subject is diagnosed with mild cognitive impairment (moderate likelihood) due to Alzheimer's disease and / or mild Alzheimer's dementia.

[0155]

[0203] Methods of treatment using anti-Aβ protofibril antibodies (including therapeutically effective doses) are disclosed in PCT / U.S. Patent Application Publication No. 2022 / 073576; No. 2022 / 079571; and No. 2022 / 041926, which are incorporated herein by reference. In some embodiments, the treatment method includes enabling monitoring and treatment decisions (e.g., changes in the dosage of BAN2401 and / or discontinuation of treatment) using biomarker levels, such as tau PET levels or the rate of change in tau PET levels.

[0156] [1. Definition]

[0204] The definitions of terms used in this application are given below.

[0157]

[0205] As used herein, the singular terms "a," "an," and "the" shall be considered to include the plural form unless the context clearly indicates otherwise.

[0158]

[0206] As used herein, the phrase "and / or" means "either or both" of the elements so connected, i.e., it refers to elements that exist as a conjunction in some cases and separately in other cases. Thus, as a non-limiting example, when used in conjunction with an open expression such as "comprising", "A and / or B" may, in some embodiments, refer to only A (optionally including elements other than B); in other embodiments, to only B (optionally including elements other than A); and in still other embodiments, to both A and B (optionally arbitrarily including other elements).

[0159]

[0207] As used herein, "at least one" means one or more of the elements included in a list of elements, but does not necessarily include at least one of each of the elements specifically listed within the list of elements, nor does it exclude any combination of elements within the list of elements. This definition also allows for the optional presence of elements other than those specifically identified within the list of elements referred to by the phrase "at least one", regardless of whether or not those other elements are related to those 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, refer to at least one (optionally including two or more) of A with B not present (and optionally including elements other than B); in another embodiment, to at least one (optionally including two or more) of B with A not present (and optionally including elements other than A); and in yet another embodiment, to at least one (optionally including two or more) of A and at least one (optionally including two or more) of B (optionally arbitrarily including other elements); and so on.

[0160]

[0208] As used herein, “about” in relation to dose, volume, or ratio includes a specified value of dose, volume, or ratio, or a range of dose, volume, or ratio, which is recognized by those skilled in the art to provide a therapeutic effect equivalent to that obtained from the specified dose, volume, or ratio. The term “about” may refer to a tolerance for a particular value as determined by those skilled in the art, which depends in part on the method of measuring or determining the value. In some embodiments, the term “about” means within ±5% of a given value or range.

[0161]

[0209] When a numerical value is presented alone or as part of a range, it should be understood that the value may vary within ±10% of the stated value.

[0162]

[0210] Where ranges of values ​​are listed in this specification, it is intended to include each value and subrange within that range. For example, "2.5 mg / kg to 10 mg / kg" is intended to include 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.

[0163]

[0211] As used herein, “adjusted mean change from baseline” refers to calculating the change in biomarker values ​​over time using statistical analysis. In some embodiments, a linear mixed-effects model (MMRM) is used to calculate at least one additional covariate in order to determine the adjusted mean change from baseline.

[0164]

[0212] As used herein, “baseline” refers to an initial measurement (e.g., a measure of cognitive function, brain structure, amyloid load, and / or fluid biomarkers) obtained at the first or early point in time and used for comparison over time to assess changes in the measurement. Changes in the measurement over time compared to baseline can be used to assess disease progression and / or the effectiveness of treatment for the disease.

[0165]

[0213] Amyloid-β1-42 (Aβ42) refers to amyloid-β monomers of amino acids 1-42 in the full-length protein (Table 5, SEQ ID NO: 13). Amyloid-β1-40 (Aβ1-40) refers to amyloid-β monomers of amino acids 1-40 in the full-length protein (Table 5, SEQ ID NO: 14).

[0166]

[0214] P-tau-181 (also written as p-tau-181 or p-tau-181) is human tau protein phosphorylated with threonine at position 181. NP-tau-181 (also written as np-tau-181 or np-tau-181) refers to human tau that is not phosphorylated with threonine at position 181. P-tau-181 / NP-tau-181 (p-tau-181 / np-tau-181, p-tau-181 / np-tau-181, P-tau-181R, p-tau-181R, or p-tau-181R) may refer to the ratio of tau phosphorylated with threonine at position 181 to tau that is not phosphorylated with threonine at position 181.

[0167]

[0215] P-tau-217 (also written as p-tau-217 or p-tau-217) is human tau protein phosphorylated with threonine at position 217. NP-tau-217 (also written as np-tau-217 or np-tau-217) refers to human tau that is not phosphorylated with threonine at position 217. P-tau-217 / NP-tau-217 (also written as p-tau-217 / np-tau-217, p-tau-217 / np-tau-217, P-tau-217R, p-tau-217R, or p-tau-217R) may refer to the ratio of tau phosphorylated with threonine at position 217 to tau that is not phosphorylated with threonine at position 217.

[0168]

[0216] P-tau231 (also written as p-tau231 or p-tau231) is human tau protein phosphorylated at threonine position 231. NP-tau231 (also written as np-tau231 or np-tau231) refers to human tau that is not phosphorylated at threonine position 231. P-tau231 / NP-tau231 (also written as p-tau231 / np-tau231, p-tau231 / np-tau231, P-tau231R, p-tau231R, or p-tau231R) may refer to the ratio of tau phosphorylated at threonine position 231 to tau that is not phosphorylated at threonine position 231.

[0169]

[0217] As used herein, total tau or t-tau refers to the measured amount of total tau in a sample, such as a CSF sample, plasma sample, or serum sample.

[0170]

[0218] Patients with “preclinical (AD)” or “pre-AD” as described herein (also referred to as “subjects”) are individuals with normal cognitive function who have intermediate or high levels of amyloid in the brain and can be identified by the asymptomatic period with or without memory impairment, as well as by the appearance of episodic memory and executive function impairments. Such patients may be identified by one or more biomarkers. Individuals with normal cognitive function may include individuals with a CDR score of 0 or individuals with normal ranges on cognitive function tests (such as MMSE, International Shopping List Test, and logical memory tests). Preclinical AD occurs prior to significant irreversible neurodegeneration and cognitive impairment and is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence of clinical symptoms. Preclinical AD biomarkers that may indicate the future onset of Alzheimer's disease include, but are not limited to, one or more of the following: amyloid, fluorodeoxyglucose (FDG), or tau; intermediate or high levels of amyloid in the brain as measured by positron emission tomography (PET) (e.g., approximately 20–40 centiloid scale, e.g., approximately 20–32 scale); cerebrospinal fluid Aβ1-42 levels and / or Aβ1-42 / 1-40 ratio; cerebrospinal fluid total tau levels; cerebrospinal fluid levels of p-tau (tau phosphorylated at position 181 (P-tau181), 217 (P-tau217), and / or 231 (P-tau231), P-tau181 / NP-tau181 ratio, and / or P-tau217 / NP-tau217 ratio); and neutron emission tomography (PET) levels. Cerebrospinal fluid levels of logranin, cerebrospinal fluid levels of neurofilament light chain peptides (NfL), and blood biomarkers measured in serum or plasma (e.g., levels of Aβ1-42, ratio of two forms of amyloid-beta peptide (Aβ1-42 / 1-40 ratio, e.g., about 0.092 to 0.094 or less than 0.092), plasma levels of total plasma tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (including tau phosphorylated at position 181 (P-tau181), position 217 (P-tau217), and / or tau phosphorylated at position 231 (P-tau231)), ratio of P-tau181 / NP-tau181, and / or ratio of P-tau217 / NP-tau217), glial fibrillary acidic protein (GFAP), and neurofilamentous light chains (NfL)).For example, among subjects treated with elenbecestat (E2609), a β-site amyloid precursor protein cleavage enzyme (BACE) inhibitor, the group with amyloid baseline positron emission tomography (PET) standardized uptake ratio (SUVr value) of 1.4 to 1.9 showed the greatest deceleration of cognitive decline during treatment. See Lynch, S. et al., "Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease." Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with a baseline florbetapir amyloid PET SUVr value of less than 1.2 did not show sufficient cognitive decline to be detectable, while subjects with an SUVr value greater than 1.6 appeared to correlate with a plateau effect where amyloid levels reached saturation, and treatment did not result in changes in cognitive function 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. Please refer to the Conference, July 22-26, 2018, Chicago, IL, USA.

[0171]

[0219] As used herein, “early AD,” or “early Alzheimer’s disease,” refers to a continuous range of AD severity from mild cognitive impairment (moderate likelihood) to mild Alzheimer’s dementia. Patients with early AD include those with mild Alzheimer’s dementia as defined herein, and patients with mild cognitive impairment (MCI) (moderate likelihood) as defined herein. In some embodiments, patients with early AD have an MMSE score of 22–30 and a total rating range of 0.5–1.0 on the Clinical Dementia Scale (CDR). Other methods for detecting early-stage Alzheimer's disease include the tests and assays detailed below, such as the National Institute on Aging - Alzheimer's Association (NIA-AA) core clinical criteria for presumptive Alzheimer's disease, described in McKhann, GM et al., “The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.” Alzheimer Dement. 2011;7:263-9. Other methods include the CDR-SB, ADCOMS composite clinical score, brief mental status test, ADAS-Cog, ADAS MCI-ADL, modified iADRS, Wechsler Scale for Memory-IV (WMS-IV LMI), and Wechsler Scale for Memory-IV (WMS-IV LMII). In some embodiments, subjects of early AD have evidence of increased amyloid or positive amyloid burden in the brain. In some embodiments, increased amyloid or positive amyloid burden in the brain is indicated and / or confirmed by PET evaluation. In some embodiments, increased amyloid or positive amyloid burden in the brain is indicated and / or confirmed by marker CSF evaluation such as Aβ1-42 (e.g., soluble CSF biomarker analysis).In some embodiments, increased amyloid or positive amyloid load in the brain is indicated and / or confirmed by measuring the level of p-tau 181. In some embodiments, increased amyloid or positive amyloid load in the brain is indicated and / or confirmed by MRI. In some embodiments, increased amyloid or positive amyloid load in the brain is indicated by retinal amyloid accumulation. In some embodiments, two or more assessment methods are used.

[0172]

[0220] "Amyloid" refers to unbranched, normally extracellular, fibers observed in vivo; furthermore, these fibers bind to the dye Congo Red and exhibit green birefringence when observed between cross-polarizing plates. Amyloid-forming proteins have been identified and associated with serious diseases, including amyloid-beta 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," "cerebral amyloid," and "amyloid-beta peptide (Aβ)" are used interchangeably.

[0173]

[0221] In some embodiments, the subjects have "high amyloid" or "intermediate amyloid" levels. As those skilled in the art will recognize, amyloid levels by amyloid PET are reported in centiloid units (CL) using the centiloid 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 centiloid method measures the tracer on a scale of 0 CL to 100 CL, where 0 is considered the anchor point and represents the mean value of a young healthy control group, and 100 CL represents the mean amyloid load present in subjects with mild to moderate dementia due to Alzheimer's disease. (Ibid.) As those skilled in the art will know, the centiloid threshold can be modified (e.g., fine-tuned) based on new or additional scientific findings (see, for example, http: / / www.gaain.org / centiloid-project). High levels of amyloid can be set relative to a baseline threshold for healthy controls determined according to methods well known to those skilled in the art. For example, a centiloid value of 32.5 can be used as the threshold for "high amyloid," and "intermediate amyloid" levels refer to Aβ amyloid PET values ​​in the range of 20–32.5 CL (e.g., 30 CL). In another example, a centiloid value of 40 can be used as the threshold for "high amyloid," and "intermediate amyloid" levels refer to Aβ amyloid PET values ​​in the range of 20–40 CL.

[0174]

[0222] Subjects with "mild Alzheimer's disease" or "mild AD dementia" as used herein are those who meet the core clinical criteria for presumptive Alzheimer's disease as defined in McKhann, GM et al. "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging - Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer Dement. 2011;7:263-9. This also includes subjects with a CDR score of 0.5–1.0 and a Memory Box score of 0.5 or higher at screening and baseline, as well as subjects showing changes in the Wechsler Memory Scale IV Logical Memory (Subscale) II (WMS-IV LMII) score.

[0175]

[0223] As used herein, subjects with "MCI due to AD - moderate likelihood" are those identified as such in accordance with the NIA-AA core clinical criteria for mild cognitive impairment due to Alzheimer's disease - moderate likelihood (see McKhann, cited above). For example, a subject may exhibit symptoms but not have progressed to dementia, and may have evidence of cerebral amyloid pathology, thereby exhibiting low heterogeneity and high similarity with subjects of mild Alzheimer's disease 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 who report a history of subjective memory decline with slow onset and slow progression in the year prior to screening, and whose report is corroborated by the informant, are also included. Memory decline and / or episodic memory impairment can be assessed by changes in the Wechsler Scale for Memory (WMS-R LM II) score.

[0176]

[0224] As used herein, “control subject,” “untreated AD subject,” or “untreated control subject” refers to a subject who has not received or has never 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 received treatment with anti-Aβ protofibril antibodies.

[0177]

[0225] The terms "patient" and "subject" are used interchangeably.

[0178]

[0226] As used herein, “MMSE” refers to the Mini-Mental State Examination, a cognitive function test commonly used for screening, but which is also often measured longitudinally in AD clinical trials. It is scored out of 30 points, with higher scores indicating less impairment and lower scores indicating greater impairment, ranging from 0 (most severe impairment) to 30 (no impairment). In some embodiments, seven items measuring temporal and spatial orientation, short-term memory, recall, attention, verbal comprehension, and spatial ability may be evaluated 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).

[0179]

[0227] As used herein, “ADAS-Cog” refers to the Alzheimer’s Disease Rating Scale – Cognitive Function. The ADAS-Cog is a widely used cognitive function rating scale in Alzheimer’s disease testing, comprising structured scales that assess memory (word recall, delayed word recall, and word recognition), thinking (following instructions), language (naming, comprehension), orientation, conceptual practice (putting a letter in an envelope), and constructive practice (copying geometric figures) (Rosen, WGet al., “A new rating scale for Alzheimer’s disease.” Am.J.Psychiatry 1984;141:1356-64). Assessments of spoken language, language comprehension, word retrieval difficulties, memory of test instructions, mazes, and digit extinction can also be obtained. In some embodiments, the ADAS-Cog is an Alzheimer’s Disease Rating Scale – Cognitive Subscale. 14 This refers to the use of ADAS-Cog14. In some embodiments, a modified version may be used, scored from 0 to 90, where 0 indicates no impairment and 90 indicates maximum impairment. In some embodiments, the ADAS-Cog14 task includes memory (word recall, delayed word recall, word recognition), thinking (following instructions), language (naming, comprehension), orientation, conceptual executive function (putting a letter in an envelope), constructive executive function (copying geometric figures), oral language, language comprehension, word retrieval difficulties, ability to remember test instructions, mazes, and number elimination (Rosen et al, 1984).

[0180]

[0228] As used herein, “CDR-SB” refers to the sum of the Clinical Dementia Scale-box scores. The CDR is a clinical scale that represents five degrees of impairment in performance across six categories: memory, orientation, judgment and problem-solving, social activities, home life and hobbies, and self-management (Berg, L. et al., “Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment.” Ann. Neurol. 1988;23:477-84). The sum of the box scores presents a measure of change, with each category having a maximum score of 3 points, and the total score being the sum of the category scores ranging from 0 to 18 points, with higher scores indicating more severe impairment.

[0181]

[0229] As used herein, the terms “CDR Global,” “Global CDR” score, and “Global Scale of Dementia CDR” score are used interchangeably. As used herein, the CDR Global score is an assessment of the degree of impairment obtained for each of the six categories of function from the six categories of the CDR scale, which are systematized into a single global scale of dementia CDR score (ranging from 0 to 3), where 0 represents no cognitive impairment, 0.5 represents mild cognitive impairment, and 1 to 3 represent mild, moderate, and severe dementia, respectively. The Global CDR score can be used as a clinical indicator to assess the severity of dementia. In some embodiments, the Global CDR score can be used to determine whether a patient’s stage of Alzheimer’s disease (AD) has progressed or remained stable; for example, an increase in the score in a later assessment indicates progression of AD, while no change in the score indicates no progression of AD.

[0182]

[0230] As used herein, “ADCOMS” refers to the Alzheimer’s disease composite score, a composite clinical score based on the analysis of four ADAS-Cog items (delayed speech recall, orientation, speech recognition, and word retrieval difficulties), two Mini-Mental State Examination (MMSE) items (temporal orientation, and visual ability), and all six CDR-SB items (personal grooming, social activities, home and hobbies, memory, orientation, and judgment and problem solving), as described in the Examples and Wang, J. et al., “ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials.” J. Neurol. Neurosurg. Psychiatry. 2016;87:993-999. ADCOMS was developed to be particularly sensitive to disease progression in the early stages of AD (i.e., preclinical AD or early AD).

[0183]

[0231] In some embodiments, ADCOMS is expressed by the following formula:

number

[0184]

[0232] As used herein, “ADCS MCI-ADL” refers to the Alzheimer’s Disease Collaborative – Activities of Daily Living Scale in Mild Cognitive Impairment (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical scale that assesses a patient’s ability to perform six basic activities of daily living. Other examples are discussed below: Kreutzer JS, DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, NY.

[0185]

[0233] As used herein, “Modified iADRS” or “iADRS” refers to a composite tool combining the scores of ADAS Cog14 (all items) and ADCS MCI-ADL (all items). The Modified iADRS score can be used to assess disease progression: Modified iADRS score = [-1(ADAS-cog14)+90] + ADCS MCI-ADL

[0186]

[0234] As used herein, “ApoE4-positive” subjects and “ApoE4 carrier” refer to subjects who possess the ε4 variant of the apolipoprotein (APOE) gene. As used herein, the APOE4 state refers to the state of a subject 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. Carriers of apolipoprotein ε4 have been shown to 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, subjects treated herein are heterozygous carriers of the apolipoprotein Eε4 gene allele. In some embodiments, subjects are homozygous carriers of the apolipoprotein Eε4 gene allele. The terms "ApoE4 negative" and "ApoE4 non-carrier" are used interchangeably.

[0187]

[0235] As used herein, whether a patient with early Alzheimer's disease (AD) is “amyloid-positive” or “amyloid-negative” may be determined based on whether the patient has a positive amyloid load. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative as indicated by a longitudinal positron emission tomography (PET) scan that evaluates the uptake of a contrast agent (e.g., amyloid contrast agent or tau contrast agent) into the brain. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by evaluating tau PET imaging. In some embodiments, a subject is “amyloid-negative” if the florbetapyr amyloid PET SUVr negative is less than 1.17. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by evaluating biomarker levels (e.g., Aβ42 / 40 ratio) in a sample from the subject, either alone or in combination with another method such as PET measurement of brain amyloid. In some embodiments, a subject is considered "amyloid-negative" if the Aβ42 / 40 ratio in the sample is 0.092 to 0.094 or higher (e.g., approximately 0.092). In some embodiments, a subject is considered "amyloid-negative" if the Aβ42 / 40 ratio in the sample exceeds 0.092. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by CSF assessment of the presence of amyloid pathology, using evaluation of markers such as p-tau 181, either alone or in combination with other methods such as PET measurement of brain amyloid. In some embodiments, amyloid-positive and amyloid-negative are determined by qualitative visual interpretation of PET scans, classifying the subject as having either "normal" or "abnormal" uptake based on the PET image pattern. The radiologist is trained and certified to recognize brain PET images with abnormal or normal uptake patterns, or amyloid detection is performed through semi-quantitative or quantitative methods. In some embodiments, the Aβ brain load is defined by a threshold for quantitatively determining whether the subject is amyloid-positive or negative based on a biomarker (e.g., serum or CSF) and / or a PET scan.In some embodiments, subjects are determined to be amyloid-positive or amyloid-negative by MRI. In some embodiments, subjects are determined to be amyloid-positive or amyloid-negative by retinal amyloid accumulation. In some embodiments, subjects are determined to be amyloid-positive or amyloid-negative by behavioral / cognitive phenotype.

[0188]

[0236] As those skilled in the art will understand, digital, computerized, and / or conventional (e.g., written) cognitive function tests can be used to detect early cognitive changes that may indicate mild cognitive impairment and / or an increased risk of developing dementia, and these can be used to identify individuals who require the treatments disclosed herein. For example, such tests can screen for cognitive impairment and potentially identify individuals with MCI. The tests can use artificial intelligence to analyze cognitive function test results and determine whether mild cognitive impairment will progress to Alzheimer's disease within one year. Early diagnosis before symptoms appear can help physicians more quickly identify individuals who require the treatments disclosed herein, delaying the onset of neurodegenerative diseases or mitigating their severity.

[0189]

[0237] As used herein, the term “treat” means the administration or application of a therapeutic agent to a disease or disorder in a subject, and includes suppression of the disease, slowing of disease progression, delaying progression, prevention of onset, reversal of disease progression (e.g., reversal of Aβ fiber accumulation), prevention of disease onset or onset, reduction or improvement of one or more symptoms of the disease or the underlying condition, cure of the disease, improvement of one or more clinical indicators, or prevention of recurrence of one or more symptoms of the disease. In some embodiments, treatment of AD in a subject includes administration (e.g., intravenous infusion) of an anti-amyloid-beta (Aβ) protofibril antibody. In some embodiments, treatment of AD in a subject includes a therapeutically effective dose by administration (e.g., intravenous infusion) of an anti-amyloid-beta (Aβ) protofibril antibody.

[0190]

[0238] As used herein, the term “infusion” refers to the active administration of one or more drugs over an infusion time of, for example, about 60 minutes. In some embodiments, the anti-amyloid-beta (Aβ) protofibril antibodies described herein are administered systemically to human subjects by infusion. In some embodiments, instead, the anti-amyloid-beta (Aβ) protofibril antibodies are administered to human subjects, for example, by subcutaneous injection. In some embodiments, the subcutaneous injection is administered once a week. In some embodiments, the subcutaneous injection is administered every other week. In some embodiments, the anti-amyloid-beta (Aβ) protofibril antibodies are administered to human subjects by intravenous infusion.

[0191]

[0239] In some embodiments, a maintenance dose of the therapeutic agent is administered to the subject. In this specification, “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, every three months (quarterly), or every 24 weeks (every six months or half a year). In some embodiments, the maintenance dose contains an anti-Aβ protofibril antibody. In some embodiments, the maintenance dose is administered as an intravenous infusion. In some embodiments, the intravenous infusion is a dose of 10 mg / kg of BAN2401 administered every two weeks. In some embodiments, the intravenous infusion is a dose of 10 mg / kg of BAN2401 administered monthly. In some embodiments, the maintenance dose is administered subcutaneously, orally, or intranasally. In some embodiments, the maintenance dose is administered subcutaneously.

[0192]

[0240] In some embodiments, the maintenance dose is administered by subcutaneous injection. In some embodiments, the maintenance dose is administered by subcutaneous injection once a week. In some embodiments, the maintenance dose is administered by subcutaneous injection every other week. In some embodiments, the maintenance dose is administered by subcutaneous injection monthly. In some embodiments, the maintenance dose is administered by subcutaneous injection every quarter. In some embodiments, the maintenance dose is administered once a week or less frequently, for example, every two weeks (every other week), every four weeks, monthly, every six weeks, every eight weeks (two months), every three months (quarters), or every six months (six months). In some embodiments, the maintenance dose is administered every other week as a 720 mg subcutaneous injection. In some embodiments, the maintenance dose is administered every other week as a 720 mg subcutaneous injection, including two simultaneous (e.g., consecutive) injections of a 360 mg subcutaneous formulation (1.8 mL x 2 at 400 mg / 2 mL).

[0193]

[0241] In some embodiments, the maintenance dose is administered as a 250 mg subcutaneous injection once weekly. In some embodiments, the maintenance dose is administered as a 250 mg subcutaneous injection once weekly, which includes an injection of 1.25 mL of the 400 mg / 2 mL subcutaneous formulation. In some embodiments, the maintenance dose is administered as a 360 mg subcutaneous injection once weekly, which includes a single injection of 360 mg of the SC formulation. In some embodiments, the maintenance dose is administered subcutaneously from an auto-injector.

[0194]

[0242] In some embodiments, the maintenance dose is administered as a subcutaneous injection of 720 mg or 500 mg every other week. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 500 mg every other week, including two simultaneous (e.g., consecutive) injections of 250 mg of the subcutaneous formulation (e.g., 1.25 mL x 2 at 400 mg / 2 mL). In some embodiments, the maintenance dose is administered as a subcutaneous injection of 500 mg every other week, including a single injection of 500 mg of the SC formulation (e.g., 2.5 mL at 400 mg / 2 mL). In some embodiments, the maintenance dose is administered subcutaneously from an auto-injector.

[0195]

[0243] In some embodiments, the maintenance dose is administered once or multiple times. In some embodiments, the maintenance dose is administered at a lower dose and / or at a lower frequency than in earlier treatment courses.

[0196]

[0244] In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may show an increase in amyloid levels in the brain. In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may worsen, for example, an increase in the plasma Aβ42 / 40 ratio may begin, indicating an increase in amyloid levels in the brain. In some embodiments, the subject may have a decrease in the Aβ42 / 40 ratio while receiving the maintenance dose. In some embodiments, the subject is switched to a maintenance dose, which is selected so that the subject's Aβ42 / 40 ratio decreases, but the Aβ42 / 40 ratio remains above the amyloid-positive threshold and can be maintained, for example, for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0197]

[0245] In some embodiments, after switching to a maintenance dose, the subject's biomarker levels may begin to increase or the rate of increase may rise. In some embodiments, such subjects may be returned to their treatment regimen. In some embodiments, for example, if such increases are lower than the tau PET levels or rate of increase observed in a control subject with AD but who has not received anti-Aβ protofibril antibodies, the subject may continue on the maintenance dose.

[0198]

[0246] As used herein, the term “prevent” means obtaining a beneficial or desired outcome, including, but not limited to, a preventive benefit. For a preventive benefit, the composition may be administered to subjects at risk of developing Alzheimer’s disease, subjects without clinical symptoms of Alzheimer’s disease but with one or more preclinical symptoms, or subjects who have not been clinically diagnosed with Alzheimer’s disease but report one or more physiological symptoms. As used herein, “prevention” may also include a therapeutic benefit, meaning the eradication or improvement of one or more physiological symptoms of the underlying disease being treated or associated with it.

[0199]

[0247] As used herein, the term "ARIA" refers to amyloid-related imaging abnormalities assessed using MRI. While not theoretically bound, ARIA is a result of the presence of amyloid in the cerebral blood vessel walls and can lead to cerebral amyloid angiopathy (CAA). While not theoretically bound, CAA is pathologically present in most Alzheimer's disease patients, but imaging findings (microbleeds) or clinical symptoms (intracranial hemorrhage or inflammatory CAA) are not observed in the majority of patients. While not theoretically bound, amyloid removal with monoclonal antibodies (e.g., anti-Aβ protofibril antibodies) may increase the risk of ARIA. In some embodiments, ARIA includes amyloid-related imaging abnormality edema / exudation (ARIA-E). In some embodiments, ARIA includes amyloid-related imaging abnormality hemorrhage (ARIA-H). In some embodiments, the severity of ARIA may be classified by radiographic imaging (e.g., MRI). In some embodiments, the severity of ARIA is classified as mild, moderate, or severe based on radiographic imaging, such as MRI. In some embodiments, a mild ARIA-E event includes a FLAIR hyperintensity limited to a single sulcus and / or cortical / subcortical white matter of <5 cm. In some embodiments, a moderate ARIA-E includes a FLAIR hyperintensity with a maximum single dimension of 5–10 cm, or two or more lesion sites, each <10 cm. In some embodiments, a severe ARIA-E event includes a >10 cm FLAIR hyperintensity with associated gyral swelling and sulcus disappearance, and may involve one or more separate / independent lesion sites. In some embodiments, a mild ARIA-H microbleeding event includes ≤4 or fewer newly occurring microbleeds. In some embodiments, a moderate ARIA-H microbleeding event includes 5–9 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 hemosiderin deposition event includes hemosiderin deposition in one lesion area. In some embodiments, a moderate ARIA-H hemosiderin deposition event includes hemosiderin deposition in two lesion areas. In some embodiments, a severe ARIA-H hemosiderin deposition event includes hemosiderin deposition in >2 lesion areas.In some embodiments, ARIA-H may include intracerebral hemorrhages of >1 cm.

[0200]

[0248] As used herein, the term “clinical worsening” refers to the worsening of one or more clinical symptoms of AD. Methods for measuring clinical worsening may be the tests and assays specified herein. In some embodiments, clinical worsening is determined by worsening ADCOMS. In some embodiments, clinical worsening is determined by worsening MMSE. In some embodiments, clinical worsening is determined by worsening ADAS-Cog. In some embodiments, clinical worsening is determined by worsening FAQ. In some embodiments, clinical worsening is determined by worsening CDR-SB. In some embodiments, clinical worsening is determined by worsening Wechsler Scale for Memory-IV Logical Memory (subscale) I and / or (subscale) II. In some embodiments, clinical worsening is determined by worsening CDR score. In some embodiments, clinical worsening refers to worsening of one or more AD biomarkers or brain measurements (e.g., by PET or MRI), e.g., worsening of brain atrophy and / or amyloid accumulation.

[0201]

[0249] As used herein, the terms “blood sample” or “blood” refer to a sample of blood, including serum and / or plasma, from a human subject. In some embodiments, blood is collected from a subject to evaluate potential biomarkers of AD (which may include amyloid fragments and isoforms, tau, and other protein biomarkers (e.g., NFL)) for the diagnosis of AD, amyloid or tau load, or their association with disease modification. In some embodiments, subjects are required to fast before collection at weeks 96 and 216, if possible. Fasting of the subject is not required in other embodiments and / or at other time points. Pre-AD biomarker levels that may suggest the onset of Alzheimer's disease include, but are not limited to, brain amyloid levels, cerebrospinal fluid (CSF) levels of Aβ1-42, CSF levels of total tau, CSF levels of neurogranin, and CSF levels of neurofilamentous light chains (NfL).

[0202] [2. Measurement of ARIA]

[0250] The methods disclosed and discussed herein are, in part, based on the finding that the risk of amyloid-related imaging abnormalities (ARIA) from treatment with anti-Aβ protofibril antibodies such as BAN2401 may depend on the concomitant use of other drugs such as anticoagulants or thrombolytics, the presence of cerebral hemorrhage, and the baseline brain condition.

[0203]

[0251] In some embodiments, amyloid-related imaging abnormalities (ARIAs) can be measured by means known in the art, which may include those described herein. In some embodiments, ARIAs are measured by MRI. In some embodiments, ARIAs are classified as ARIA-E with edema or ARIA-H with hemosiderin deposition. In some embodiments, ARIA-E may be observed on MRI as cerebral edema or intrasulcal exudate. In some embodiments, ARIA-H may be observed on MRI as cerebral microhemorrhage or superficial hemosiderin deposition.

[0204]

[0252] In some embodiments, the patient is monitored for ARIA by radiographic imaging (e.g., MRI) before treatment (e.g., treatment with anti-Aβ protofibril antibodies, e.g., treatment with BAN2401). In some embodiments, the patient is monitored for ARIA by radiographic imaging (e.g., MRI) at least once after treatment (e.g., treatment with anti-Aβ protofibril antibodies, e.g., treatment with BAN2401). In some embodiments, the patient is monitored for ARIA by radiographic imaging (e.g., MRI) two or more times after treatment (e.g., treatment with anti-Aβ protofibril antibodies, e.g., treatment with BAN2401). In some embodiments, the patient is monitored for ARIA at least once after discontinuation of treatment. In some embodiments, the patient is monitored for ARIA at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after discontinuation of treatment.

[0205]

[0253] In some embodiments, subjects with ARIA experience headache, confusion, and / or seizures, which can be used to identify subjects with ARIA or to indicate further assessment of ARIA. In some embodiments, ARIA is assessed at specified intervals during treatment. In some embodiments, ARIA is assessed when a subject experiences symptoms of ARIA. In some embodiments, the maximum serum concentration (Cmax) of anti-Aβ protofibril antibody can be used as a predictor of ARIA-E risk. In some embodiments, the use of subcutaneous formulations may result in a reduced risk of ARIA-E compared to IV administration (e.g., due to lower Cmax).

[0206]

[0254] In some embodiments, ARIA can be classified by the severity of clinical symptoms. For example, mild clinical symptoms are characterized by discomfort that does not interfere with daily activities. Moderate clinical symptoms are characterized by discomfort sufficient to reduce or affect normal daily activities. Severe clinical symptoms are incapacitation, which may result in an inability to work or perform normal daily activities.

[0207]

[0255] In some embodiments, ARIA may be classified by radiographic severity, for example, the extent of signal abnormalities in MRI. In some embodiments, radiographic severity is based on signal abnormalities on T2-weighted image / fluid decay inversion recovery (FLAIR) sequences. In some embodiments, the radiographic severity of ARIA-E may be classified as mild if the FLAIR hyperintensity is limited to a single groove and / or cortical / subcortical white matter <5 cm. In some embodiments, the radiographic severity of ARIA-E may be classified as moderate if the FLAIR hyperintensity is a single maximum diameter of 5-10 cm, or if there are two or more lesion sites, each <10 cm. In some embodiments, the radiographic severity of ARIA-E may be classified as severe if the FLAIR hyperintensity is >10 cm with associated gyral swelling and groove disappearance. One or more individual / independent lesion sites may be observed.

[0208]

[0256] In some embodiments, ARIA can be classified by radiographic severity, for example, by the number and / or size of microbleeds and / or the number and / or size of lesion areas of hemosiderin deposition on the cerebral surface. In some embodiments, the radiographic severity of ARIA-H (microbleeds) can be classified as mild if there are ≤4 or fewer newly occurring microbleeds. In some embodiments, the radiographic severity of ARIA-H (microbleeds) can be classified as moderate if there are 5 to 9 newly occurring microbleeds. In some embodiments, the radiographic severity of ARIA-H (microbleeds) can be classified as severe if there are 10 or more newly occurring microbleeds.

[0209]

[0257] In some embodiments, the radiographic severity of ARIA-H (cerebral surface hemosiderin deposition disease) may be classified as mild if cerebral surface hemosiderin deposition is present in one lesion area. In some embodiments, the radiographic severity of ARIA-H (cerebral surface hemosiderin deposition disease) may be classified as moderate if cerebral surface hemosiderin deposition is present in two lesion areas. In some embodiments, the radiographic severity of ARIA-H (cerebral surface hemosiderin deposition disease) may be classified as severe if cerebral surface hemosiderin deposition is present in >2 areas.

[0210]

[0258] In some embodiments, if the severity of clinical symptoms and radiographic severity are mild, treatment with an anti-Aβ protofibril antibody such as BAN2401 can be continued. For example, in the case of ARIA-E, if the clinical severity is asymptomatic and the radiographic severity is mild, treatment can be continued. In some embodiments, in the case of ARIA-E, if the clinical severity is mild and the radiographic severity is mild, treatment can be continued based on clinical judgment. In some embodiments, in the case of ARIA-E, if the clinical severity is moderate or severe, treatment can be discontinued. In some embodiments, for ARIA-E, if the radiographic severity is moderate or severe, treatment can be discontinued. In some embodiments, treatment may be discontinued until MRI shows the disappearance of radiographic findings and the resolution of symptoms (if present). Follow-up MRI may be performed 2 to 4 months after the initial confirmation of ARIA to evaluate the disappearance. In some embodiments, treatment can be resumed after radiographic stabilization and the resolution of symptoms (if present). In some embodiments, treatment may be permanently discontinued.

[0211]

[0259] In some embodiments, for ARIA-H, treatment can be continued if the clinical severity is asymptomatic and the radiographic severity is mild. In some embodiments, for ARIA-H, if the clinical severity is symptomatic, treatment can be discontinued regardless of whether the radiographic severity is mild, moderate, or severe. In some embodiments, treatment may be discontinued until MRI shows the disappearance of radiographic findings and the resolution of symptoms (if present). Follow-up MRI may be performed 2 to 4 months after the initial confirmation of ARIA to evaluate the disappearance. In some embodiments, treatment can be resumed after radiographic stabilization and the resolution of symptoms (if present). In some embodiments, treatment may be permanently discontinued.

[0212] [3. Measurement of intracerebral hemorrhage]

[0260] The content and methods disclosed herein are partly based on the finding that the risk of cerebral hemorrhage (e.g., microbleeds, intracerebral hemorrhage) associated with treatment with anti-Aβ protofibril antibodies such as BAN2401 is dependent on the presence of cerebral hemorrhage and the state of the brain at baseline. In some embodiments, patients with cerebral hemorrhage, e.g., intracerebral hemorrhage, microbleeds at baseline are at higher risk of ARIA.

[0213]

[0261] The incidence and size of cerebral hemorrhages can be measured by means known in the art, including those described herein. In some embodiments, cerebral hemorrhages are measured by MRI. In some embodiments, cerebral hemorrhages are measured by the number of hemorrhages. In some embodiments, cerebral hemorrhages are measured by the size of the hemorrhages. In some embodiments, microhemorrhages refer to cerebral hemorrhages with a diameter of less than 1 cm as measured by radiographic imaging. In some embodiments, intracerebral hemorrhages refer to cerebral hemorrhages with a diameter of more than 1 cm as measured by radiographic imaging.

[0214]

[0262] In some embodiments, patients are monitored for cerebral hemorrhage by radiographic imaging (e.g., MRI) prior to treatment (e.g., treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401). In some embodiments, patients who have microbleeds or intracerebral hemorrhage at baseline and have been treated with an anti-Aβ protofibril antibody such as BAN2401 are administered steroids. In some embodiments, patients are monitored for cerebral hemorrhage at least once by radiographic imaging (e.g., MRI) after treatment, e.g., treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401. In some embodiments, patients are monitored for cerebral hemorrhage two or more times by radiographic imaging (e.g., MRI) after treatment, e.g., treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401.

[0215]

[0263] In some embodiments, patients may be monitored after one or more doses of an anti-Aβ protofibril antibody (e.g., BAN2401), for example, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more doses. In some embodiments, treatment may be continued if the severity of clinical symptoms and / or radiographic severity are asymptomatic or mild. In some embodiments, for example, if the severity of clinical symptoms and / or radiographic severity is moderate or severe, treatment may be interrupted and / or discontinued.

[0216]

[0264] In some embodiments, patients are monitored for cerebral hemorrhage at least once after discontinuation of treatment. 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 discontinuation of treatment. In some embodiments, patients with microbleeds or intracerebral hemorrhage at baseline are not treated with anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, patients who do not show microbleeds or intracerebral hemorrhage at baseline are treated with anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, patients with microbleeds or intracerebral hemorrhage at baseline who have been treated with anti-Aβ protofibril antibodies such as BAN2401 are monitored more frequently for, for example, ARIA than patients without microbleeds or intracerebral hemorrhage at baseline. In some embodiments, patients presenting with CAA at baseline are not treated with anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, treatment is discontinued for patients who develop CAA.

[0217] [4. Measurement of brain white matter]

[0265] The baseline state of a patient's brain white matter and changes in the white matter of a subject can be measured by means known in the art, which may include the means described herein. In some embodiments, the patient's white matter is evaluated by MRI. In some embodiments, the thickness of the patient's white matter is evaluated by radiographic imaging (e.g., MRI) before treatment, e.g., treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401. In some embodiments, patients with changes in white matter from baseline, e.g., decreased white matter thickness, have an increased risk of ARIA with treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401. In some embodiments, the patient's white matter is monitored for changes at least once after treatment (e.g., treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401) by radiographic imaging (e.g., MRI). In some embodiments, the patient's white matter is monitored two or more times by radiographic imaging (e.g., MRI) after treatment, such as treatment with an anti-Aβ protofibril antibody, such as treatment with BAN2401.

[0218]

[0266] In some embodiments, patients may be monitored after one or more doses of an anti-Aβ protofibril antibody (e.g., BAN2401), for example, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more doses. In some embodiments, treatment may be continued if the severity of clinical symptoms and / or radiographic severity are asymptomatic or mild. In some embodiments, for example, if the severity of clinical symptoms and / or radiographic severity is moderate or severe, treatment may be interrupted and / or discontinued.

[0219]

[0267] In some embodiments, patients are monitored for changes in their white matter at least once after discontinuation of treatment. In some embodiments, patients are monitored for changes in their white matter at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after discontinuation of treatment. In some embodiments, subjects who show changes or decreases in brain white matter compared to baseline, for example by brain imaging, are not selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, subjects who do not show a decrease in brain white matter before treatment, for example by brain imaging, are selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0220] [5. Patient selection based on cerebral hemorrhage and / or cerebral white matter]

[0268] In some embodiments, a subject's baseline microbleeding or intracerebral hemorrhage status may increase the risk of ARIA events, intracerebral hemorrhage, or microbleeding events after administration of an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, patients who have not experienced or are not currently experiencing ARIA events and / or intracerebral hemorrhage or microbleeding prior to treatment are selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, subjects who have experienced or are currently experiencing intracerebral hemorrhage or microbleeding at baseline are not selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, subjects who show changes or decreases in brain white matter compared to baseline, as measured by brain imaging, are not selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, for example, subjects who do not show a reduction in brain white matter before treatment, as measured by brain imaging, are selected as candidates for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0221]

[0269] In some embodiments, subjects who have experienced or currently have intracerebral hemorrhage or microbleeding at baseline are selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401) and are monitored for ARIA events at a higher frequency throughout the treatment period than subjects who do not show a decrease in brain white matter. In some embodiments, subjects showing changes or decreases in brain white matter (e.g., measured by brain imaging compared to baseline) are selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401) and are monitored for ARIA events at a higher frequency throughout the treatment period than subjects who do not show a decrease in brain white matter. In some embodiments, subjects showing changes or decreases in brain white matter may be monitored before treatment with an anti-Aβ protofibril antibody (e.g., BAN2401) and before one or more infusions of the anti-Aβ protofibril antibody, e.g., before the 5th, 7th, and 14th infusions. In some embodiments, subjects may be continuously monitored throughout the treatment period.

[0222] [6. Other risk factors for ARIA]

[0270] In some embodiments, when a subject is treated with an anti-Aβ protofibril antibody (e.g., treatment with BAN2401), other factors may influence the subject's risk of ARIA. Subjects may be monitored for these risk factors before or during administration of the anti-Aβ protofibril antibody. In some embodiments, subjects found to have risk factors before treatment may be excluded from treatment with an anti-Aβ protofibril antibody such as BAN2401, or alternative therapies may be administered. In some embodiments, subjects with risk factors may initiate treatment with an anti-Aβ protofibril antibody (e.g., BAN2401), but may be monitored for ARIA during treatment, for example, at a higher frequency than subjects without risk factors. In some embodiments, ARIA is monitored by radiographic imaging of the subject's brain (e.g., MRI). In some embodiments, if a subject develops ARIA, treatment may be discontinued. In some embodiments, subjects without risk factors before treatment may be selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0223]

[0271] In some embodiments, ApoE4 allele carriers may have an increased risk of ARIA during treatment with anti-Aβ protofibril antibodies (e.g., treatment with BAN2401). Therefore, in some embodiments, the subject's ApoE4 status is assessed by DNA testing using a biological sample such as blood or buccal mucosa swab before treatment (e.g., treatment with anti-Aβ protofibril antibodies, e.g., BAN2401). In some embodiments, subjects who are carriers of the ApoE4 allele (e.g., heterozygous or homozygous for the ApoE4 allele) may not be treated with anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, subjects who are carriers of the ApoE4 allele (e.g., heterozygous or homozygous for the ApoE4 allele) may initiate treatment with anti-Aβ protofibril antibodies (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, if ARIA develops in a subject who is a carrier of the ApoE4 allele (e.g., heterozygous or homozygous for the ApoE4 allele), treatment may be discontinued. In some embodiments, subjects who are not carriers of the ApoE4 allele (e.g., heterozygous or homozygous for the ApoE4 allele) are selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0224]

[0272] In some embodiments, subjects with higher blood pressure (also called higher mean arterial pressure) (e.g., before and / or during treatment) compared to a control (e.g., blood pressure of a healthy subject or threshold blood pressure measurement based on the population mean) may have an increased risk of ARIA if treated with an anti-Aβ protofibril antibody (e.g., treatment with BAN2401). In some embodiments, the subject's mean arterial pressure is assessed before treatment (e.g., treatment with an anti-Aβ protofibril antibody, e.g., treatment with BAN2401) by, for example, auscultation, measurement of vibrations in blood flow and calculation of blood flow, or blood pressure measurement with an invasive probe inserted directly into the arterial lumen. In some embodiments, subjects with higher mean arterial pressure compared to a control (e.g., a healthy subject) may not be treated with an anti-Aβ protofibril antibody 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, high mean arterial pressure may be 180 mmHg / 120 mmHg or higher. In some embodiments, subjects with high mean arterial pressure compared to the control group may be initiated with an anti-Aβ protofibril antibody (e.g., BAN2401), but may be monitored for ARIA more frequently during treatment than subjects with lower mean arterial pressure compared to the control. In some embodiments, treatment may be discontinued if a subject's blood pressure rises during treatment and / or if a subject with high mean arterial pressure is found to have developed ARIA. In some embodiments, subjects with lower mean arterial pressure are selected for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0225]

[0273] In some embodiments, subjects with a higher amyloid load compared to a control (e.g., a healthy subject) (as determined by, for example, amyloid PET, or fluid biomarkers such as the Aβ42 / 40 ratio, measured before and / or during treatment) may have an increased risk of ARIA if treated with an anti-Aβ protofibril antibody (e.g., treatment with BAN2401). In some embodiments, the amyloid load of a subject is assessed before treatment (e.g., treatment with an anti-Aβ protofibril antibody, e.g., BAN2401) by, for example, PET imaging for amyloid PET, or detection of fluid biomarkers such as the Aβ42 / 40 ratio. In some embodiments, subjects with a high amyloid load compared to a control (e.g., a healthy subject) may not be treated with an anti-Aβ protofibril antibody such as BAN2401. In some embodiments, subjects with a higher amyloid load compared to the control group may be initiated with an anti-Aβ protofibril antibody (e.g., BAN2401), but may be monitored for ARIA more frequently during treatment than subjects with a lower amyloid load compared to the control. In some embodiments, treatment may be discontinued if a subject develops a higher amyloid load and / or if ARIA develops in a subject with a higher amyloid load. In some embodiments, subjects without a higher amyloid load are selected as candidates for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0226]

[0274] In some embodiments, subjects with classical cerebral surface hemosiderin deposition (e.g., pre-treatment and / or during treatment) may have an increased risk of ARIA-E when treated with an anti-Aβ protofibril antibody (e.g., treatment with BAN2401). In some embodiments, the subject's brain is scanned for cerebral surface hemosiderin deposition, for example, by imaging (e.g., by MRI), before treatment (e.g., treatment with an anti-Aβ protofibril antibody, e.g., BAN2401). In some embodiments, subjects with classical cerebral surface hemosiderin deposition may not be treated with an anti-Aβ protofibril antibody such as BAN2401. In some embodiments, subjects with classical cerebral surface hemosiderin deposition may initiate treatment with an anti-Aβ protofibril antibody (e.g., BAN2401), but may be monitored for ARIA at a higher frequency during treatment than subjects without classical cerebral surface hemosiderin deposition. In some embodiments, treatment may be discontinued if a subject is found to develop classical cerebral surface hemosiderin deposition disease, and / or if a subject with classical cerebral surface hemosiderin deposition disease is found to develop ARIA-E. In some embodiments, subjects without classical cerebral surface hemosiderin deposition disease are selected as subjects for treatment with an anti-Aβ protofibril antibody (e.g., BAN2401).

[0227] [7. Use of steroids in the treatment of severe ARIA]

[0275] In some embodiments, patients with an increased risk of intracerebral hemorrhage or microbleeding events and / or ARIA are administered steroids before and / or during treatment with an anti-Aβ protofibril antibody such as BAN2401. In some embodiments, patients exhibiting severe ARIA during treatment with an anti-Aβ protofibril antibody (e.g., BAN2401) are administered steroids. Steroid therapy can be administered by any known route, such as intravenous and / or oral routes. Steroid doses and administration schedules can follow those known in the art. In some embodiments, patients with severe radiological or symptomatic ARIA-E are administered steroids at doses and / or frequencies consistent with standard treatments well known to those skilled in the art.

[0228] [8. Concomitant use with anticoagulants, antiplatelet agents, and thrombolytic agents]

[0276] While not bound by theory, surprisingly, patients receiving certain anticoagulants or thrombolytic agents concurrently have been found to have a similar or lower risk of ARIA events, intracerebral hemorrhage, or microbleeds compared to those receiving anti-Aβ protofibril antibodies such as BAN2401 alone. Again, while not bound by theory, some patients receiving certain anticoagulants or thrombolytic agents may experience improved treatment outcomes when administered anti-Aβ protofibril antibodies such as BAN2401.

[0229]

[0277] In some embodiments, patients with AD or early-stage AD may be administered or treated with anticoagulants or thrombolytic agents (e.g., aspirin, antiplatelet agents, anticoagulants, fibrinolytic agents, 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 agent. In some embodiments, the thrombolytic agent is an anticoagulant. In some embodiments, the thrombolytic agent is a fibrinolytic agent. In some embodiments, the thrombolytic agent is tissue plasminogen activator. In some embodiments, patients receiving treatment with anticoagulants are administered anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, subjects treated with anticoagulants and administered anti-Aβ protofibril antibodies such as BAN2401 have a risk of ARIA events or intracerebral hemorrhage that is equivalent to or reduced compared to subjects administered anti-Aβ protofibril antibodies such as BAN2401 alone. In some embodiments, subjects treated with antiplatelet agents are administered anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, subjects treated with antiplatelet agents and administered anti-Aβ protofibril antibodies such as BAN2401 have a risk of ARIA events or intracerebral hemorrhage that is equivalent to or reduced compared to subjects administered anti-Aβ protofibril antibodies such as BAN2401 alone. In some embodiments, subjects treated with aspirin are administered anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, subjects treated with aspirin and administered an anti-Aβ protofibril antibody such as BAN2401 have a risk of ARIA events or intracerebral hemorrhage that is equivalent to or reduced compared to subjects administered an anti-Aβ protofibril antibody such as BAN2401 alone. In some embodiments, subjects receiving an anti-Aβ protofibril antibody such as BAN2401 are not administered anticoagulants or thrombolytic agents. In some embodiments, subjects receiving treatment with anticoagulants or thrombolytic agents are not selected as subjects for treatment with an anti-Aβ protofibril antibody such as BAN2401.In some embodiments, patients receiving anti-Aβ protofibril antibodies such as BAN2401 are not administered tissue plasminogen activator. In some embodiments, patients receiving treatment with tissue plasminogen activator are not selected as candidates for treatment with anti-Aβ protofibril antibodies such as BAN2401. In some embodiments, patients receiving treatment with tissue plasminogen activator are administered anti-Aβ protofibril antibodies such as BAN2401, and in this case, additional monitoring for ARIA is performed, for example. In some embodiments, patients receiving anti-Aβ protofibril antibodies such as BAN2401 and also receiving anticoagulants or thrombolytic agents are monitored for ARIA events. In some embodiments, patients receiving anti-Aβ protofibril antibodies such as BAN2401 and also receiving anticoagulants or thrombolytic agents are deprived of anti-Aβ protofibril antibodies until treatment with anticoagulants or thrombolytic agents is discontinued.

[0230]

[0278] In some embodiments, the subject's brain can be monitored at any time during treatment with an anti-Aβ protofibril antibody such as BAN2401 (e.g., by MRI). Additional monitoring may be performed if the subject has factors indicating an increased risk of intracranial hemorrhage, such as being under anticoagulation therapy. In some embodiments, subjects administered steroids may be further monitored, for example, by MRI.

[0231] [9. Monitoring of patient selection and changes to dosing plans based on biomarkers] [a. Measurement of tau PET

[0279] The disclosures and methods described herein are based in part on the finding that biomarkers such as tau PET levels can be used to select and monitor patients for treatment, and to make treatment decisions such as increasing or decreasing the amount or frequency of antibody administration, introducing additional therapeutic agents, switching to a maintenance dose, and / or discontinuing treatment with anti-Aβ protofibril antibodies. Treatment with anti-Aβ protofibril antibodies such as BAN2401 can result in a reduction in tau accumulation rate compared to control patients, for example, in brain regions such as the temporal lobe, as measured by tau PET levels (e.g., measured by tau PET imaging). In some embodiments, this correlates with a reduction in cerebral amyloid load and improvement in cognitive function outcomes in subjects. While not theoretically bound, in various embodiments, tau PET levels (e.g., tau PET standardized uptake ratio (SUVr)) may be used as a minimally invasive and / or additional biomarker to refine the measurement of therapeutic effects and / or to enable monitoring and treatment decisions. Such decisions include increasing or decreasing the amount of anti-Aβ protofibril antibody administered, increasing or decreasing the frequency of administration, introducing additional therapeutic agents, and / or discontinuing treatment with anti-Aβ protofibril antibody.

[0232]

[0280] As used herein, “tau PET” refers to tau positron emission tomography. In some embodiments, tau PET imaging (also called PET scan) is performed to evaluate tau pathology. In some embodiments, tau PET is evaluated using a PET tracer, and the same tracer is used in follow-up evaluations. In some embodiments, the [18F]MK-6240 tracer is used for PET imaging.

[0233]

[0281] Using tau positron emission tomography (PET) imaging, both whole-brain analysis (e.g., average of 5-6 cortical regions) and brain region analysis (e.g., temporal region) can be used to confirm the presence of tau pathology in the brain of early AD subjects during the screening phase of the study and / or to evaluate the effect of at least one anti-Aβ protofibril antibody on amyloid levels in the brain. In some embodiments, the PET scan uses the [18F]MK-6240 (florkinitau) tracer. In some embodiments, tau loading can be revealed by visual interpretation of PET imaging uptake (e.g., by a trained radiologist). In several embodiments, brain regions are evaluated for contrast agent uptake. In some embodiments, tau PET levels in the temporal region are evaluated. In some embodiments, tau PET levels in the frontal region are evaluated. In some embodiments, tau PET levels in the parietal region are evaluated. In some embodiments, tau PET levels in the occipital region are evaluated. In some embodiments, tau PET levels in the cingulate region are evaluated. In some embodiments, the temporal region includes the medial temporal region. In some embodiments, the medial temporal region includes the hippocampus, entorhinal cortex, parahippocampus, and / or anteromedial / lateral temporal lobe. In some embodiments, the temporal region includes the metatemporal region. In some embodiments, the metatemporal region includes the amygdala, entorhinal cortex, parahippocampus, intermediate / medial temporal lobe and posterior temporal lobe, and / or fusiform region. In some embodiments, the temporal region includes the temporal lobe. In some embodiments, the temporal lobe includes the superior anterior / posterior temporal lobe, intermediate / inferior temporal lobe, posterior temporal lobe, and / or fusiform cortex. In some embodiments, the entire cortical gray matter is evaluated for tau PET levels. In some embodiments, the reference region used for tau PET level evaluation is the ventral cerebellum (Cb).

[0234]

[0282] In some embodiments, “tau PET level” can be determined by measuring tau PET imaging and comparing it to a reference region using the standardized uptake ratio (SUVr). As used herein, “tau PET level,” “intracerebral tau level,” and “tau load” are used interchangeably. As used herein, tau PET level refers to a PET measurement of tau level within a brain region (e.g., temporal lobe). Methods for calculating tau PET SUVr are known in the art and may include those described herein. In some embodiments, standardized uptake ratio quantitative analysis of amyloid levels is performed using PMOD PNEURO Biomedical Image Quantification Software (PMOD Technologies, Zurich, Switzerland). In some embodiments, before averaging individual images (e.g., 5-minute emission frames) using, for example, a PMOD averaging function (which averages PET frames to improve the signal-to-noise ratio), the subject's motion in the X, Y, and Z planes is first evaluated for the PET images, and motion is corrected as necessary. In some embodiments, a corresponding MRI is created from the subject (e.g., using matrix size reduction, trimming the MRI to include only the brain, segmentation to separate the image into a binary map of gray matter, white matter, and CSF, and cranial decryption to leave only the brain mask). In some embodiments, a PMOD matching function is used to match the averaged PET image with the created MRI and align the images in the same orientation. In some embodiments, a brain normalization function, such as one provided by PMOD software, is used together with the Brain Norm and rigid body matching transformation matrix to generate the averaged PET. In some embodiments, this averaged PET is normalized to the same orientation as the segmented MRI of the subject (Senjem et al, 2005) 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.Standardized uptake values ​​(SUVs) can be calculated using PMOD software, which is calculated using normalized PET, subject weight, and tracer injection volume, for the whole gray matter mapping region and three white matter regions (pons, cerebellar white matter, and subcortical white matter), and are obtained in SUV units. In some embodiments, SUVr is the ratio of the whole 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 a composite reference region consisting of subcortical white matter, ventral cerebellum, extracted whole cerebellum, whole cerebellum adjusted by subcortical white matter, cerebellar gray matter, and cerebellar cortex, pontine subcortical white matter, and cerebellar white matter.

[0235]

[0283] In some embodiments, the adjusted mean change from baseline is measured before treatment and at least once after the start of treatment (e.g., over a period of at least 6 months after the initial dose of the therapeutic agent). In some embodiments, the adjusted mean change from baseline is measured over a period of at least 12 months after the initial dose of the therapeutic agent. In some embodiments, the adjusted mean change from baseline is measured over a period of at least 13 months after the initial dose of the therapeutic agent. In some embodiments, the adjusted mean change from baseline is measured over a period of at least 18 months after the initial dose of the therapeutic agent. In some embodiments, the adjusted mean change from baseline of the target tau PET SUVr value is less than 0.15 after administration of the initial dose of the composition. In some embodiments, the adjusted mean change from baseline of the target tau PET SUVr value is less than 0.10 after administration of the initial dose of the composition. In some embodiments, the adjusted mean change from baseline of the target tau PET SUVr value is less than 0.05 after administration of the initial dose of the composition. In some embodiments, the adjusted mean change from baseline in the target tau PET SUVr value is less than 0.15 13 months after administration of the first dose of the therapeutic agent. In some embodiments, the adjusted mean change from baseline in the target tau PET SUVr value is less than 0.05 after administration of the first dose of the composition. In some embodiments, the adjusted mean change from baseline in the target tau PET SUVr value is less than 0.15 18 months after administration of the first dose of the therapeutic agent.

[0236]

[0284] Another method for measuring tau by positron emission tomography (PET) is known in the art. The method is Tau IQ This includes algorithms (for example, for quantitative measurement of tau PET radioactive tracers, see Whittington et al., J. Nucl Med. 2021 Sep 1;62(9):1292-1300).

[0237]

[0285] Tau PET level measurements may be used alone to assess therapeutic efficacy, or in combination with one or more measurements in biological fluids (e.g., p-tau 181 and / or Aβ1-42:Aβ1-40 ratio), PET measurements of Aβ (e.g., by radioactive tracer uptake), MRI evaluation of Aβ plaques, and / or behavioral measurements, as discussed herein. Such assays may also be used to diagnose patients eligible for treatment (e.g., by measuring tau PET levels alone or in combination with the measurement of one or more additional markers of AD pathology in a subject, and determining that the subject is eligible for treatment because the tau PET level is higher than the level observed in healthy control subjects). In some embodiments, subjects are selected for treatment because of high tau PET levels in a brain region of the subject, where the tau PET level is higher than that of subjects without AD. In some embodiments, subjects are selected for treatment because of high tau PET levels in the temporal lobe of the subject's brain, where the tau PET level is greater than 1.4 as measured by amyloid PET SUVr. In some embodiments, subjects are selected for treatment due to high tau PET levels in the temporal region of the subject's brain, where the tau PET level is greater than 1.5 as measured by amyloid PET SUVr. In some embodiments, measurement of tau PET levels may be used instead of another method for measuring intracerebral tau levels and / or another marker for Aβ. In some embodiments, measurement of tau PET levels may be used in conjunction with the measurement of one or more additional markers. In some embodiments, patients may be monitored by one or more additional biomarkers, but are not limited to: (a) tau detected by PET scan from either visual interpretation or a semi-quantitative threshold (SUVr or centiroid); (b) total cerebrospinal fluid (CSF) tau (t-tau); and / or (c) blood biomarkers (e.g., total plasma tau (T-tau) and / or phosphorylated tau (P-tau) (e.g., p-tau-181)).In some embodiments, the patient's tau PET level may be monitored in conjunction with one or more of the Aβ1-42:Aβ1-40 ratio and / or p-tau 181 measurements in a body fluid sample (e.g., a blood sample). In some embodiments, the above combination includes GFAP measurement in serum or plasma. In some embodiments, tau PET level measurement may be used instead of another method for measuring intracerebral tau levels to determine the therapeutic effect and / or to make treatment decisions such as whether to continue treatment or switch to a maintenance dose.

[0238]

[0286] In some embodiments, tau PET levels can be used to calculate the relative change from a baseline measurement (e.g., a tau PET level measurement before the start of treatment). In some embodiments, tau PET level measurements can be repeated after the start of the treatment regimen to monitor the therapeutic effect. In some embodiments, a tau PET level increase of only about 0.05 to 0.1 over 13 months in a brain region indicates therapeutic effect. In some embodiments, a tau PET level increase of only about 0.05 to 0.1 over 18 months in a brain region indicates therapeutic effect. In some embodiments, a tau PET level increase of only about 0.05 to 0.1 over 13 months in the temporal lobe of the brain indicates therapeutic effect. In some embodiments, a tau PET level increase of only about 0.05 to 0.1 over 18 months in the temporal lobe of the brain indicates therapeutic effect.

[0239]

[0287] In some embodiments, the rate of change in tau PET levels is calculated based on two measurements from the subject. In some embodiments, the rate of change in tau PET levels is calculated based on three or more measurements from the subject. In some embodiments, the rate of change in tau PET levels indicates the rate of tau accumulation in the subject's brain.

[0240]

[0288] In some embodiments, the rate of change in tau PET levels is calculated based on at least two measurements from the subject, where the first measurement is taken before treatment and the second measurement is taken after the start of treatment, and treatment is continued for at least 13 or 18 months after the first dose of the therapeutic agent. In some embodiments, the rate of change in tau PET levels is compared to the rate of change in tau PET levels of an untreated control subject with AD who has not received treatment. In some embodiments, a decrease in the rate of increase of tau PET compared to an untreated control subject indicates a therapeutic effect. In some embodiments, a decrease in the rate of increase of tau PET over 6 months compared to an untreated control subject indicates a therapeutic effect. In some embodiments, a decrease in the rate of increase of tau PET over 12 months compared to an untreated control subject indicates a therapeutic effect. In some embodiments, a decrease in the rate of increase of tau PET over 13 months compared to an untreated control subject indicates a therapeutic effect. In some embodiments, a decrease in the rate of increase of tau PET over 18 months compared to an untreated control subject indicates a therapeutic effect.

[0241]

[0289] In methods for measuring clinical efficacy or monitoring treatment, a set threshold can be used to determine changes in brain tau levels, for example, to identify patients suitable for treatment with anti-Aβ protofibril antibodies, to determine whether to continue treatment, to determine whether to switch to a maintenance dose, or to conclude that a patient is amyloid-negative. In some embodiments, the tau PET level threshold may be evaluated in conjunction with other measures of brain amyloid load, such as amyloid PET scans, CSF, or serum or plasma biomarkers, to assist in determining whether a subject is suitable for treatment or continued treatment. In some embodiments, tau PET levels may be used instead of other methods for measuring brain tau levels. In some embodiments, tau PET levels above 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, a subject is selected for treatment with anti-amyloid β (Aβ) protofibril antibodies, in which case the subject has a tau PET level greater than about 1.4 in a brain region. In some embodiments, the subject is selected for treatment with an anti-amyloid-beta (Aβ) protofibril antibody, in which case the subject has a tau PET level greater than approximately 1.5 within a brain region. In some embodiments, the brain region is the temporal lobe. In some embodiments, the brain region is the temporal lobe. In some embodiments, the brain region is the metatemporal lobe. In some embodiments, the brain region is the intermediate temporal lobe.

[0242] [b. Measurement of the Aβ42 / 40 ratio]

[0290] The disclosures and methods described herein rely in part on the finding that biomarkers such as the Aβ42 / 40 ratio, either alone or in combination with other biomarkers, can be used to select and monitor patients for treatment, and to make treatment decisions such as increasing or decreasing the amount of antibody administered, increasing or decreasing the frequency of administration, deciding whether to introduce additional therapeutic agents, deciding whether to switch to a maintenance dose, and / or discontinuing treatment with anti-Aβ protofibril antibodies. A method for measuring Aβ42 and 40 and calculating the ratio in a blood sample is disclosed in PCT / U.S. Patent Application Publication 2022 / 073576 (incorporated herein by reference). Therapies including anti-Aβ protofibril antibodies such as BAN2401 may result in an increase in the Aβ42 / 40 ratio, which correlates with a reduction in cerebral amyloid load and improvement in cognitive function outcomes in subjects.

[0243]

[0291] Methods for measuring the Aβ42 / 40 ratio are known in the art, including assays using LC MS / MS. Examples of such methods include the PrecivityADTM assay (e.g., Kirmess et al., J. Clinica Chimica Acta 519:267-275 (2021)) and the Sysmex assay (https: / / www.eisai.com / news / 2019 / news201990.html) for measuring Aβ42 and Aβ40 in a sample for the purpose of calculating the ratio.

[0244]

[0292] Measurement of the Aβ42 / 40 ratio may be used alone to assess therapeutic efficacy, or in combination with one or more additional criteria, such as tau PET levels, PET measurements of Aβ radioactive tracers, MRI evaluation of Aβ plaques, and / or behavioral measurements, as discussed herein. Such assays may also be used to diagnose patients who are eligible for treatment (for example, by measuring the Aβ42 / 40 ratio alone or in combination with measuring one or more additional markers of Alzheimer's disease pathology in a subject, and determining that the subject is eligible for treatment because the ratio is lower than that observed in healthy control subjects). In some embodiments, measurements of the Aβ42 / 40 ratio may be used instead of other methods for measuring brain amyloid levels, such as PET scans, to determine whether a subject is eligible for treatment. In some embodiments, measurements of the Aβ42 / 40 ratio may be used instead of other methods for measuring brain amyloid levels, such as PET scans, to determine therapeutic efficacy and / or to make treatment decisions, such as whether to continue treatment or switch to a maintenance dose.

[0245]

[0293] In some embodiments, the measurement of the Aβ42 / 40 ratio may utilize the relative change from a baseline measurement. In some embodiments, the measurement of the Aβ42 / 40 ratio may use a set threshold to determine changes in brain amyloid levels, for example, to identify patients suitable for treatment with anti-Aβ protofibril antibodies, to determine whether to continue treatment, to determine whether to switch to a maintenance dose, or to conclude that a patient is amyloid-negative. In some embodiments, the threshold may be evaluated in combination with another measurement of brain amyloid load, such as a PET scan, to assist in determining whether a subject is suitable for treatment or continued treatment. In some embodiments, the Aβ42 / 40 ratio threshold is 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 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.099, 0.1, or an approximation thereof. In some embodiments, the threshold is approximately 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 choose to continue treatment or increase the dosage in the dosing regimen. In some embodiments, an increase in the Aβ42 / 40 ratio above the threshold may be used as an indicator that treatment may be terminated (e.g., terminated to transition to a maintenance regimen) and / or to decide to reduce the dosage in the dosing regimen or discontinue treatment. In some embodiments, a decrease in the Aβ42 / 40 ratio below the threshold may be used to determine whether to discontinue the maintenance dosing regimen (e.g., return to the previous treatment regimen).

[0246] [Measurement of CP-Tau Level]

[0294] The disclosures and methods described herein rely in part on the finding that using biomarkers such as p-tau levels, and in combination with other biomarkers such as phosphorylated tau (p-tau) levels (including tau phosphorylated at position 181 (P-tau 181), position 217 (P-tau 217), and / or position 231 (P-tau 231), and / or the ratio of P-tau 181 / NP-tau 181, and / or the ratio of P-tau 217 / NP-tau 217), may enable the selection and monitoring of patients for treatment, as well as the determination of whether to increase or decrease the amount of antibody administered, 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 protofibril antibodies. p-tau levels can be measured in CSF, serum, or plasma, as disclosed in PCT / U.S. Patent Application Publication No. 2022 / 079571, which is incorporated herein by reference. Therapies including anti-Aβ protofibril antibodies such as BAN2401 may result in a reduction in p-tau 181 levels, which correlates with a reduction in cerebral amyloid load and improved cognitive function outcomes in subjects.

[0247]

[0295] Methods for measuring the p-tau ratio are known in the art, including immunoassays (e.g., Quanterix® Simoa® p-tau assay) and / or techniques based on mass spectrometry (IP / LC-MS / MS). Plasma p-tau 181 is elevated in the early stages of AD, as determined by the Braak stage classification (I-II), and this continues to rise as the disease progresses to Braak stages V-VI (Janelidze et al., “Plasma P-tau 181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia,” Nat. Med., 26(3):379-386 (2020)). This biomarker correlates strongly with amyloid PET and tau PET, showing a 3.5-fold increase in AD compared to controls, a moderate increase in the MCI group, and has also been shown to differentiate clinically diagnosed AD patients from other taopathies (Thijssen et al., “Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration,” Nat.Med.,26(3):387-397(2020); Janelidze et al.).

[0248]

[0296] p-tau levels (e.g., p-tau-181 levels, p-tau-217 levels, and / or p-tau-231 levels, and / or the p-tau-181 / np-tau-181 ratio, and / or the p-tau-217 / np-tau-217 ratio) may be used alone to assess therapeutic effects, or in combination with one or more additional criteria, such as tau PET levels, PET measurements of Aβ radioactive tracer renewal, MRI evaluation of Aβ plaques, and / or behavioral measurements, as described herein. Furthermore, such assays can also be used to diagnose patients who are eligible for treatment (for example, by measuring p-tau levels (e.g., p-tau 181 level, p-tau 217 level, p-tau 231 level, and / or p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio, either alone or in combination with the measurement of one or more additional markers of Alzheimer's disease pathology in the subject, and determining that the subject is eligible for treatment because the levels are higher than those observed in healthy control subjects)). In some embodiments, p-tau levels (e.g., p-tau 181 level, p-tau 217 level, and / or p-tau 231 level, and / or p-tau 217 level) are measured. Measurement of the ratio of u-181 / np-tau-181 and / or the ratio of p-tau-217 / np-tau-217 may be used instead of other methods for measuring brain amyloid levels, such as PET scans, to determine whether a subject is suitable for treatment. In some embodiments, measurement of p-tau levels (e.g., p-tau-181 levels, p-tau-217 levels, and / or p-tau-231 levels, and / or the ratio of p-tau-181 / np-tau-181 and / or the ratio of p-tau-217 / np-tau-217) may be used instead of other methods for measuring brain amyloid levels, such as PET scans, to determine the effectiveness of treatment and / or to make treatment decisions, such as whether to continue treatment or switch to a maintenance dose.

[0249]

[0297] In some embodiments, the measurement of p-tau 181 levels in plasma or serum may utilize the relative change from a baseline measurement. In some embodiments, the change in p-tau 181 levels can be used to evaluate the therapeutic effect. In some embodiments, a decrease in p-tau 181 levels indicates a therapeutic effect, e.g., a decrease in brain amyloid levels. In some embodiments, the measurement of p-tau 181 levels may be used to determine a set threshold to determine a change in brain amyloid levels, e.g., to identify and / or screen patients suitable for treatment (e.g., with anti-Aβ protofibril antibodies), or to determine whether to continue treatment, or to determine whether to switch to a maintenance dose, or to conclude that a patient is amyloid-negative. In some embodiments, the threshold may be evaluated in combination with another measurement of brain amyloid load, such as a PET scan, to help determine whether a subject is suitable for treatment or continued treatment. In some embodiments, the p-tau 181 level threshold may be used instead of another method of measuring brain amyloid levels, such as a PET scan. In some embodiments, a p-tau 181 level threshold of approximately 2.2–2.3 pg / mL or higher is used to identify and / or select patients suitable for treatment with, for example, an anti-Aβ protofibril antibody. In some embodiments, a p-tau 181 level threshold of approximately 2.2 pg / mL or higher is used to identify and / or select patients suitable for treatment with, for example, an anti-Aβ protofibril antibody. In some embodiments, a p-tau 181 level threshold of approximately 2.3 pg / mL or higher is used to identify and / or select patients suitable for treatment with, for example, an anti-Aβ protofibril antibody. In certain such embodiments, the p-tau 181 level is measured using the Quanterix® Simoa® p-tau assay. 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 the p-tau 181 level above the threshold may indicate the need to select continued treatment or an increase in the dosing plan.In some embodiments, a decrease in p-tau 181 levels below a threshold may be used to terminate treatment (e.g., termination prioritizing a switch to maintenance therapy) and / or to decide on dose reduction or discontinuation of treatment in the dosing plan.

[0250]

[0298] In some embodiments, p-tau 181 levels can be measured in blood, for example, when blood-based tests are faster, easier, and / or more cost-effective than cerebrospinal fluid (CSF) assays or imaging methods. In particular, p-tau 181 has been shown to correlate with cerebral amyloid load, tau accumulation, and clinical progression in preclinical and early AD individuals (Wang YL et al., Plasma p-tau 181 Level Predicts Neurodegeneration and Progression to Alzheimer's Dementia: A Longitudinal Study. Front Neurol. 438 2021;12:695696.; Jack CR et al., Predicting amyloid PET and tau PET stages with plasma biomarkers. Brain. 2023;146:2029-44). In some embodiments, a higher tau PET level (e.g., p-tau 181) in a subject compared to a healthy control indicates that the subject has pre-AD, is at risk of AD, or has early AD, and may progress within the following 18 months and / or predict a 36-month progression from Aβ+ mild cognitive impairment to AD.

[0251] [d. GFAP levels in plasma or serum]

[0299] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount to a subject results in a decrease in glial fibrillary acidic protein (GFAP) in the subject's plasma or serum. While not theoretically bound, GFAP levels can be used as a marker of astrocyte activation. GFAP levels can be measured by techniques known in the art, such as immunoassays (e.g., Quanterix® Simoa® assay) and / or techniques based on mass spectrophotometric analysis (IP / LC-MS / MS). In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount to a subject results in a decrease in GFAP levels in the subject's plasma or serum. In some embodiments, administration of a composition comprising at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a reduction 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% of plasma or serum GFAP levels relative to baseline.

[0252]

[0300] In some embodiments, serum GFAP levels can be used to select patients for treatment, and to monitor and make treatment decisions such as increasing or decreasing the amount of antibody administered, increasing or decreasing the frequency of administration, deciding whether to introduce additional therapeutic agents, deciding whether to switch to a maintenance dose, and / or discontinuing treatment with anti-Aβ protofibril antibodies. In some embodiments, additional biomarkers may indicate effective treatment in combination with a decrease in GFAP levels over the same period. In some embodiments, improvements in other biomarkers may indicate effective treatment in combination with a decrease in GFAP levels over the same period. In some embodiments, improvements in other biomarkers may indicate effective treatment in combination with a decrease in GFAP levels compared to an untreated control. In some embodiments, indicators of treatment effectiveness can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0253] [e. Neurogranin levels in cerebrospinal fluid]

[0301] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount to a subject results in a decrease in the cerebrospinal fluid level of neurogranin in the subject. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount to a subject results in a decrease in the cerebrospinal fluid level of neurogranin by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% compared to baseline.

[0254]

[0302] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in neurogranin levels in the cerebrospinal fluid after 18 months of administration of the composition containing at least one anti-Aβ protofibril antibody in a therapeutically effective amount. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in neurogranin levels in the cerebrospinal fluid after 18 months of administration of the composition by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% compared to baseline.

[0255]

[0303] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease of at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL compared to baseline. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease of at least about 65 pg / mL in neurocranial fluid levels compared to baseline.

[0256]

[0304] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease of at least approximately 25 pg / mL, at least approximately 30 pg / mL, at least approximately 35 pg / mL, at least approximately 40 pg / mL, at least approximately 45 pg / mL, at least approximately 50 pg / mL, at least approximately 55 pg / mL, at least approximately 60 pg / mL, or at least approximately 65 pg / mL compared to baseline after 18 months of administration of the composition. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease of at least 65 pg / mL in neurocranin levels compared to baseline after 18 months of administration of the composition.

[0257]

[0305] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[0258]

[0306] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount is administered every other week or monthly. In some embodiments, a composition containing 10 mg / kg of BAN2401 is administered every other week. In some embodiments, a composition containing 10 mg / kg of BAN2401 is administered monthly.

[0259]

[0307] In some embodiments, neurogranin levels in the cerebrospinal fluid (CSF) can be used to select and monitor patients for treatment, and to make treatment decisions such as increasing or decreasing the amount or frequency of antibody administration, deciding whether to introduce additional therapeutic agents, deciding whether to switch to a maintenance dose, and / or discontinuing treatment with anti-Aβ protofibril antibodies. In some embodiments, additional biomarkers may indicate effective treatment in combination with a decrease in CSF levels over the same period. In some embodiments, improvements in other biomarkers may indicate effective treatment in combination with a decrease in CSF levels over the same period. In some embodiments, improvements in other biomarkers may indicate effective treatment in combination with a decrease in CSF levels compared to an untreated control. In some embodiments, indicators of treatment effectiveness can be used to reduce the amount of antibody administered, decrease the frequency of administration, or switch to a maintenance dose.

[0260] [f. Level of neurofilament light chain]

[0308] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chains compared to placebo. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chains compared to placebo.

[0261]

[0309] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chains after 18 months of administration of the composition compared to placebo. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid and / or plasma or serum levels of neurofilament light chains after 18 months of administration of the composition compared 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% compared to baseline.

[0262]

[0310] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in the production of neurofilament light chain levels in the cerebrospinal fluid (CSF) exceeding approximately 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, and 75 pg / mL compared to baseline. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in the production of neurofilament light chain levels in the CSF of approximately 75 pg / mL or less compared to baseline.

[0263]

[0311] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in the production of neurofilament light chain levels in the cerebrospinal fluid (CSF) exceeding approximately 35 pg / mL, 40 pg / mL, 45 pg / mL, 50 pg / mL, 55 pg / mL, 60 pg / mL, 65 pg / mL, 70 pg / mL, and 75 pg / mL after 18 months of administration of the composition, compared to baseline. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in the production of neurofilament light chain levels in the CSF of approximately 75 pg / mL or less after 18 months of administration of the composition, compared to baseline.

[0264]

[0312] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[0265]

[0313] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is 10 mg / kg. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount is administered every other week or monthly. In some embodiments, a composition containing 10 mg / kg of BAN2401 is administered every other week. In some embodiments, a composition containing 10 mg / kg of BAN2401 is administered monthly.

[0266]

[0314] In some embodiments, additional biomarkers and plasma or serum levels of neurofilament light chains can be used to select and monitor patients for treatment, and to make treatment decisions such as increasing or decreasing the amount of antibody administered, increasing or decreasing the frequency of administration, deciding whether to introduce additional therapeutic agents, deciding whether to switch to a maintenance dose, and / or deciding whether to discontinue treatment with anti-Aβ protofibril antibodies. In some embodiments, improvement in additional biomarkers, combined with a decrease in plasma or serum levels of neurofilament light chains over the same period, may indicate effective treatment. In some embodiments, improvement in additional biomarkers, combined with a decrease in plasma or serum levels of neurofilament light chains over the same period, may indicate effective treatment. In some embodiments, improvement in additional biomarkers, combined with a decrease in plasma or serum levels of neurofilament light chains compared to an untreated control, may indicate effective treatment. In some embodiments, indicators of treatment effectiveness can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0267] [g. Cerebrospinal fluid levels of phosphorylated tau]

[0315] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount reduces cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau). In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount reduces CSF levels of phosphorylated tau (p-tau) by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline.

[0268]

[0316] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid levels of phosphorylated tau after 18 months of administration of the composition. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid levels of phosphorylated tau by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline after 18 months of administration of the composition containing at least one anti-Aβ protofibril antibody in a therapeutically effective amount.

[0269]

[0317] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease 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 of phosphorylated tau in cerebrospinal fluid compared to baseline. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease of at least about 95 pg / mL of phosphorylated tau in cerebrospinal fluid compared to baseline.

[0270]

[0318] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid (CSF) levels of phosphorylated tau compared to baseline levels after 18 months of administration of the composition containing at least one anti-Aβ protofibril antibody in a therapeutically effective amount, 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. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in a decrease in cerebrospinal fluid (CSF) levels of phosphorylated tau compared to baseline levels after 18 months of administration of the composition containing at least one anti-Aβ protofibril antibody in a therapeutically effective amount.

[0271]

[0319] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[0272]

[0320] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount is administered every other week or monthly. In some embodiments, a composition containing 10 mg / kg of BAN2401 is administered every other week. In some embodiments, a composition containing 10 mg / kg of BAN2401 is administered monthly.

[0273]

[0321] In some embodiments, additional biomarkers and cerebrospinal fluid (CSF) levels of phosphorylated tau can be used to select and monitor patients for treatment, and to make treatment decisions such as increasing or decreasing the amount of antibody administered, increasing or decreasing the frequency of administration, deciding whether to introduce additional therapeutic agents, deciding whether to switch to a maintenance dose, and / or deciding whether to discontinue treatment with anti-Aβ protofibril antibodies. In some embodiments, improvements in additional biomarkers, combined with a decrease in CSF levels of phosphorylated tau over the same period, may indicate effective treatment. In some embodiments, improvements in additional biomarkers, combined with a decrease in CSF levels of phosphorylated tau over the same period, may indicate effective treatment. In some embodiments, improvements in additional biomarkers, combined with a decrease in CSF levels of phosphorylated tau compared to an untreated control group, may indicate effective treatment. In some embodiments, indicators of treatment effectiveness can be used to reduce the amount of antibody administered, reduce the frequency of administration, or switch to a maintenance dose.

[0274] [h. Brain volume]

[0322] In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in an improvement in overall hippocampal atrophy as measured by volumetric MRI (vMRI) compared to placebo. In some embodiments, the subject's brain volume (e.g., total ventricular volume, left ventricular volume and / or right ventricular volume, total volume, right hippocampal volume and / or left hippocampal volume, cortical thickness) is measured before treatment. In some embodiments, the subject's brain volume (e.g., total ventricular volume, left ventricular volume and / or right ventricular volume, total volume, right hippocampal volume and / or left hippocampal volume, cortical thickness) is measured 6 months, 12 months, and / or 18 months after treatment. In some embodiments, administration of a composition containing at least one anti-Aβ protofibril antibody disclosed herein in a therapeutically effective amount results in an improvement in brain volume atrophy as measured by vMRI compared to placebo.

[0275] [10. Subjects with Alzheimer's disease (AD), subjects suspected of having AD, or subjects at risk of developing AD]

[0323] Subjects receiving treatment in this specification include individuals who have AD or are suspected of having AD. In some embodiments, subjects show changes (e.g., increases, decreases, changes in the rate and / or extent of increases, or changes in the rate and / or extent of decreases) in one or more biomarkers associated with AD pathology (e.g., the biomarkers described above) compared to a baseline measurement. In some embodiments, the baseline measurement may be a measurement obtained from the same subject (e.g., at an earlier point in time), or a measurement in a body part, tissue, or fluid of the subject in which biomarker levels do not change in response to AD pathology. In some embodiments, the baseline measurement may be a measurement obtained from another subject, such as a healthy control subject, or an average of measurements obtained from two or more reference subjects.

[0276]

[0324] In some embodiments, subjects may, prior to treatment, exhibit changes and / or differences in measurements of one or more biomarkers associated with AD pathology, for example, compared to reference measurements (e.g., measurements from healthy controls), one or more of the following: (a) an increase in brain amyloid (e.g., a centroid value of approximately 20–40, e.g., a centroid value of approximately 20–32), measured, for example by amyloid PET; (b) an increase in brain tau (e.g., measured by positron emission tomography (PET)); (c) a decrease in cerebrospinal fluid levels of Aβ1-42 (e.g., a decrease in the Aβ1-42 / 1-40 ratio); and / or total tau, phosphorylated tau isoforms (e.g., p-tau-181, p-tau-217, and / or p-tau-231, p-tau-181 / np-tau-181 ratio, and / or p-tau-217 / np-tau-217 (d) Increased levels of neurogranin and / or neurofilament light chains (NfL), and (d) Decreased serum or plasma levels of Aβ1-42 (e.g., decreased Aβ1-42 / 1-40 ratio in plasma or serum), and / or increased levels of total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau-181, P-tau-217, and / or P-tau-231), P-tau-181 / NP-tau-181 ratio, and / or P-tau-217 / NP-tau-217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL). In some embodiments, subjects may show changes in the ratio of phosphorylated tau-217 to unphosphorylated tau-217 in plasma or serum (also known as the P-tau-217 / NP-tau-217 ratio, P-tau-217R, or p-tau-217R), for example, this ratio may increase in subjects who have, are suspected of having, or are at risk of having AD. While not bound by theory, the biomarkers disclosed herein may be useful for predicting amyloid PET status (Rissman et al., 2024, Alzheimers & Dementia, 20(2):1214-1224; Janelidze et al., 2022, Alzheimer's & Dementia, 18:283-293), as well as for the detection and diagnosis of AD (Hampel et al., 2023, Neuron, 111(18):2781-2799).In some embodiments, the amyloid PET state can be predicted using at least one of p-tau-217 / np-tau-217, Aβ42 / Aβ40, and p-tau-181 / np-tau-181. In some embodiments, the amyloid PET state can be predicted using measured values ​​of p-tau-217 and / or Aβ42 / Aβ40. In some embodiments, the amyloid PET state can be predicted using a combination of p-tau-217 and Aβ42 / Aβ40. In some embodiments, the amyloid PET state can be predicted by combining the p-tau-217 / np-tau-217 ratio and the Aβ42 / Aβ40 ratio.

[0277]

[0325] In some embodiments, the subject is amyloid-positive, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), MRI, and / or retinal amyloid accumulation.

[0278]

[0326] In some embodiments, the subject has AD and, for example, has been diagnosed with AD. For example, the subjects are diagnosed as follows: (a) mild cognitive impairment due to Alzheimer's disease (moderate likelihood) and / or mild Alzheimer's dementia; (b) mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute on Aging-Alzheimer's Association (NIA-AA) core clinical criteria; (c) mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a pre-treatment CDR global score of 0.5 and a Memory Box score of 0.5 or higher; (d) mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a history of subjective memory impairment with slow onset and slow progression in the year prior to treatment (e.g., corroborated by an informant); (e) mild Alzheimer's dementia based on the NIA-AA core clinical criteria for Alzheimer's dementia; or (f) mild Alzheimer's dementia based on a pre-treatment CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or higher.

[0279]

[0327] In some embodiments, subjects have early-stage Alzheimer's disease (AD). Subjects with early-stage AD may have symptoms ranging in severity from mild cognitive impairment (moderate likelihood) to mild Alzheimer's disease. In some embodiments, subjects with early-stage AD have an MMSE score of 22–30 and a Clinical Dementia Scale (CDR) score in the overall range of 0.5–1.0.

[0280]

[0328] In some embodiments, the subject is suspected of having AD based, for example, on one or more biomarkers and / or cognitive symptoms related to dementia.

[0281]

[0329] In some embodiments, subjects are at risk of developing Alzheimer's disease (AD) but have not yet shown cognitive symptoms of dementia. For example, subjects may have risk factors related to age or genetic mutations. In some embodiments, subjects are ApoE4 positive. In some embodiments, subjects are at least 65 years old, e.g., 65–80 years old. In some embodiments, subjects are 55–64 years old and have at least one risk factor selected from: (i) a first-degree relative diagnosed with dementia before the age of 75; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) elevated brain amyloid based on PET or cerebrospinal fluid (CSF) testing performed prior to the administration. In some embodiments, subjects at risk of AD show elevated brain amyloid, measured and / or confirmed by, for example, PET evaluation, but do not show detectable cognitive symptoms. In some embodiments, subjects at risk of Alzheimer's disease (AD) are compared to a control subject or control population with amyloid PET; tau in the brain (e.g., measured by positron emission tomography (PET)), cerebrospinal fluid levels of one or more Aβ1-42 (or Aβ1-42 / 1-40 ratio in cerebrospinal fluid), total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau-181, P-tau-217, and / or P-tau-231), P-tau-181 / NP-tau-181 ratio, P-tau-217 / NP-tau-217 ratio, neuroradioactive This indicates changes in biomarkers such as tau and neurofilament light chains (NfL), and / or changes in serum or plasma levels of one or more of the following: Aβ1-42 (or Aβ1-42 / 1-40 ratio), total tau, phosphorylated tau (P-tau) isoforms (e.g., P-tau-181, P-tau-217, and / or P-tau-231), P-tau-181 / NP-tau-181 ratio, and / or P-tau-217 / NP-tau-217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chains (NfL).

[0282]

[0330] In some embodiments, subjects at risk of developing Alzheimer's disease (AD) may have preclinical AD (also known as pre-AD, where subjects do not exhibit cognitive impairment but have elevated brain amyloid levels based on changes in one or more biomarkers associated with AD pathology). For example, a subject may show changes in one or more biomarkers associated with AD pathology, but no cognitive impairment is observed as measured by clinical symptoms of AD. In some embodiments, the subject's Global Clinical Dementia Scale (CDR) score is 0. In some embodiments, the subject's Mini-Mental State Examination (MMSE) score is 27 or higher (including educational adjustments). In some embodiments, subjects have a better WMS-IV LMII score than one standard deviation lower than the age-adjusted mean of the Wechsler Scale of Memory IV Logical Memory (subscale) II (WMS-IV LMII); that is, subjects aged 50-64 have a score greater than 15, subjects aged 65-69 have a score greater than 12, subjects aged 70-74 have a score greater than 11, subjects aged 75-79 have a score greater than 9, and subjects aged 80-90 have a score greater than 7.

[0283] [11. Anti-β-amyloid protofibril antibody]

[0331] In some embodiments, an antibody that binds to Aβ (also called an anti-Aβ antibody) is an antibody that binds to any form of Aβ (e.g., conformation), such as Aβ monomers, oligomers (e.g., different forms of Aβ oligomers such as dimers, trimers, tetramers, pentamers, hexamers, nocumerers, dodecamers, etc.), paranucleoli (e.g., partially folded monomers that form nuclei for fibril elongation), protofibrils, or mature fibrils. In some embodiments, an anti-Aβ antibody may bind to two or more forms of Aβ. For example, an exemplary anti-Aβ antibody is a pan-Aβ antibody (e.g., a pan-AβpE3 antibody) that reacts with high molecular weight oligomers, protofibrils, and fibril forms of Aβ found in various plaque types. In some embodiments, an anti-Aβ antibody preferentially binds to a particular form of Aβ. For example, an exemplary Aβ antibody is an anti-Aβ protofibril antibody that binds to at least protofibrils. In some embodiments, the anti-Aβ protofibril antibody preferentially binds to protofibrils and may also bind to other forms of Aβ. In some embodiments, the anti-Aβ protofibril antibody may preferentially bind to protofibrils compared to other forms of Aβ. In some embodiments, the anti-Aβ protofibril antibody preferentially binds to protofibrils and does not bind to other forms of Aβ.

[0284]

[0332] In some embodiments, any anti-Aβ protofibril antibody may be used in the methods disclosed herein. In some embodiments, the antibody comprises one or more sequences from Tables 1-4, which include, for example, a complete set of six complementarity-determining regions (CDRs) and / or a complete set of variable regions and / or a complete set of heavy and light chain sequences from the table. In some embodiments, the anti-Aβ protofibril antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR1, 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 protofibril antibody comprises a heavy chain complementary 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 protofibril antibody comprises a human heavy chain and light chain variable region framework. In some embodiments, the anti-Aβ protofibril antibody comprises a human IgG1 heavy chain constant region and a human Ig kappa light chain constant region. In some embodiments, the anti-Aβ protofibril antibody comprises a heavy chain 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 relation to antibody sequences or structures, "CDR" refers to a complementarity-determining region that provides the primary determinants of antigen binding. Generally, the antigen-binding site has six CDRs; three in VH (HCDR1, HCDR2, HCDR3) and three in VL (LCDR1, LCDR2, LCDR3). The CDRs can be determined according to the Kabat numbering scheme. This can be determined according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991, hereafter referred to as the "Kabat Report").

[0285]

[0333] In some embodiments, at least one anti-Aβ protofibril antibody includes a human constant region. In some embodiments, the human constant region of at least one anti-Aβ protofibril antibody includes a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE and any of their allele variants, as disclosed in the Kabat report. In this disclosure, one or more of such sequences may be used. 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 described in SEQ ID NO: 11.

[0286]

[0334] In some embodiments, the human constant region of at least one anti-Aβ antibody includes a light chain constant region selected from the κ-λ chain constant region and any allele variant thereof, as discussed in the Kabat report. One or more such sequences may be used herein. In some embodiments, the light chain constant region is selected from κ and its allele variants. The amino acid sequence of the human κ chain constant region is known in the art and is described in SEQ ID NO: 12.

[0287]

[0335] In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401, also known as lecanemab. The terms “BAN2401” and “lecanemab” are used interchangeably and refer to the humanized IgG1 monoclonal version of mAb158, a mouse monoclonal antibody designed to target protofibrils, disclosed in International Publication No. 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 comprises three heavy chain complementary 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 complementary 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 International Publication No. 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 heavy and light chain sequences of BAN2401 are shown in Sequence IDs 9 and 10, and are described in International Publication No. 2007 / 108756 and the Journal of Alzheimer's Disease 43:575-588 (2015).

[0288]

[0336] In some embodiments, the isolated anti-Aβ protofibril antibody used for treatment is present at a concentration of at least 80 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 100 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 200 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration in the range of 80 mg / mL to 300 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration in the range of 85 mg / mL to 275 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration in the range of 90 mg / mL to 250 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration in the range of 95 mg / mL to 225 mg / mL. In some embodiments, isolated anti-Aβ protofibril antibodies are present at concentrations ranging from 100 mg / mL to 200 mg / mL. In some embodiments, isolated antibodies or fragments thereof are 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, isolated antibodies or fragments thereof are present at a concentration of 100 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 200 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 300 mg / mL. In some embodiments, the isolated antibody or fragment thereof is BAN2401. As used herein, “fragment” of an antibody refers to a portion of the antibody, for example, a portion containing its antigen-binding region or variable region.Non-limiting examples of fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, diabodies, linear antibodies, and single-chain antibody molecules.

[0289] [12. A therapeutically effective amount of at least one anti-Aβ protofibril antibody]

[0337] In various embodiments, the methods of the present disclosure involve administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody to a subject. As used herein, the term “therapeutably effective amount” means an amount of the compound or pharmaceutical composition sufficient to produce the desired therapeutic effect.

[0290]

[0338] Those skilled in the art will understand that the therapeutically effective amount of at least one anti-Aβ protofibril antibody administered to a subject may vary depending on several factors, including pharmacodynamic properties, route of administration, frequency of treatment, and the health status, age, and weight of the subject receiving treatment, and will be able to determine an appropriate amount for each subject using the information disclosed herein.

[0291]

[0339] In some embodiments, the therapeutically effective dose is a dose selected to improve and / or maintain efficacy and improve at least one of safety and / or tolerability. In some embodiments, the therapeutically effective dose is selected to reduce at least one side effect and simultaneously improve and / or maintain efficacy. Therapeutic effective doses of anti-Aβ protofibril antibody and methods for measuring therapeutic efficacy are disclosed in PCT / U.S. Patent Application Publication No. 2022 / 073576; No. 2022 / 079571; and No. 2022 / 041926, which are incorporated herein by reference.

[0292]

[0340] In some embodiments, at least one anti-Aβ protofibril antibody in the following concentrations is administered to the subject based on their body weight: 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.

[0293]

[0341] In some embodiments, at least one anti-Aβ protofibril 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.

[0294]

[0342] In some embodiments, at least one anti-Aβ protofibril 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.

[0295]

[0343] In some embodiments, at least one anti-Aβ protofibril 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 g / 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.

[0296]

[0344] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 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 g / kg, 17 g / kg, 18 mg / kg, 19 g / kg, or 20 mg / kg relative to the subject's body weight. In some embodiments, at least one anti-Aβ protofibril 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.

[0297]

[0345] In some embodiments, the subject is administered at a dose of 0.5 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 1 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 2 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 2.5 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 3 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 4 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 5 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 6 mg / kg of at least one anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 7 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 7.5 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 8 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 9 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 10 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 11 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 12 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 12.5 mg / kg of at least one type of anti-Aβ protofibril antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 13 mg / kg of at least one anti-Aβ protofibril antibody relative to their body weight.In some embodiments, the subject is administered at a dose of 14 mg / kg of body weight of at least one type of anti-Aβ protofibril antibody. In some embodiments, the subject is administered at a dose of 15 mg / kg of body weight of at least one type of anti-Aβ protofibril antibody. In some embodiments, the subject is administered at a dose of 16, 17, 18, 19, or 20 mg / kg of body weight of at least one type of anti-Aβ protofibril antibody. In some embodiments, the subject is administered at a dose of 21, 22, 23, 24, or 25 mg / kg of body weight of at least one type of anti-Aβ protofibril antibody.

[0298]

[0346] In some embodiments, at least one anti-Aβ protofibril 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.

[0299]

[0347] As mentioned above, in some embodiments, at least one anti-Aβ protofibril antibody is BAN2401. Therefore, in some embodiments, the subject is administered BAN2401 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.

[0300]

[0348] In some embodiments, BAN2401 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.

[0301]

[0349] In some embodiments, BAN2401 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.

[0302]

[0350] In some embodiments, BAN2401 is administered to the subject at concentrations 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 g / 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.

[0303]

[0351] In some embodiments, BAN2401 is administered to the subject at doses of 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 g / kg, 17 g / kg, 18 mg / kg, 19 g / kg, and 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, based on the subject's body weight.

[0304]

[0352] In some embodiments, the subject is administered 0.5 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 1 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 2 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 2.5 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 3 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 4 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 5 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 6 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 7 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 7.5 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 8 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 9 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 10 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 11 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 12 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 12.5 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 13 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 14 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 15 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg / kg of BAN2401 relative to their body weight. In some embodiments, the subject is administered 21, 22, 23, 24, or 25 mg / kg of BAN2401 relative to their body weight.In some embodiments, BAN2401 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.

[0305]

[0353] In some embodiments, the subject is administered BAN2401 at a dose of 2.5 mg / kg to 10 mg / kg relative to their body weight. In some embodiments, the subject is administered BAN2401 at a dose of 5 mg / kg to 10 mg / kg relative to their body weight. In some embodiments, the subject is administered BAN2401 at a dose of 2.5 mg / kg relative to their body weight. In some embodiments, the subject is administered BAN2401 at a dose of 5 mg / kg relative to their body weight. In some embodiments, the subject is administered BAN2401 at a dose of 7.5 mg / kg relative to their body weight. In some embodiments, the subject is administered BAN2401 at a dose of 10 mg / kg relative to their body weight.

[0306]

[0354] In some embodiments, subjects are administered an initial dose of anti-Aβ protofibril antibody without an initial titration step to the therapeutic dose (e.g., subjects start treatment at 10 mg / kg without titration). In some embodiments, doses of BAN2401 can be used without requiring a prior titration step. In some embodiments, subjects are switched to a maintenance dose without an initial titration step to the maintenance dose. In certain cases, administering a therapeutic dose without a titration step may result in additional therapeutic benefits for the patient, such as a rapid conversion of plasma biomarkers to amyloid-negative, or it may facilitate the early identification of patients who do not show therapeutic changes in plasma biomarkers in response to anti-Aβ protofibril antibody (non-responders) and who would benefit from alternative treatments.

[0307] [13. Administration Plan and Route of Administration]

[0355] In various embodiments, methods for treating Alzheimer's disease (AD) are disclosed herein, which include administering an anti-Aβ protofibril antibody (e.g., BAN2401) to a subject. In some embodiments, the subject has early AD. In some embodiments, an anti-Aβ protofibril antibody (e.g., BAN2401) is administered to a subject who has pre-AD or is suspected of having AD. In some embodiments, the anti-Aβ protofibril antibody is administered to the subject according to a dosing plan (also called “dosing plan,” “treatment regimen,” or “treatment”), for example, a schedule that specifies the dose of anti-Aβ protofibril antibody per hour, including the number of doses and dosing intervals over a given period. In some embodiments, the dosing plan includes administering the anti-Aβ protofibril antibody at a specified dose according to a schedule (e.g., on a repeat basis). In some embodiments, the anti-Aβ protofibril antibody may be administered daily, once weekly (also referred to as "weekly"), 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 protofibril antibody may be administered intravenously and / or subcutaneously. In some embodiments, the dosing plan includes the administration of at least one initial dose (also referred to as a therapeutic dose) and at least one maintenance dose. In some embodiments, the dosing plan includes the administration of at least one dose of the anti-Aβ protofibril antibody via one route of administration. In some embodiments, the dosing plan includes the administration of at least one dose of the anti-Aβ protofibril antibody via two or more routes of administration (for example, the antibody is initially administered intravenously and then switched to subcutaneous administration).

[0308]

[0356] In some embodiments, the anti-Aβ protofibril antibody is administered intravenously, for example, by injection into a peripheral vein. In the upper limbs, the median ulnar or radial cutaneous vein of the arm, or the metacarpal vein on the back of the hand may be used. In the lower limbs, the dorsal venous plexus of the foot may be used.

[0309]

[0357] After 18 months, population modeling predicts that the reduction in amyloid-beta plaque levels will persist even when the frequency of administration at 10 mg / kg is reduced to once every four weeks.

[0310]

[0358] In some embodiments, the anti-Aβ protofibril antibody is administered subcutaneously. In the case of subcutaneous injection, the anti-Aβ protofibril antibody is injected into the tissue layer between the skin and muscle, such as the adipose tissue just beneath the skin. In some embodiments, the subcutaneous injection is administered to 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 amount of injection solution administered subcutaneously is less than 2 mL.

[0311]

[0359] In some embodiments, the anti-Aβ protofibril antibody is administered subcutaneously using a vial and syringe (also known as "vial / syringe," "syringe / vial," or "SC vial"). For example, the anti-Aβ protofibril antibody in the subcutaneous formulation is transferred from the vial to a syringe and then injected into the subject from the syringe.

[0312]

[0360] In some embodiments, the anti-Aβ protofibril antibody is administered using an autoinjector (also known as an "autoinjector," "AI," "AI device," or "SC AI"). An exemplary autoinjector is the YpsoMate® 2.25 mL AI device, which is approved in the United States and Europe as a product for Ajovy® (fremanezumab v-frm). In some embodiments, the autoinjector may include a plastic PLAJEX® syringe, a tapered needle (24G-29G), a V-shaped spring, a spring force, and a component collar. It may also be a single-use, disposable injection device consisting of a housing with a content confirmation window, a spring actuation mechanism, and an internal needle safety feature. In some embodiments, the 2.25 mL PLAJEX® syringe is pre-filled with the anti-Aβ protofibril antibody. At least one AI device may be required for the administration of the anti-Aβ protofibril antibody.

[0313]

[0361] In some embodiments, the anti-Aβ protofibril antibody is administered intravenously in at least one dose and subcutaneously in at least one dose. For example, the anti-Aβ protofibril antibody (e.g., BAN2401) may be administered intravenously to a subject once a week over a period such as 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 months, followed by subcutaneous administration of the antibody. In some embodiments, the anti-Aβ protofibril antibody is administered subcutaneously using a vial-syringe, followed by subcutaneous administration using an artificial injection (AI). In some embodiments, the anti-Aβ protofibril antibody is administered subcutaneously using a vial-syringe or AI, followed by intravenous administration.

[0314]

[0362] In some embodiments, the treatment method includes switching between intravenous and subcutaneous administration, or from an initial dose to a maintenance dose, at a set point in time (e.g., 18 months or 24 months later). In some embodiments, the treatment method includes determining whether to switch between intravenous and subcutaneous administration, or from an initial dose to a maintenance dose, using biomarker levels, if measured at a set point in time (e.g., 18 months or 24 months later). In some embodiments, the maintenance dose is administered subcutaneously (e.g., as one or more subcutaneous injections).

[0315]

[0363] In some embodiments, BAN2401 (also known as LEQEMBI, lecanemab, or lecanemab-ilumbu) is supplied as an intravenous solution, is preservative-free, sterile, and is a clear to milky white and colorless to pale yellow solution intended for intravenous administration by dilution. In some embodiments, LEQEMBI may be supplied in single-dose vials available at concentrations of 500 mg / 5 mL (100 mg / mL) or 200 mg / 2 mL (100 mg / mL). In some embodiments, the solution contains 100 mg of lecanemab-ilumbu per mL, along with arginine hydrochloride (42.13 mg), histidine (0.18 mg), histidine hydrochloride monohydrate (4.99 mg), polysorbate 80 (0.50 mg), and water for injection, with a pH of approximately 5.0. In some embodiments, LEQEMBI is diluted with 250 mL of 0.9% sodium chloride injection (USP). In some embodiments, the dose of LEQEMBI is 10 mg / kg of the subject's body weight.

[0316] [a. Starting dose]

[0364] In some embodiments, anti-Aβ protofibril antibodies can be administered to a subject (e.g., a subject with AD, a subject suspected of having AD, or a subject at risk of AD) according to a dosing plan (also called an administration plan), in which a therapeutically effective dose is administered repeatedly at regular intervals. In some embodiments, the dose may also be called the starting dose, therapeutic dose, or initial dose. The starting dose is administered to the subject according to a dosing plan (e.g., an initial dosing plan, also called an initial administration plan) that administers an initial dose of anti-Aβ protofibril antibody at regular intervals (e.g., daily, weekly, bi-weekly, or monthly) over a period of time until the subject shows evidence of improvement in Alzheimer's disease (AD) pathology and / or slowing of AD progression. In some embodiments, this period is at least 18 months or at least 24 months. In some embodiments, this period is 18 months. In some embodiments, this period is 24 months. In some embodiments, this period is approximately 12, 18, 24, 30, 36, 42, 48, 54, or 60 months. In some embodiments, the starting dose is administered until the subject becomes amyloid-negative.

[0317]

[0365] In some embodiments, at least one initial dose of anti-Aβ protofibril antibody is administered intravenously to the subject. An exemplary dosing regimen may include intravenous administration of anti-Aβ protofibril antibody (e.g., BAN2401) at a dose of 10 mg / kg. In some embodiments, BAN2401 is administered intravenously once a week at a dose of 10 mg / kg for, for example, at least 18 months or at least 24 months, or until, for example, the subject becomes amyloid-negative or reaches one or more other biomarker levels (e.g., changes in biomarkers discussed herein). In some embodiments, BAN2401 is administered intravenously every other week at a dose of 10 mg / kg for, for example, at least 18 months or at least 24 months, or until, for example, the subject becomes amyloid-negative or reaches one or more other biomarker levels (e.g., changes in biomarkers discussed herein).

[0318]

[0366] In some embodiments, at least one initial dose of an anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously, for example, using a vial-syringe or auto-injector. An exemplary dosing plan may include subcutaneous administration of 720 mg of the anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, this dose may be administered as a single 720 mg injection. In some embodiments, the 720 mg dose may be administered by two simultaneous (e.g., consecutive) injections of 360 mg each (1.8 mL x 2 at 400 mg / 2 mL or 1.8 mL x 2 at 200 mg / mL). In some embodiments, BAN2401 is administered subcutaneously once a week at a dose of 720 mg for, for example, 18 months. In some embodiments, BAN2401 is administered subcutaneously once a week at a dose of 720 mg for, for example, 24 months. In some embodiments, BAN2401 is administered subcutaneously once a week at a dose of 720 mg for, for example, at least 18 months or at least 24 months, or until, for example, the subject becomes amyloid-negative or reaches one or more other biomarker levels (e.g., changes in biomarkers discussed herein). In some embodiments, BAN2401 is administered subcutaneously every other week at a dose of 720 mg for, for example, at least 18 months or at least 24 months, or until, for example, the subject becomes amyloid-negative or reaches one or more other biomarker levels (e.g., changes in biomarkers discussed herein). The 720 mg dose may be administered by two simultaneous (e.g., consecutive) injections of 360 mg each (1.8 mL x 2 at 400 mg / 2 mL or 1.8 mL x 2 at 200 mg / mL).

[0319]

[0367] In some embodiments, various starting doses of anti-Aβ protofibril antibody (e.g., BAN2401) can be administered. In some embodiments, subcutaneous doses of anti-Aβ protofibril antibody (e.g., BAN2401) can be administered two or more times. For example, a subject can transition from a first dose of antibody in a first period to a second dose of antibody in a second period. For example, a dose of 720 mg can be administered subcutaneously once a week over the first period, followed by a dose of 500 mg once a week over the second period. In some embodiments, a dose of 720 mg in the first period is administered by two consecutive injections of 360 mg (1.8 mL x 2 of the subcutaneous formulation at 200 mg / mL), followed by a dose of 500 mg in the second period by two consecutive injections of 250 mg (1.25 mL x 2 of the subcutaneous formulation at 200 mg / mL). In some embodiments, the first period is less than approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months, or shorter than the time it takes for the subject to become amyloid-negative or to reach one or more biomarker levels discussed herein. In some embodiments, the first period is less than 18 months. In some embodiments, the second period includes the first period plus the time remaining after 18 months, so the first and second periods together are approximately 18 months. In some embodiments, subjects are administered 720 mg of anti-Aβ protofibril antibody (e.g., BAN2401) subcutaneously weekly via auto-injector over a first period, and then 500 mg of anti-Aβ protofibril antibody (e.g., BAN2401) subcutaneously weekly via auto-injector over a second period.

[0320]

[0368] In some embodiments, the initial administration plan for an Aβ protofibril antibody (e.g., BAN2401) may include administration of the antibody in two or more doses and / or via two or more routes of administration. In some embodiments, the subject may transition from a first dose of antibody administered intravenously in a first period to a second dose of antibody administered intravenously or subcutaneously in a second period. In some embodiments, the subject may transition from a first dose of antibody administered intravenously in a first period to a second dose of antibody administered subcutaneously in a second period. For example, a first dose of 10 mg / kg may be administered intravenously to the subject every other week over a first period (e.g., 6 or 12 months), followed by a second dose of 720 mg or less (e.g., 500 mg) over a second period (e.g., 6 or 12 months). In some embodiments, an initiation regimen including a first dose of Aβ protofibril antibody (e.g., BAN2401) administered intravenously over a first period and a second dose of Aβ protofibril antibody administered subcutaneously over a second period may be followed by a maintenance regimen including, for example, subcutaneous administration of a 360 mg dose of antibody every other week or a 250 mg dose of antibody every other week. In some embodiments, the target's exposure to anti-Aβ protofibril antibody differs depending on whether the dose is administered using a vial / syringe or AI. In some embodiments, exposure to the antibody is greater when using AI than when using a vial / syringe. Therefore, the dose administered subcutaneously using AI may be lower than the dose administered subcutaneously using a vial-syringe. In some embodiments, if the target's systemic exposure is based on intravenous administration (e.g., 10 mg / kg every other week), the exposure from the dose administered subcutaneously using the AI ​​method may be higher than the exposure obtained using the vial / syringe method. Therefore, doses administered subcutaneously using AI may be lower than doses administered subcutaneously using vials / syringes. In some embodiments, systemic exposure from a dose of 10 mg / kg administered intravenously every other week is approximately equivalent to exposure from a dose of 720 mg administered subcutaneously weekly using the vial / syringe method, or from a dose of 500 mg administered subcutaneously weekly using the AI ​​method.For example, the dose of anti-Aβ protofibril 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 protofibril antibody administered subcutaneously using the AI ​​method is 65%, 66%, 67%, 68%, 69%, or 70% of the dose administered subcutaneously using the vial / syringe method.

[0321]

[0369] In some embodiments, at least one starting dose of anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously using an autoinjector (AI). An exemplary dosing plan may include subcutaneous administration of a 500 mg dose of anti-Aβ protofibril antibody (e.g., BAN2401) using, for example, an AI. The 500 mg dose c...

Claims

1. A method for treating Alzheimer's disease (AD) in a subject who has Alzheimer's disease (AD), is suspected of having AD, or is at risk of having AD, comprising subcutaneously administering an anti-Aβ protofibril antibody to the subject in a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), the antibody having three heavy chain complementation-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 complementation-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).

2. A method for delaying the clinical progression of a subject with AD, a subject suspected of having AD, or a subject at risk of AD, comprising subcutaneously administering an anti-Aβ protofibril antibody to the subject in a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), comprising three heavy chain complementation-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 complementation-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).

3. A method for reducing brain amyloid levels in subjects with AD, suspected of having AD, or at risk of AD, comprising subcutaneously administering to the subject 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), an antibody having three heavy chain complementation-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 complementation-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).

4. A method for converting an amyloid-positive subject to an amyloid-negative state, comprising subcutaneously administering an anti-Aβ protofibril antibody to the subject in a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), the antibody having three heavy chain complementation 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 complementation 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).

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

6. The method according to any one of claims 1 to 5, wherein when the anti-Aβ protofibril antibody is administered subcutaneously at a dose of 150 mg to 600 mg, for example, 200 mg to 550 mg (for example, 500 mg), the risk of developing ARIA is reduced compared to when it is administered subcutaneously at a higher dose, for example, 720 mg.

7. The method according to any one of claims 1 to 6, wherein the anti-Aβ protofibril antibody is administered in 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 according to any one of claims 1 to 7, wherein the anti-Aβ protofibril antibody is administered subcutaneously at a dose of 500 mg.

9. The method according to any one of claims 1 to 8, wherein the aforementioned dose is administered in two parts, for example, consecutively.

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

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

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

13. The method according to any one of claims 1 to 12, wherein the anti-Aβ protofibril antibody is administered, for example, in an initial dose during a first period according to an initial administration plan, and then, for example, in a maintenance dose during a second period according to a maintenance administration plan.

14. The method according to claim 13, wherein the initial administration plan includes intravenous administration or subcutaneous administration of each initial dose.

15. The method according to claim 13 or 14, wherein the maintenance administration plan includes subcutaneous administration or intravenous administration of each maintenance dose.

16. The method according to claim 13 or claim 15, wherein the initial administration plan includes at least one initial dose administered intravenously and at least one initial dose administered subcutaneously.

17. The method according to any one of claims 13, 14, or 16, wherein the maintenance administration plan comprises at least one maintenance dose administered intravenously and at least one maintenance dose administered subcutaneously.

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

19. The method according to claim 13, wherein the starting dose of the anti-Aβ protofibril antibody is 150 mg to 600 mg, for example, 200 mg to 550 mg, preferably 500 mg, and is administered subcutaneously.

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

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

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

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

24. The method according to any one of claims 13 to 22, wherein the maintenance dose is administered every other week.

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

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

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

28. The method according to any one of claims 13 to 27, wherein the first period is continued until the subject becomes amyloid-negative.

29. The method according to claim 13, wherein the anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously once weekly at an initial dose of 500 mg for at least 18 months, followed by a second period at a maintenance dose of 250 mg once weekly.

30. The method according to claim 13, wherein the anti-Aβ protofibril antibody (e.g., BAN2401) is administered subcutaneously once weekly at an initial dose of 500 mg for at least 24 months, followed by a second period at a maintenance dose of 250 mg once weekly.

31. The method according to any one of claims 13 to 30, wherein the second period is started when one or more biomarkers in the subject show a reduction or slowing of AD progression.

32. The method according to any one of claims 13 to 31, wherein the second 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 over the lifetime of the subject.

33. The method according to any one of claims 13 to 32, wherein the maintenance dose is administered subcutaneously using an auto-injector (AI).

34. The method according to any one of claims 13 to 17, wherein the anti-Aβ protofibril antibody is administered intravenously every other week at a dose of 10 mg / kg relative to the body weight of the subject.

35. The method according to any one of claims 1 to 34, wherein the anti-Aβ protofibril antibody is contained in the pharmaceutical composition in the form of a pre-filled syringe.

36. The method according to any one of claims 1 to 34, wherein the anti-Aβ protofibril antibody is contained in a pharmaceutical composition delivered via an autoinjector.

37. The method according to any one of claims 1 to 36, wherein the anti-Aβ protofibril antibody comprises a heavy chain complementary 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.

38. The method according to any one of claims 1 to 37, wherein the anti-Aβ protofibril antibody is BAN2401 (lecanemab).

39. The method according to any one of claims 1 to 38, wherein the subject shows a change and / or difference in the measured value of one or more biomarkers related to AD pathology before treatment.

40. The change and / or difference of the measured value is as follows: a. For example, by measuring by amyloid PET, an increase in brain amyloid (e.g., a centiloid value of approximately 20-40, e.g., a centiloid value of approximately 20-32), b. For example, by measuring the increase in brain tau using positron emission tomography (PET), c. Decreased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or increased total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 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-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). The method according to claim 39, selected from the following.

41. The method according to any one of claims 1 to 38, wherein the subject shows a change and / or difference in the measured value of one or more biomarkers related to AD pathology during and / or after treatment.

42. The change and / or difference in the aforementioned measured values ​​is as follows: a. For example, by measuring by amyloid PET, a decrease in brain amyloid (for example, a centiloid value of approximately 20-40, for example, a centiloid value of approximately 20-32), b. For example, by measuring the decrease in brain tau using positron emission tomography (PET), c. Increased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or decreased total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231, p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 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-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or decreased neurofilamentous light chain (NfL). The method according to claim 40, selected from the following.

43. The method according to any one of claims 1 to 42, wherein the subject is amyloid-positive before administration, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), CSF evaluation of total tau, CSF evaluation of p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio), MRI, retinal amyloid accumulation, and / or blood biomarker evaluation (e.g., plasma Aβ1-42 / 1-40 ratio, plasma p-tau 181, plasma p-tau 217, plasma p-tau 231 levels, p-tau 181 / np-tau 181 ratio, and / or p-tau 217 / np-tau 217 ratio).

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

45. The method according to any one of claims 1 to 44, wherein the subject is monitored for the onset of ARIA.

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

47. The aforementioned subjects are between 55 and 64 years old, and also meet the following criteria: (i) A first-degree relative who is under 75 years of age and has been diagnosed with dementia; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Elevated brain amyloid levels based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration. The method according to any one of claims 1 to 45, wherein the method has at least one risk factor selected from the following.

48. The method according to any one of claims 1 to 47, wherein the subject has Alzheimer's disease.

49. The method according to any one of claims 1 to 48, wherein the subject has early Alzheimer's disease.

50. The aforementioned subjects are as follows: a. Diagnosed with mild cognitive impairment due to Alzheimer's disease (moderate likelihood), and / or mild Alzheimer's dementia; b. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute of Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a pre-treatment CDR Global Score of 0.5 and a Memory Box Score of 0.5 or higher; d. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a medical history of subjective memory impairment with slow onset and slow progression within one year prior to treatment (e.g., corroborated by an informant); e. Mild Alzheimer's disease based on the NIA-AA core clinical criteria for almost certain Alzheimer's disease; or f. Mild Alzheimer's disease based on a pre-treatment CDR score of 0.5–1.0 and a Memory Box score of 0.5 or higher. The method according to any one of claims 1 to 49, wherein the person has been diagnosed with any of the following conditions.

51. The subject of the above is the method according to any one of claims 1 to 47, which is suspected of being AD.

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

53. The method according to claim 52, wherein the subject at risk of developing AD has pre-AD.

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

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

56. The method according to any one of claims 52 to 55, wherein the subject has a Mini-Mental State Examination (MMSE) score of 27 or higher, including the pre-administration educational adjustments.

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

58. A method for treating Alzheimer's disease (AD) in a subject who has AD, is suspected of having AD, or is at risk of having AD, comprising administering an anti-Aβ protofibril antibody to the subject, the antibody having three heavy chain complementation 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 complementation 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), wherein the antibody is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the body weight of the subject; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

59. A method for delaying the clinical progression of a subject having AD, suspected AD, or at risk of AD, comprising administering to the subject an anti-Aβ protofibril antibody having three heavy chain complementation 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 complementation 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), wherein the antibody is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the body weight of the subject; For example, after administering the initial dose for 18 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

60. A method for reducing brain amyloid levels in a subject having AD, suspected AD, or at risk of AD, comprising administering an anti-Aβ protofibril antibody to the subject, the antibody having three heavy chain complementation-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 complementation-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), wherein the antibody is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the body weight of the subject; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

61. A method for converting an amyloid-positive subject to an amyloid-negative state, comprising administering an anti-Aβ protofibril antibody to the subject, the antibody having three heavy chain complementation 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 complementation 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), wherein the method is as follows: The steps include administering the antibody intravenously every other week at a starting dose of 10 mg / kg relative to the body weight of the subject; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

62. The method according to any one of claims 58 to 61, 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.

63. The method according to any one of claims 58 to 62, wherein the antibody in the initial dose is administered intravenously for at least 18 months.

64. The method according to any one of claims 58 to 63, wherein the antibody in the initial dose is administered intravenously for at least 24 months.

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

66. The method according to any one of claims 58 to 64, wherein the maintenance dose of the antibody is administered every other week.

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

68. The method according to any one of claims 58 to 66, wherein the maintenance dose of the antibody is administered using AI.

69. A method for treating Alzheimer's disease (AD) in a subject who has AD, is suspected of having AD, or is at risk of developing AD, comprising administering an anti-Aβ protofibril antibody to the subject, the antibody having three heavy chain complementation 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 complementation regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3), wherein the antibody is as follows: The steps include: administering the antibody subcutaneously weekly at a starting dose of 500 mg; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

70. A method for delaying the clinical progression of a subject having AD, suspected AD, or at risk of AD, comprising administering to the subject an anti-Aβ protofibril antibody having three heavy chain complementation 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 complementation 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), wherein the antibody is as follows: The steps include: administering the antibody subcutaneously weekly at a starting dose of 500 mg; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

71. A method for reducing brain amyloid levels in a subject having AD, suspected AD, or at risk of AD, comprising administering an anti-Aβ protofibril antibody to the subject, which has three heavy chain complementation-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 complementation-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), wherein the antibody is as follows: The steps include: administering the antibody subcutaneously weekly at a starting dose of 500 mg; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

72. A method for converting an amyloid-positive subject to an amyloid-negative state, comprising administering an antibody to the subject having three heavy chain complementation 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 complementation 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), wherein the antibody is as follows: The steps include: administering the antibody subcutaneously weekly at a starting dose of 500 mg; For example, after administering the initial dose for 18 or 24 months, the antibody is administered subcutaneously at a maintenance dose of 250 mg weekly or bi-weekly. A method carried out in accordance with a dosage plan that includes the following.

73. The method according to any one of claims 69 to 72, 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.

74. The method according to any one of claims 69 to 73, wherein the antibody in the initial dose is administered subcutaneously for at least 18 months.

75. The method according to any one of claims 69 to 73, wherein the antibody in the initial dose is administered subcutaneously for at least 24 months.

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

77. The method according to any one of claims 69 to 76, wherein the initial dose of the antibody is administered using AI.

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

79. The method according to any one of claims 69 to 77, wherein the maintenance dose of the antibody is administered every other week.

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

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

82. The method according to any one of claims 69 to 81, wherein the anti-Aβ protofibril antibody comprises a heavy chain complementary 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.

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

84. The method according to any one of claims 69 to 83, wherein the subject shows a change in the measured value of one or more biomarkers related to AD pathology before treatment.

85. The change in the measured value is as follows: a. For example, by measuring by amyloid PET, an increase in brain amyloid (e.g., a centiloid value of approximately 20-40, e.g., a centiloid value of approximately 20-32), b. For example, by measuring the increase in brain tau using positron emission tomography (PET), c. Decreased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or increased total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 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-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL). The method according to claim 84, selected from the following.

86. The method according to any one of claims 69 to 84, wherein the subject shows a change and / or difference in the measured value of one or more biomarkers related to AD pathology during and / or after treatment.

87. The change and / or difference of the measured value is as follows: a. For example, by measuring by amyloid PET, a decrease in brain amyloid (for example, a centiloid value of approximately 20-40, for example, a centiloid value of approximately 20-32), b. For example, by measuring the decrease in brain tau using positron emission tomography (PET), c. Increased cerebrospinal fluid levels of Aβ1-42 / 1-40 ratio, and / or decreased total tau, p-tau (e.g., p-tau 181, p-tau 217, and / or p-tau 231, p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 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-tau 181, P-tau 217, and / or P-tau 231), p-tau 181 / np-tau 181 ratio, p-tau 217 / np-tau 217 ratio, glial fibrillary acidic protein (GFAP), and / or decreased neurofilamentous light chain (NfL). The method according to claim 86, selected from the following.

88. The method according to any one of claims 58 to 87, wherein the subject is amyloid-positive before administration, as indicated by, for example, PET evaluation, CSF evaluation of Aβ(1-42), MRI, and retinal amyloid accumulation.

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

90. The method according to any one of claims 58 to 89, wherein the subject is monitored for the onset of ARIA.

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

92. The aforementioned subjects are aged 55 to 64 years, and also meet the following criteria: (i) A first-degree relative who is under 75 years of age and has been diagnosed with dementia; (ii) at least one apolipoprotein E4 variant (APOE4) allele; and (iii) Elevated brain amyloid levels based on PET or cerebrospinal fluid (CSF) examination performed prior to the administration. The method according to any one of claims 58 to 90, having at least one risk factor selected from.

93. The method according to any one of claims 58 to 93, wherein the subject has Alzheimer's disease.

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

95. The aforementioned subjects are as follows: a. Diagnosed with mild cognitive impairment due to Alzheimer's disease (moderate likelihood), and / or mild Alzheimer's dementia; b. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on the National Institute of Aging-Alzheimer's Association (NIA-AA) core clinical criteria; c. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a pre-treatment CDR Global Score of 0.5 and a Memory Box Score of 0.5 or higher; d. Mild cognitive impairment due to Alzheimer's disease (moderate likelihood) based on a history of subjective memory impairment with slow onset and slow progression within one year prior to treatment (e.g., corroborated by an informant); e. Mild Alzheimer's disease based on the NIA-AA core clinical criteria for Alzheimer's disease; or f. Mild Alzheimer's disease based on a pre-treatment CDR score of 0.5–1.0 and a Memory Box score of 0.5 or higher. The method according to any one of claims 58 to 94, wherein the person has been diagnosed with any of the following conditions.

96. The subject of the above is the method according to any one of claims 58 to 92, which is suspected of being AD.

97. The aforementioned subject is at risk of developing AD, according to any one of claims 58 to 92.

98. The method according to claim 97, wherein the subject at risk of developing AD has pre-AD.

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

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

101. The method according to any one of claims 97 to 100, wherein the subject has a Mini-Mental State Examination (MMSE) score of 27 or higher, including the pre-administration educational adjustments.

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

103. A method for treating subjects who have early-stage AD, are suspected of having early-stage AD, or are at risk of developing early-stage AD, and who have received a first anti-Aβ antibody, The procedure involves administering a second anti-Aβ antibody to the subject, which has three heavy chain complementation 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 complementation 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), which is as follows: The second antibody is administered intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the body weight of the subject; or The second antibody is administered subcutaneously every week or every other week at a maintenance dose of 250 mg. A method carried out in accordance with a dosage plan that includes the following.

104. A method for delaying the clinical deterioration of a subject who has received a first anti-Aβ antibody, The procedure involves administering a second anti-Aβ antibody to the subject, which has three heavy chain complementation 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 complementation 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), which is as follows: The second antibody is administered intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the body weight of the subject; or The second antibody is administered subcutaneously every week or every other week at a maintenance dose of 250 mg. A method carried out in accordance with a dosage plan that includes the following.

105. A method for reducing the brain amyloid level of a subject who has received a first anti-Aβ antibody, The procedure involves administering a second anti-Aβ antibody to the subject, which has three heavy chain complementation 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 complementation 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), which is as follows: The second antibody is administered intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the body weight of the subject; or The second antibody is administered subcutaneously every week or every other week at a maintenance dose of 250 mg. A method carried out in accordance with a dosage plan that includes the following.

106. A method for maintaining the amyloid level of a subject who has received a first anti-Aβ antibody, The procedure involves administering a second anti-Aβ antibody to the subject, which has three heavy chain complementation 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 complementation 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), which is as follows: The second antibody is administered intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the body weight of the subject; or The second antibody is administered subcutaneously every week or every other week at a maintenance dose of 250 mg. A method carried out in accordance with a dosage plan that includes the following.

107. A method for treating subjects who have early AD, are suspected of having early AD, or are at risk of developing early AD, Administering the first anti-Aβ antibody to the subject, The procedure involves administering a second anti-Aβ antibody to the subject, which has three heavy chain complementation 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 complementation 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), which is as follows: The second antibody is administered intravenously every other week or monthly at a maintenance dose of 10 mg / kg relative to the body weight of the subject; or The second antibody is administered subcutaneously every week or every other week at a maintenance dose of 250 mg. A method carried out in accordance with a dosage plan that includes the following.

108. The method according to any one of claims 103 to 107, wherein the maintenance dose of the antibody to be administered subcutaneously is administered using a vial-syringe.

109. The method according to any one of claims 103 to 107, wherein the maintenance dose of the antibody administered subcutaneously is administered using AI.

110. The method according to any one of claims 103 to 109, wherein the first anti-Aβ antibody is selected from aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, or soranezumab.

111. The method according to claim 110, wherein the first anti-Aβ antibody is donanemab.

112. A method for treating a subject who has, is suspected of having, or is at risk of having early-stage Alzheimer's disease (AD), comprising administering to the subject an anti-Aβ protofibril antibody having three heavy chain complementation 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 complementation 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), wherein the antibody is as follows: The step of administering the antibody intravenously every other week at a first starting dose of 10 mg / kg relative to the body weight of the subject; The steps include administering the antibody subcutaneously weekly at a second starting dose of 720 or 500 mg, and For example, a step in which, after 18 or 24 months of treatment with the initial dose, the antibody is administered subcutaneously at a dose of 250 mg weekly. A method carried out in accordance with a dosage plan that includes the following.

113. The method according to any one of claims 1 to 112, wherein the subject receives a thrombolytic agent or an antiplatelet agent, rather than an anticoagulant.

114. The method according to claim 113, wherein the subject is receiving an antiplatelet drug.

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

116. The method according to claim 115, wherein the thrombolytic agent is selected from aspirin or a fibrin-solving agent.

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

118. The method according to claim 116, wherein the subject is receiving a fibrin-dissolving agent.

119. The method according to any one of claims 1 to 118, wherein the subject has experienced or is at high risk of experiencing a cerebral hemorrhage event, such as a microhemorrhage or intracerebral hemorrhage, or an ARIA event prior to treatment.

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

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