Treatment methods using p-tau 181 levels

Abstract

Methods are provided for diagnosing, selecting, monitoring, and treating a subject with Alzheimer's disease (AD) or a subject suspected of having AD or another disorder associated with amyloid accumulation in the brain. [Solution] A method for treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising measuring or having measured p-tau 181 levels in a blood sample obtained from the subject, and if the subject's p-tau 181 level is above a threshold, administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8.

Description

[Technical Field]

[0001] This invention was made in part with federal support under Grant Nos. R01AG054029, R01AG061848, and 5U24AG057437-04 awarded by the National Institutes of Health. The federal government has certain rights in this invention.

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Nos. 63 / 306,060, filed February 10, 2022; 63 / 269,394, filed March 15, 2022; and 63 / 364,617, filed May 12, 2022, each entitled "METHODS OF TREATMENT USING P-TAU181 LEVEL," the contents of which are expressly incorporated herein by reference in their entireties. [Background technology]

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

[0004] The disease generally involves a generalized decline in cognitive function, which progresses slowly and ultimately leaves patients bedridden. Patients with AD typically survive only 3 to 10 years after the onset of symptoms, although extreme cases of 2 and 20 years have been reported (Hebert, LE, et al., Alzheimer's disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122). Despite the fact that AD is rarely listed as the cause of death on death certificates, and therefore mortality rates attributable to AD are significantly underestimated, AD is the seventh most common cause of all deaths in the United States and the fifth most common cause of death among Americans over the age of 65 (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94).

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

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

[0007] Despite recent advances in AD treatments, including those targeting Aβ, there remains a need for better monitoring of treatment, including noninvasive assays, to assess treatment efficacy and adjust a subject's treatment regimen. Currently, disease monitoring relies heavily on Aβ positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker assays, which are expensive and may increase a subject's risk of complications. Summary of the Invention [Means for solving the problem]

[0008] Thus, disclosed herein are improved methods for selecting, monitoring, and treating patients with AD. In some embodiments, the patient: a. Measuring the concentration of phosphorylated tau 181 (p-tau 181) in a blood sample obtained from the subject; b. optionally, measuring amyloid beta 1-42 (Aβ42) and amyloid beta 1-40 (Aβ40) concentrations in a blood sample obtained from the subject to determine the ratio of Aβ42 to Aβ40 (Aβ42 / 40 ratio); and c. Selecting for treatment patients who have p-tau181 concentrations above a threshold and, optionally, also have an Aβ42 / 40 ratio below a threshold (e.g., a threshold of about 0.092). are selected for treatment.

[0009] In various embodiments, measuring or having measured a first level of phosphorylated tau 181 (p-tau 181) in a first blood sample obtained from the subject; administering to the subject a first dose of an anti-amyloid beta (Aβ) protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of a first dose of an anti-Aβ protofibril antibody (although it should be understood that additional doses may be administered between these sample collection times); If the second level is the same as or higher than the first level, (i) administering to the subject a second dose of an anti-Aβ protofibril antibody that is higher than the first dose of the anti-Aβ protofibril antibody, or (ii) administering to the subject another AD treatment, and If the second level is lower than the first level, administering to the subject a second dose of the anti-Aβ protofibril antibody that is equal to or lower than the first dose of the anti-Aβ protofibril antibody. The method includes treating Alzheimer's disease (AD) in a subject having or suspected of having AD.

[0010] In some embodiments, the anti-Aβ protofibril antibody is administered in two or more first doses and two or more second doses. In some embodiments, when the second dose is higher than the first dose, the second dose is administered in a higher amount and / or more frequently than the first dose. In some embodiments, when the second dose is lower than the first dose, the second dose is administered in a lower amount and / or less frequently than the first dose.

[0011] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject; administering to the subject a first dose of an anti-Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the first dose of the anti-Aβ protofibril antibody; If the second level is lower than the first level, administering to the subject a second dose of the anti-Aβ protofibril antibody that is equal to or lower than the first dose of the anti-Aβ protofibril antibody. The method includes treating AD in a subject having or suspected of having AD.

[0012] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject; administering to the subject a first dose of an anti-Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the first dose of the anti-Aβ protofibril antibody; If the second level is the same as or higher than the first level, (i) administering a second dose of an anti-Aβ protofibril antibody that is higher than the first dose of the anti-Aβ protofibril antibody, or (ii) administering to the subject another AD treatment. The method includes treating AD in a subject having or suspected of having AD.

[0013] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject; administering to the subject a first dose of an Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the first dose of the anti-Aβ protofibril antibody; If the second level is the same as or higher than the first level, (i) administering a second dose of an anti-Aβ protofibril antibody that is higher than the first dose of the anti-Aβ protofibril antibody, or (ii) administering to the subject another AD treatment; and If the second level is lower than the first level, administering a second dose of an anti-Aβ protofibril antibody that is equal to or lower than the first dose of the anti-Aβ protofibril antibody. Contains; The present method of thereby reducing brain amyloid includes reducing brain amyloid in a subject having or suspected of having AD.

[0014] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject; administering to the subject a first dose of an Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the first dose of the anti-Aβ protofibril antibody; If the second level is lower than the first level, administering a second dose of an anti-Aβ protofibril antibody that is equal to or lower than the first dose of the anti-Aβ protofibril antibody. Contains; The present method of thereby reducing brain amyloid includes reducing brain amyloid in a subject having or suspected of having AD.

[0015] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject; administering to the subject a first dose of an Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the first dose of the anti-Aβ protofibril antibody; If the second level is the same as or higher than the first level, (i) administering a second dose of an anti-Aβ protofibril antibody that is higher than the first dose of the anti-Aβ protofibril antibody, or (ii) administering to the subject another AD treatment. Including, The present method of thereby reducing brain amyloid includes reducing brain amyloid in a subject having or suspected of having AD.

[0016] In some embodiments, administering to a subject a dose of an Aβ protofibril antibody; measuring or having measured post-dose p-tau181 levels in a blood sample obtained from the subject; and Comparing the post-dose level in the blood sample to a blood sample obtained from the subject prior to administration of the dose of Aβ protofibril antibody or to a control level, e.g., a blood sample obtained from a subject not diagnosed with AD, and if the post-dose level is lower than the pre-dose level or the control level, the treatment is considered effective. The method includes monitoring the effectiveness of the treatment in a subject having or suspected of having AD.

[0017] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject prior to administration of the anti-Aβ protofibril antibody; administering to the subject a first dose of an Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the anti-Aβ protofibril antibody; administering to a subject a dose of an Aβ protofibril antibody; comparing the first and second levels, wherein the second level being lower than the first level indicates a reduction in amyloid beta in the subject. The method includes detecting a decrease in brain Aβ levels.

[0018] In some embodiments, measuring or having measured a first p-tau181 level in a first blood sample obtained from the subject; administering to the subject a first dose of an Aβ protofibril antibody; measuring, or having measured, a second p-tau181 level in a second blood sample obtained from the subject after administration of the first dose of the anti-Aβ protofibril antibody; If the second level is the same as or higher than the first level, (i) administering a second dose of an anti-Aβ protofibril antibody that is higher than the first dose of the anti-Aβ protofibril antibody, or (ii) administering to the subject another AD treatment; and If the second level is lower than the first level, administering a second dose of an anti-Aβ protofibril antibody that is equal to or lower than the first dose of the anti-Aβ protofibril antibody. The method includes reducing brain amyloid in a subject in need thereof.

[0019] In some embodiments, a. measuring or having measured p-tau181 levels in a blood sample obtained from the subject; and b. If the subject's p-tau181 level is above a threshold, administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. Including, The method includes treating prodromal Alzheimer's disease (prodromal AD) in a subject, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8, and the subject is cognitively normal. [Brief explanation of the drawings]

[0020] [Figure 1] Least-squares mean (±SE) change from baseline in plasma p-tau181 over time - Overall - PD analysis population. [Figure 2] Correlation between change from baseline in plasma p-tau181 and amyloid PET SUVr at 18 months - Overall - PD analysis population. Only subjects with actual data at 12 and / or 18 months in the PET substudy were included. Adjusted mean difference from placebo = least squares mean of active treatment - least squares mean of placebo, estimated from first-order MMRM analysis. Solid line is estimated linear regression line. [Figure 3] Scatterplot of change from baseline in amyloid PET SUVr and plasma p-tau 181 - CORE. Subjects with both plasma p-tau 181 and amyloid PET SUVR at CORE baseline and CORE 18 months are presented. Only PET data using florbetapir tracer are included. [Figure 4]Correlation between change from baseline in plasma p-tau181 and CDR-SB at 18 months (core) - Overall - PD analysis population. Only subjects with actual plasma p-tau181 data at 12 and / or 18 months were included. Adjusted mean difference from placebo = least squares mean of active treatment - least squares mean of placebo, estimated from first-order MMRM analysis. Solid line is estimated linear regression line. [Figure 5] Correlation between change from baseline in plasma p-tau181 and ADCOMS at 18 months (core) - Overall - PD analysis population. Only subjects with actual data on plasma p-tau181 at 12 and / or 18 months were included. Adjusted mean difference from placebo = least squares mean of active treatment - least squares mean of placebo, estimated from first-order MMRM analysis. Solid line is estimated linear regression line. [Figure 6] Correlation between change from baseline in plasma p-tau181 and ADAS-Cog at 18 months (core) - Overall - PD analysis population. Only subjects with actual data on plasma p-tau181 at 12 and / or 18 months were included. Adjusted mean difference from placebo = least squares mean of active treatment - least squares mean of placebo, estimated from first-order MMRM analysis. Solid line is estimated linear regression line. [Figure 7] Line graph of mean change (±SE) from OLE baseline in plasma p-tau181 by visit (OLE phase) - OLE PD analysis population. Only PET data using florbetapir tracer are included. Plots are presented by core study treatment arm. [Figure 8] Scatterplots of mean change from OLE baseline in plasma p-tau181 and change from OLE baseline in PET SUVr (OLE phase) - OLE PD analysis population. Only PET data using florbetapir tracer are included. Plots are presented by core study treatment arm. [Figure 9A]Data correlation of plasma PET SUVr, Aβ42 / 40 ratio, and p-tau181 in Study 201 core, GAP, and OLE (patients who progressed beyond EAD were excluded from the OLE enrollment population). [Figure 9B] Data correlation of plasma PET SUVr, Aβ42 / 40 ratio, and p-tau181 in Study 201 core, GAP, and OLE (patients who progressed beyond EAD were excluded from the OLE enrollment population). [Figure 10] PK / PD model of p-tau181. [Figure 11] Plasma p-tau181 efficacy model. [Figure 12] Model-predicted plasma p-tau181 after various titration regimens. Solid lines and shaded ranges indicate predicted median values ​​and 95% CI, respectively. [Figure 13] Model-predicted curves of CFB of SUVr versus CFB of plasma p-tau181. The solid line and shaded range indicate the predicted median and 95% CI, respectively. [Figure 14] Scatter plot of change from baseline in amyloid PET SUVR and plasma p-tau 181 at 18 months - Study 201 core (PD analysis population). Values ​​were imputed using the analyte lower limit of quantitation (= 0.764 pg / mL; 4x the assay lower limit of quantitation = 0.191 pg / mL). The solid line is the estimated linear regression line. [Figure 15A] Correlations between amyloid PET SUVR, plasma Aβ42 / 40 ratio, and plasma p-tau181 with CDR-SB in study 201 core, gap period, and 201 OLE phases (patients who progressed beyond EAD were excluded from the OLE enrollment population). Data are presented by treatment assignment in the core study. In the OLE phase, placebo subjects received LEC10-BW. Bold black boxes indicate treatment-naive subjects who received initial exposure to lecanemab. [Figure 15B]Correlations between amyloid PET SUVR, plasma Aβ42 / 40 ratio, and plasma p-tau181 with CDR-SB in study 201 core, gap period, and 201 OLE phases (patients who progressed beyond EAD were excluded from the OLE enrollment population). Data are presented by treatment assignment in the core study. In the OLE phase, placebo subjects received LEC10-BW. Bold black boxes indicate treatment-naive subjects who received initial exposure to lecanemab. [Figure 15C] Correlations between amyloid PET SUVR, plasma Aβ42 / 40 ratio, and plasma p-tau181 with CDR-SB in study 201 core, gap period, and 201 OLE phases (patients who progressed beyond EAD were excluded from the OLE enrollment population). Data are presented by treatment assignment in the core study. In the OLE phase, placebo subjects received LEC10-BW. Bold black boxes indicate treatment-naive subjects who received initial exposure to lecanemab. [Figure 16] Correlation between plasma p-tau181 and ADCOMS in study 201 core, gap, and OLE phases. Data are presented by core study treatment assignment (patients who progressed beyond the EAD were excluded from the OLE enrollment). In the OLE phase, placebo subjects received LEC10-BW. Bold black boxes indicate treatment-naive subjects who received initial exposure to lecanemab. [Figure 17] Correlation between plasma p-tau181 and ADAS-Cog14 in study 201 core, gap, and OLE phases. Data are presented by core study treatment assignment (patients who progressed beyond the EAD were excluded from the OLE enrollment). In the OLE phase, placebo subjects received LEC10-BW. Bold black boxes indicate treatment-naive subjects who received initial exposure to lecanemab. [Figure 18]Model-predicted SUVr, plasma Aβ42 / 40 ratio, and p-tau181 after 18 months of treatment with lecanemab at 10 mg / kg every other week or 10 mg / kg monthly. Solid lines and shaded areas indicate predicted medians and 95% CI, respectively. The black dotted line in the SUVr plot represents SUVr = 1.17 and indicates the amyloid-negative line. For SUVr, a baseline SUVr = 1.38 (median value from Study 201) was assumed. [Figure 19] Model-predicted SUVr and plasma Aβ42 / 40 ratio and p-tau181 after continuous 10 mg / kg biweekly treatment with or without treatment interruption. The black dotted line in the SUVr plot represents SUVr=1.17, indicating the amyloid-negative line. A lower limit of SUVr=1.0 (theoretical lower limit) was assumed for SUVr. DETAILED DESCRIPTION OF THE INVENTION

[0021] The "amyloid hypothesis" proposes that amyloid beta (Aβ) peptides play a central role in the pathogenesis of AD. Specifically, it is hypothesized that an imbalance between Aβ production and Aβ clearance leads to the deposition of Aβ plaques in brain tissue, which in turn leads to the formation of neurofibrillary tangles containing tau protein, thereby causing AD neurodegeneration. Aβ peptides generally exist in a dynamic continuum of conformational states; species tend to progress from monomeric Aβ to soluble Aβ assemblies (which range from low-molecular-weight oligomers to higher-molecular-weight protofibrils) and ultimately to insoluble fibrils (plaques). Targeting these soluble and insoluble Aβ tangles and plaques may offer therapeutic benefits.

[0022] Several immunotherapies have been developed to reduce the amount of insoluble Aβ fibrils deposited in the brain, but a simple correlation between the amount and progression of insoluble amyloid plaques and the clinical course of AD remains unclear. While treatment strategies continue to focus on removing insoluble amyloid plaques, additional therapeutic approaches may include reducing toxic Aβ aggregates, such as protofibrils, which may contribute to the neurodegenerative hallmarks of AD (see, e.g., Dodort, J.-C. and May, P., “Overview on rodent models of Alzheimer's disease,” Curr. Protocols Neurosci. 2005;9:22-1-9:22-6; Englund, H. et al., “Sensitive ELISA detection of amyloid-β protofibrils in biological samples,” J. Neurochem. 2007;103:334-45; and Gotz, J. et al., “Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior, and therapy,” Mol. Psychiat. 2004;9:664-83).

[0023] In various embodiments, anti-Aβ protofibril antibodies such as BAN2401, and other anti-Aβ protofibril antibodies, may be used to treat AD, e.g., by slowing its progression, in subjects who are in the early stages of the disease, where amyloid is deposited in the brain, but where the downstream neurodegenerative cascade believed to be initiated by amyloid deposition is still relatively early in its course (i.e., where limited brain tissue loss has occurred and associated clinical deficits are minimal).

[0024] In various embodiments, disclosed herein are methods of treating, monitoring treatment, and altering Aβ levels in patients receiving an anti-Aβ protofibril antibody, such as BAN2401, comprising assessing p-tau181 levels. In some embodiments, the methods involve measuring p-tau181 levels in a pre-treatment sample (e.g., a plasma sample) from a subject with or suspected of having AD, and / or measuring again in another sample during treatment (although it should be understood that additional doses may be administered between these sample collection times). In some embodiments, a decrease in p-tau181 levels indicates therapeutic efficacy, e.g., a reduction in brain Aβ. In some embodiments, if a decrease in p-tau181 levels is detected after the second sample collection, a subsequent dose of treatment is administered. In some embodiments, treatment may be titrated based on changes in p-tau181 levels; for example, if a decrease in p-tau181 levels is detected, the dosage or frequency of treatment may be reduced, either alone or in combination with additional therapies such as BACE inhibitors or anti-tau antibodies. In some embodiments, if p-tau181 levels do not decrease after a second sample collection, the dosage or frequency of treatment may be increased, or an alternative treatment may be selected. In some embodiments, additional demographic patient characteristics, such as age, and whether the subject is a carrier of the apolipoprotein E ε4 gene allele may be used to predict amyloid positivity (e.g., West et al., Mol Neurodegen (2021) 16-30; Jansen et al., JAMA (2015) 1924-1938; Ossenkoppele et al., JAMA (2015) 1939-1950). In some embodiments, measurements of p-tau181 levels from a subject normalized for age and / or apolipoprotein E ε4 gene allele are used to assess whether a sample (e.g., a plasma sample) from a subject indicates the subject as amyloid positive or negative.For example, in some embodiments, a patient who is a carrier of the apolipoprotein E ε4 gene allele may be considered amyloid positive with a p-tau 181 level lower than the ratio required to indicate amyloid positivity in a non-carrier subject. Similarly, in another example, an older subject may be considered amyloid positive with a p-tau 181 level lower than the ratio required to indicate positivity in a younger subject. In some embodiments, p-tau 181 levels are used in a receiver operating characteristic (ROC) analysis to predict amyloid positivity. In some embodiments, additional demographic patient characteristics, such as age, and whether the subject is a carrier of the apolipoprotein E ε4 gene allele may be used in a ROC analysis along with p-tau 181 levels to predict amyloid positivity. In some embodiments, the prediction that a patient is amyloid positive is used to determine dosage or treatment frequency.

[0025] In some embodiments, the methods include identifying patients suitable for treatment by measuring p-tau levels in a pre-treatment sample, e.g., a blood sample, from a subject having or suspected of having AD, and / or monitoring the effectiveness of treatment by measuring again in another sample during treatment (although it should be understood that additional doses may be administered between these sample collection times). In some embodiments, if a decrease in p-tau181 levels is detected between the first and second sample collections, treatment may be stopped and / or reduced (e.g., reduced frequency and / or dosage). In some embodiments, further measurements of p-tau181 levels may be made in a sample from the subject after treatment is stopped or reduced. In some embodiments, if an increase in p-tau181 levels is detected, treatment is resumed, the dosage increased, and / or the frequency of administration increased. In some embodiments, the dosage or frequency of treatment is increased, e.g., until the dosage and / or frequency of treatment is restored to the dosage and / or frequency used in the previous treatment, before the dose reduction and / or extended frequency of administration was initiated. In some embodiments, the methods involve measuring p-tau181 levels in a sample from the subject during treatment and again after treatment has been discontinued or the dosage or frequency of treatment has been reduced (it should be understood that additional doses may have been administered between these sample collection times). In some embodiments, if an increase in p-tau181 levels is detected, treatment is resumed or the dosage or frequency of treatment is increased compared to the dosage or frequency during the period when the levels decreased. In some embodiments, after multiple measurements are taken during treatment, a decision may be made to discontinue and / or reduce treatment based on a decrease in p-tau181 levels (e.g., based on the p-tau181 levels tending to show a decrease with each subsequent measurement). In some embodiments, multiple measurements may be taken after treatment has been discontinued or reduced, and a decision may be made to resume and / or increase treatment based on an increase in p-tau181 levels (e.g., based on the p-tau181 levels tending to show an increase with each subsequent measurement).In some embodiments, one or more additional measurements of p-tau 181 levels may be made in a sample from the subject after reinstating treatment or following an increased treatment regimen. In some embodiments, if a decrease in p-tau 181 levels is observed in subsequent measurements, treatment is continued. In some embodiments, the measurement of p-tau 181 levels is made in conjunction with the measurement of one or more additional biomarkers (e.g., using a decrease in PET SUVr as an indicator of amyloid plaque reduction during and / or after treatment). In some embodiments, if a decrease in p-tau levels is detected between the first sample collection and a subsequent, e.g., second, third, or fourth sample collection, treatment may be discontinued. In some embodiments, treatment may be discontinued due to poor therapeutic efficacy.

[0026] In some embodiments, any of the methods comprising measuring p-tau181 levels may further comprise measuring one or more additional biomarkers, e.g., measuring amyloid beta 1-40 (Aβ40) and amyloid beta 1-42 (Aβ42) levels to determine the ratio of Aβ42 to Aβ40 (Aβ42 / 40 ratio). In some embodiments, the Aβ42 / 40 ratio is measured in a sample, e.g., a blood sample, from a subject with or suspected of having AD before treatment and again in another sample during treatment (although it should be understood that additional doses may be administered between these sample collection times). In some embodiments, if an increase in the Aβ42 / 40 ratio is detected between the first and second sample collections, treatment may be discontinued and / or reduced (e.g., frequency and / or dosage reduced). In some embodiments, further measurements of the Aβ42 / 40 ratio may be performed in a sample from the subject after treatment has been discontinued or reduced. In some embodiments, if a decrease in the Aβ42 / 40 ratio is detected, treatment is resumed, the dosage increased, and / or the administration frequency increased. In some embodiments, the dosage or treatment frequency is increased until it returns to the dosage and / or frequency used in the previous treatment, e.g., before the dose reduction and / or extended administration frequency was initiated. In some embodiments, the method includes measuring the Aβ42 / 40 ratio in a sample from the subject during treatment and measuring it again after treatment has been discontinued or the dosage or treatment frequency has been reduced (it should be understood that additional doses may have been administered between these sample collection times). In some embodiments, if a decrease in the Aβ42 / 40 ratio is detected, treatment is resumed or the dosage or treatment frequency is increased compared to the dosage or frequency during the period when the ratio decreased. In some embodiments, after multiple measurements during treatment, treatment may be discontinued and / or reduced based on an increase in the Aβ42 / 40 ratio (e.g., based on the Aβ42 / 40 ratio tending to show an increase with each subsequent measurement).In some embodiments, multiple measurements may be taken after treatment is discontinued or reduced, and then treatment may be resumed and / or increased based on a decrease in the Aβ42 / 40 ratio (e.g., based on the Aβ42 / 40 ratio trending downward with each subsequent measurement). In some embodiments, one or more additional measurements of the Aβ42 / 40 ratio may be taken in a sample from the subject after treatment is resumed or after an increased treatment regimen. In some embodiments, if an increase in the Aβ42 / 40 ratio is observed in subsequent measurements, treatment is continued. In some embodiments, the measurement of the Aβ42 / 40 ratio is performed in conjunction with the measurement of one or more additional biomarkers (e.g., using a decrease in PET SUVr as an indicator of amyloid plaque reduction during and / or after treatment). In some embodiments, if a decrease in the Aβ42 / 40 ratio is detected between the first sample collection and a subsequent sample collection, e.g., the second, third, or fourth sample collection, treatment may be discontinued. In some embodiments, treatment may be discontinued due to poor therapeutic efficacy.

[0027] In some embodiments, if an increase in the Aβ42 / 40 ratio is detected in the subject between the first and second sample collections and a decrease in p-tau 181 levels is detected in those samples, treatment is discontinued and / or reduced (e.g., frequency and / or dosage reduced). In some embodiments, if a decrease in the Aβ42 / 40 ratio is detected and an increase in p-tau 181 levels is detected in the subject after discontinuing and / or reducing initial treatment, treatment is resumed and / or increased (e.g., frequency and / or dosage increased).

[0028] In some embodiments, if a decrease in the Aβ42 / 40 ratio is detected between the first sample and a subsequent sample, e.g., the second, third, or fourth, treatment may be discontinued. In some embodiments, treatment may be discontinued due to poor therapeutic efficacy.

[0029] In some embodiments, provided herein are methods of reducing and / or slowing clinical decline in a subject, e.g., a subject with prodromal AD or early Alzheimer's disease, comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody (e.g., BAN2401) to a patient with p-tau181 levels above a threshold. In some embodiments, the anti-Aβ protofibril antibody (e.g., BAN2401) is administered in a therapeutically effective amount such that p-tau181 levels are reduced to below a threshold. In some embodiments, reduced p-tau181 levels result in a slower decline in cognitive function in the patient (e.g., a patient with prodromal AD or early AD) compared to the decline that would occur in the absence of treatment.

[0030] For example, in some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody followed by switching to a maintenance dose. In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg until the patient becomes amyloid-negative (e.g., administering BAN2401 at 10 mg / kg). In some embodiments, treatment involves intravenous administration of an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg until the patient becomes amyloid-negative (e.g., administering BAN2401 at 10 mg / kg), followed by switching to a maintenance dose. In some embodiments, the subject is switched to the maintenance dose without an initial titration step to reach the maintenance dose. In some embodiments, the subject is switched to the maintenance dose via at least one dose adjustment until the maintenance dose is reached; for example, the subject's dosage or administration frequency may be reduced in multiple steps until the final maintenance dose administration regimen is achieved (e.g., stepwise reduction from a subcutaneous therapeutic dose administration regimen of 720 mg weekly to a maintenance dose administration regimen of 360 mg weekly or 720 mg every other week, with intermediate dose titrations at intermediate amounts or durations, such as 540 mg weekly or 720 mg every 10 days). In some embodiments, the subject's maintenance dose is administered at the same amount and / or frequency as the dose during the treatment period. In some embodiments, the subject's maintenance dose is 50% of the dose during the treatment period. An anti-Aβ protofibril antibody, such as BAN2401, may be formulated into a pharmaceutical composition as disclosed in PCT / IB2021 / 000155 (International Publication No. WO 2021 / 186245), which is incorporated herein by reference. In some embodiments, the composition comprises 80 mg / mL to 120 mg / mL BAN2401, 240 mM to 360 mM arginine, 0.03% w / v to 0.08% w / v polysorbate 80, and 30 mM to 70 mM citrate buffer. In some embodiments, the arginine is arginine, arginine hydrochloride, or a combination thereof.In some embodiments, the composition comprises a liquid dosage form comprising 100 mg / mL BAN2401, 50 mmol / L citrate, 350 mmol / L arginine, and 0.05% polysorbate 80. In some embodiments, the composition comprises 80 mg / mL to 240 mg / mL BAN2401, 140 mM to 260 mM arginine hydrochloride, 0.01% w / v to 0.1% w / v polysorbate 80, and 15 mM to 35 mM histidine buffer. In some embodiments, the composition comprises 100 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80. In some embodiments, treatment is continued until a desired improvement in one or more biomarkers or other treatment outcome measures is achieved, e.g., until an increase in the Aβ42 / 40 ratio is observed in a sample (e.g., a plasma sample) compared to the ratio in a sample taken from the subject before treatment, e.g., before 18 months of treatment. In some embodiments, the maintenance dose administration regimen may further include one or more additional therapies in addition to the anti-Aβ protofibril antibody, e.g., it may include administering E2814.

[0031] In some embodiments, treatment involves subcutaneous administration of an anti-Aβ protofibril antibody, e.g., BAN2401, followed by switching to a subcutaneous maintenance dose. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., until the patient becomes amyloid-negative, or for at least 18 months, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation, e.g., weekly subcutaneous injections of 720 mg in sequential injections. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., at a dose of 720 mg, for at least 18 months, or for at least 18 months, e.g., until the patient becomes amyloid-negative, followed by switching to a weekly subcutaneous maintenance dose, e.g., a 360 mg dose. In some embodiments, the treatment involves administering BAN2401 subcutaneously weekly, e.g., at a dose of 720 mg, for at least 18 months, or until the patient is amyloid-negative, followed by switching to a biweekly subcutaneous maintenance dose, e.g., at a dose of 720 mg. In some embodiments, the treatment involves administering BAN2401 subcutaneously weekly, e.g., at a dose of 720 mg, for at least 18 months, or until the patient is amyloid-negative, followed by switching to a monthly subcutaneous maintenance dose, e.g., at a dose of 720 mg. In some embodiments, the subject's maintenance dose is administered in the same amount and / or frequency as the dose administered during the treatment period. In some embodiments, the subject's maintenance dose is 50% of the dose administered during the treatment period. In some embodiments, BAN2401 is formulated as disclosed in PCT / IB2021 / 000155 (International Publication No. 2021 / 186245), which is incorporated herein by reference. In some embodiments, the composition comprises 80 mg / mL to 240 mg / mL BAN2401, 140 mM to 260 mM arginine hydrochloride, 0.01% w / v to 0.1% w / v polysorbate 80, and 15 mM to 35 mM histidine buffer. In some embodiments, the composition comprises a liquid dosage form comprising 200 mg / mL BAN2401, 25 mmol / L histidine, 200 mmol / L arginine, and 0.05% polysorbate 80.In some embodiments, treatment involves subcutaneously administering BAN2401 twice weekly, e.g., at 720 mg per dose, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative. In some embodiments, treatment is continued until a desired improvement in one or more biomarkers or other treatment outcome measures is achieved, e.g., when an increase in the Aβ42 / 40 ratio is observed in a sample (e.g., a plasma sample) compared to the ratio in a sample taken from the subject before treatment, e.g., before 18 months of treatment.

[0032] In some embodiments, a maintenance dose is administered following the treatment period. In some embodiments, the treatment involves intravenous administration of an anti-Aβ protofibril antibody followed by switching to an intravenous maintenance dose. In some embodiments, the treatment involves intravenous administration of an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or, e.g., at 10 mg / kg until the patient becomes amyloid-negative (e.g., after administration of BAN2401 at 10 mg / kg), followed by switching to an intravenous maintenance dose. In some embodiments, the treatment involves intravenous administration of an anti-Aβ protofibril antibody followed by switching to a subcutaneous maintenance dose. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg, for at least 18 months, or until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a subcutaneous maintenance dose, e.g., 720 mg administered weekly or every other week, or 360 mg administered weekly. In some embodiments, the maintenance dose is administered intravenously, e.g., after a period of intravenous treatment as disclosed above. In some embodiments, an intravenous maintenance dose, e.g., 10 mg / kg BAN2401 titration, is administered weekly, every two weeks, monthly, every two months, or every three months (quarter-yearly). In some embodiments, the intravenous maintenance dose is administered every two weeks. In some embodiments, the intravenous maintenance dose is administered every four weeks. In some embodiments, the intravenous maintenance dose is administered every six weeks. In some embodiments, the intravenous maintenance dose is administered every eight weeks (every two months). In some embodiments, the intravenous maintenance dose is administered every three months (every quarter year). In some embodiments, the intravenous maintenance dose is administered every 24 weeks (every six months or six months). In some embodiments, the intravenous maintenance dose is 2.5 mg / kg to 10 mg / kg. In some embodiments, the maintenance dose is administered as a biweekly intravenous dose of 10 mg / kg BAN2401. In some embodiments, the maintenance dose is administered as a 10 mg / kg intravenous dose every four weeks (monthly). In some embodiments, the maintenance dose is administered as a 10 mg / kg intravenous dose every six weeks.In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 8 weeks (every two months). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 12 weeks (every three months or quarter yearly). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 24 weeks (every six months or six months). In some embodiments, the treatment comprises intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week, e.g., for at least 18 months, or until the patient becomes amyloid-negative, followed by switching to a weekly intravenous maintenance dose. In some embodiments, the treatment comprises intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week, e.g., for at least 18 months, or until the patient becomes amyloid-negative, followed by switching to a biweekly intravenous maintenance dose. In some embodiments, the treatment involves administering an anti-Aβ protofibril antibody intravenously every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg until the patient is amyloid-negative, followed by a monthly intravenous maintenance dose. ... In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at, for example, 10 mg / kg every two weeks for at least 18 months, or until, for example, the patient is amyloid negative, followed by switching to an intravenous maintenance dose every quarter year.

[0033] In some embodiments, the maintenance dose is administered subcutaneously (e.g., administered as one or more subcutaneous injections). In some embodiments, the treatment involves intravenous administration of an anti-Aβ protofibril antibody followed by switching to a subcutaneous maintenance dose. In other embodiments, the treatment involves subcutaneous administration of an anti-Aβ protofibril antibody followed by switching to an intravenous maintenance dose. In some embodiments, the treatment involves intravenous administration of an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a subcutaneous maintenance dose. In some embodiments, the treatment involves intravenous administration of an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg until the patient becomes amyloid-negative, followed by switching to a weekly subcutaneous maintenance dose. In some embodiments, the treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to a weekly subcutaneous maintenance dose of 360 mg. In some embodiments, the treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to a weekly subcutaneous maintenance dose of 720 mg. In some embodiments, the treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to a weekly subcutaneous maintenance dose of 720 mg. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at, for example, 10 mg / kg every other week for at least 18 months, or until, for example, the patient is amyloid negative, followed by switching to a monthly subcutaneous maintenance dose of 720 mg.In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at 10 mg / kg every other week for at least 18 months, or until the patient is amyloid negative, for example, followed by switching to a subcutaneous maintenance dose of 720 mg every quarter year.

[0034] In some embodiments, a patient will initiate a treatment comprising intravenously administering an anti-Aβ protofibril antibody, e.g., at a dose of 10 mg / kg, and then switch to a treatment (e.g., maintenance treatment) comprising subcutaneously administering the anti-Aβ protofibril antibody, e.g., at a dose of 720 mg. In some embodiments, a patient will initiate a treatment comprising intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week, and then switch to a treatment comprising subcutaneously administering BAN2401 weekly, e.g., at a dose of 720 mg, for a total treatment period of at least 18 months, or until the patient becomes amyloid-negative. In some embodiments, a patient will initiate a treatment comprising intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week, and then switch to a treatment comprising subcutaneously administering BAN2401 weekly, e.g., at a dose of 720 mg, followed by a switch to a weekly subcutaneous maintenance dose of 360 mg. In some embodiments, a patient will begin treatment with an anti-Aβ protofibril antibody administered intravenously at 10 mg / kg every other week, and then switch to treatment with BAN2401 administered subcutaneously weekly, e.g., at a dose of 720 mg, followed by a monthly subcutaneous maintenance dose of 720 mg.

[0035] In some embodiments, the maintenance dose is administered as a subcutaneous injection of an anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of a subcutaneous formulation of an anti-Aβ protofibril antibody. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of 720 mg, comprising two parallel injections of a subcutaneous formulation of 360 mg (2 x 1.8 mL of 400 mg / 2 mL), e.g., sequential injections. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection of 720 mg, comprising two parallel injections of a subcutaneous formulation of 360 mg (2 x 1.8 mL of 400 mg / 2 mL), e.g., sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a quarter-yearly subcutaneous injection of 720 mg, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a biweekly subcutaneous injection of 720 mg, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the subcutaneous formulation, e.g., a monthly subcutaneous injection of 720 mg, including sequential injections. In some embodiments, the maintenance dose is administered as two parallel 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous injections of the formulation, e.g., 720 mg subcutaneous injections every quarter year, including sequential injections. In some embodiments, the subcutaneous maintenance dose is administered weekly. In some embodiments, the subcutaneous maintenance dose is administered every two weeks. In some embodiments, the subcutaneous maintenance dose is administered every four weeks (monthly). In some embodiments, the subcutaneous maintenance dose is administered every six weeks. In some embodiments, the subcutaneous maintenance dose is administered every eight weeks (every two months). In some embodiments, the subcutaneous maintenance dose is administered every three months (every 12 weeks or quarter year).In some embodiments, the subcutaneous maintenance dose is administered weekly, every 2 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks, every 16 weeks, every 24 weeks, every 48 weeks, monthly, every 2 months, every 3 months, every 4 months, every 6 months, or every 12 months. In some embodiments, the subcutaneous maintenance dose comprises an anti-Aβ protofibril antibody at a dose of 300 mg to 800 mg, 300 mg to 400 mg, 400 mg to 500 mg, 400 mg to 450 mg, 450 mg to 500 mg, 500 mg to 600 mg, 500 mg to 550 mg, 550 mg to 600 mg, 600 mg to 700 mg, 600 mg to 650 mg, 650 mg to 700 mg, 700 mg to 800 mg, 700 mg to 750 mg, or 750 mg to 800 mg. In some embodiments, the maintenance dose is 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, or 390 mg. In some embodiments, the maintenance dose is 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, or 490 mg. In some embodiments, the maintenance dose is 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, or 590 mg. In some embodiments, the maintenance dose is 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, or 690 mg. In some embodiments, the maintenance dose is 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, or 790 mg. In some embodiments, the maintenance dose is 800 mg to 1600 mg, 800 mg to 1000 mg, 800 mg to 900 mg, 900 mg to 1000 mg, 1000 mg to 1200 mg, 1000 mg to 1100 mg, 1100 mg to 1200 mg, 1200 mg to 1400 mg, 1200 mg to 1300 mg, 1300 mg to 1400 mg, 1400 mg to 1600 mg, 1400 mg to 1500 mg, or 1500 mg to 16000 mg.In some embodiments, the maintenance dose is 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, or 980 mg. In some embodiments, the maintenance dose is 1000 mg, 1020 mg, 1040 mg, 1060 mg, 1080 mg, 1100 mg, 1120 mg, 1140 mg, 1160 mg, or 1180 mg. In some embodiments, the maintenance dose is 1200 mg, 1220 mg, 1240 mg, 1260 mg, 1280 mg, 1300 mg, 1320 mg, 1340 mg, 1360 mg, or 1380 mg. In some embodiments, the maintenance dose is 1400 mg, 1420 mg, 1440 mg, 1460 mg, 1480 mg, 1500 mg, 1520 mg, 1540 mg, 1560 mg, or 1580 mg. In some embodiments, the maintenance dose is provided in a single dose, e.g., a single subcutaneous injection of 720 or 1440 mg, or in two or more doses, e.g., two parallel 360 mg doses totaling 720 mg or two 720 mg doses totaling 1440 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 580 mg. In some embodiments, the maintenance dose is 720 mg. In some embodiments, the maintenance dose is 1440 mg. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of 720 mg. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of 360 mg. In some embodiments, the maintenance dose is administered as a 720 mg subcutaneous injection every other week. In some embodiments, the maintenance dose is administered as a 1440 mg subcutaneous injection every other week. In some embodiments, the maintenance dose is provided as a single 1440 mg biweekly administration, including two parallel 720 mg subcutaneous formulations totaling 1440 mg, for example, sequential administration.

[0036] In some embodiments, treatment involves subcutaneous administration of an anti-Aβ protofibril antibody, e.g., BAN2401, followed by switching to an intravenous maintenance dose. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., until the patient is amyloid-negative, or for at least 18 months, e.g., two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL), e.g., 720 mg subcutaneous injections comprising sequential injections. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., at a dose of 720 mg, for at least 18 months, or for at least 18 months, or for at least 18 months, or for at least 18 months, and then switching to a maintenance dose. In some embodiments, treatment involves weekly subcutaneous administration of BAN2401, e.g., at a dose of 720 mg, for at least 18 months, or ...0 mg / kg intravenous maintenance dose. In some embodiments, treatment involves administering BAN2401 subcutaneously weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every other week. In some embodiments, treatment involves administering BAN2401 subcutaneously weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every month. In some embodiments, treatment involves administering BAN2401 subcutaneously weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every 6 weeks. In some embodiments, treatment involves administering BAN2401 subcutaneously weekly, e.g., at a dose of 720 mg, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every 8 weeks.In some embodiments, the treatment involves subcutaneously administering BAN2401 weekly, e.g., at a dose of 720 mg, for at least 18 months, or for example, until the patient is amyloid-negative, followed by switching to an intravenous maintenance dose of 10 mg / kg every quarter year. In some embodiments, the subject's maintenance dose is administered in the same amount and / or frequency as the dose administered during the treatment period. In some embodiments, the subject's maintenance dose is 50% of the dose administered during the treatment period.

[0037] In some embodiments, the maintenance dose is administered intravenously, for example, after an intravenous treatment period as disclosed above. In some embodiments, an intravenous maintenance dose, e.g., a titration of 10 mg / kg BAN2401, is administered weekly, every two weeks, monthly, every two months, or every three months (every quarter year). In some embodiments, the intravenous maintenance dose is administered every two weeks. In some embodiments, the intravenous maintenance dose is administered every four weeks. In some embodiments, the intravenous maintenance dose is administered every six weeks. In some embodiments, the intravenous maintenance dose is administered every eight weeks (every two months). In some embodiments, the intravenous maintenance dose is administered every three months (every quarter year). In some embodiments, the intravenous maintenance dose is administered every 24 weeks (every six months or every six months). In some embodiments, the intravenous maintenance dose is between 2.5 mg / kg and 10 mg / kg. In some embodiments, the maintenance dose is administered as a biweekly intravenous dose of 10 mg / kg BAN2401. In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 4 weeks (monthly). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 6 weeks. In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 8 weeks (every 2 months). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 12 weeks (every 3 months or quarter yearly). In some embodiments, the maintenance dose is administered as an intravenous dose of 10 mg / kg every 24 weeks (every 6 months or 6 months). In some embodiments, the treatment involves intravenously administering an anti-Aβ protofibril antibody at 10 mg / kg every other week, for example, for at least 18 months, or until, for example, the patient becomes amyloid-negative, followed by switching to a weekly intravenous maintenance dose. In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg, for at least 18 months, or until the patient is amyloid-negative, followed by switching to a biweekly intravenous maintenance dose.In some embodiments, the treatment involves administering an anti-Aβ protofibril antibody intravenously every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg until the patient is amyloid-negative, followed by a monthly intravenous maintenance dose. ... In some embodiments, treatment involves administering an anti-Aβ protofibril antibody intravenously at, for example, 10 mg / kg every two weeks for at least 18 months, or until, for example, the patient is amyloid negative, followed by switching to an intravenous maintenance dose every quarter year.

[0038] In some embodiments, the patient is initiated on an intravenous maintenance dose, e.g., titration of 10 mg / kg BAN2401 as disclosed above, followed by a subcutaneous maintenance dose, e.g., 720 mg subcutaneous injections comprising two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the formulation, e.g., sequential injections. In some embodiments, the patient is initiated on a subcutaneous maintenance dose, e.g., 720 mg subcutaneous injections comprising two parallel injections of 360 mg (2 x 1.8 mL of 400 mg / 2 mL) of the formulation, e.g., sequential injections, and then is switched to an intravenous maintenance dose, e.g., 10 mg / kg BAN2401 as disclosed above.

[0039] In some embodiments, the patient is switched back from the maintenance dose to the initial treatment dose if it is determined that the patient is no longer amyloid negative, e.g., as determined by measuring p-tau 181 levels above a threshold in a blood sample taken after switching to the maintenance dose and / or as determined by PET SUVr. In some embodiments, the patient's treatment is discontinued if it is determined that the patient is no longer amyloid negative, e.g., as determined by measuring p-tau 181 levels above a threshold in a blood sample taken after switching to the maintenance dose.

[0040] In some embodiments, the maintenance dose is administered at least every three months (e.g., every quarter year) or every 12 weeks. In some embodiments, after switching to the maintenance dose, p-tau181 levels are measured in a sample (e.g., a plasma sample) from the subject. In some embodiments, the maintenance dose and / or frequency is selected to maintain the p-tau181 levels achieved after completion of initial treatment (e.g., after 18 months of treatment). In some embodiments, the maintenance dose and / or frequency is selected to maintain p-tau181 levels below the p-tau181 levels before initial treatment. In some embodiments, the patient's amyloid levels may be monitored during treatment with the maintenance dose, for example, by blood biomarkers. In some embodiments, during treatment with the maintenance dose, the patient's amyloid levels may be monitored by one or more biomarkers, including, but not limited to: (a) amyloid detected by PET scan, either visually or at a semi-quantitative threshold (SUVr or centiloid); (b) cerebrospinal fluid (CSF) Aβ1-42 and / or Aβ1-42 / 1-40 ratio; and / or (c) blood biomarkers, such as plasma Aβ1-42, total tau (T-tau), and / or phosphorylated tau (P-tau) (e.g., p-tau181). In some embodiments, the patient's biomarkers may be monitored at least once after switching to the maintenance dose. In some embodiments, the patient's biomarkers are assessed at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after switching to the maintenance dose. In some embodiments, if p-tau181 levels remain unchanged, the maintenance dose is continued. In some embodiments, if one or more biomarkers worsen, e.g., if p-tau181 levels increase compared to levels measured in samples at the end of the initial treatment period (e.g., 18 months after initiation of treatment), the subject is returned to the original dose regimen (e.g., 10 mg / kg BAN2401 every other week).In some embodiments, if one or more biomarkers worsen, for example, if p-tau181 levels increase in samples taken at the end of the initial treatment period (e.g., 18 months after initiation of treatment), the subject is administered a higher dose (e.g., a 50% increase in the maintenance dose). In some embodiments, if one or more biomarkers worsen, for example, if p-tau181 levels increase in samples taken at the end of the initial treatment period (e.g., 18 months after initiation of treatment), the subject is administered treatment more frequently (e.g., from biweekly to weekly administration).

[0041] In some embodiments, the subject's maintenance dose is administered in the same amount and / or frequency as the dose administered during the treatment period. In some embodiments, the subject's maintenance dose is 50% of the dose administered during the treatment period. In some embodiments, the maintenance dose is selected based on whether the patient is an ApoE4 carrier (e.g., in conjunction with an assessment of changes in p-tau181 levels), e.g., carriers require a greater reduction in p-tau181 levels to transition from initial treatment to the maintenance dose than non-carriers. In some embodiments, the maintenance dose includes two or more dose settings, where a first dose setting is selected from the maintenance doses exemplified above, and the second and / or subsequent dose settings each include a lower amount and / or frequency than the first or previous dose setting. In some embodiments, switching to the second or subsequent dose setting is determined based on one or more biomarkers exemplified above, where the level of the biomarker is different from (e.g., improved compared to) the level used in switching from the initial dose to the first dose setting in the maintenance dose.

[0042] In some embodiments, after switching to the maintenance dose, the subject's biomarker levels will indicate an increase in amyloid levels in the brain. In some embodiments, after switching to the maintenance dose, the subject's biomarker levels, such as the plasma Aβ42 / 40 ratio, will begin to decrease, indicating an increase in amyloid levels in the brain. In some embodiments, the subject on the maintenance dose will exhibit a decrease in the Aβ42 / 40 ratio. In some embodiments, the subject is prescribed a maintenance dose selected such that the subject will exhibit a decrease in the Aβ42 / 40 ratio, but the Aβ42 / 40 ratio remains above the amyloid positivity threshold, for example, for at least 1 year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0043] In some embodiments, after switching to the maintenance dose, the subject's biomarker levels, e.g., p-tau 181, will begin to increase, indicating increasing amyloid levels in the brain. In some embodiments, the subject on the maintenance dose will exhibit an increase in plasma p-tau 181. In some embodiments, the subject on the maintenance dose will exhibit an increase in p-tau 181, but the p-tau 181 levels remain below the amyloid positivity threshold, for example, for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0044] In some embodiments, treatment of a patient is discontinued if the patient no longer has early stage AD as determined by, for example, cognitive assessment, PET SUVr, and / or plasma biomarkers such as p-tau181 levels (e.g., if p-tau181 levels exceed a threshold and / or if SUVr negativity increases to above 1.17 as measured using florbetapir).

[0045] In some embodiments, treatment is interrupted if favorable biomarker levels are achieved. In some embodiments, treatment is interrupted if favorable biomarker levels are achieved after completion of initial treatment. In some embodiments, treatment is interrupted if favorable biomarker levels are achieved and / or maintained during maintenance dosing (e.g., for a set period of time, such as six months or one year). In some embodiments, treatment is interrupted if low p-tau181 levels are achieved, for example, after completion of initial treatment or during a maintenance dosing regimen. In some embodiments, maintenance dosing is interrupted if p-tau181 levels fall below the p-tau181 levels achieved after completion of initial treatment. In some embodiments, treatment is interrupted if SUVr amyloid negativity levels are 1.17 or lower, as measured using florbetapir, after completion of initial treatment or during a maintenance dosing regimen.

[0046] In some embodiments, if favorable biomarker levels are achieved after completion of a set duration of maintenance treatment (e.g., 6 months or 1 year), the maintenance dose is discontinued. In some embodiments, if low p-tau181 levels are achieved, the maintenance dose is discontinued. In some embodiments, if the SUVr amyloid-negative level is 1.17 or below as measured using florbetapir, the maintenance dose is discontinued.

[0047] In some embodiments, if favorable biomarker levels are not maintained during the course of maintenance treatment (e.g., if p-tau181 levels do not decrease compared to pre-treatment p-tau181 levels and / or if SUVr negativity increases to above 1.17 when measured using florbetapir), the maintenance dose is discontinued. In some embodiments, if favorable biomarker levels are not maintained during the course of maintenance treatment (e.g., if p-tau181 levels do not decrease compared to pre-treatment p-tau181 levels and / or if SUVr negativity increases to above 1.17 when measured using florbetapir), the maintenance dose is discontinued.

[0048] In some embodiments, after treatment is discontinued, the patient's amyloid levels may be monitored for regression, for example, by blood biomarkers. In some embodiments, after treatment is discontinued, the patient's amyloid levels may be monitored for regression by one or more biomarkers, including, but not limited to: (a) amyloid detected by PET scan, either visually or by semi-quantitative threshold (SUVr or centiloid); (b) cerebrospinal fluid (CSF) Aβ1-42 and / or Aβ1-42 / 1-40 ratio; and / or (c) blood biomarkers, such as plasma Aβ1-42, tau, total tau (T-tau), and / or P-tau (e.g., P-tau181). In some embodiments, the patient's biomarkers may be monitored at least once after treatment is discontinued. In some embodiments, the patient's biomarkers are monitored at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, or 24 months after treatment is discontinued. In some embodiments, treatment is resumed when the patient's biomarker levels become less favorable, e.g., when p-tau181 levels increase, e.g., to higher p-tau181 levels than before initial treatment.

[0049] In some embodiments, the maintenance dose is administered at least every three months (e.g., every three months, every two months, monthly, biweekly, or weekly). In some embodiments, the maintenance dose and / or frequency is selected to maintain the PET SUVr level achieved after completion of initial treatment. In some embodiments, the maintenance dose is selected to maintain amyloid-negative or below PET SUVr levels (e.g., a PET SUVr of 1.17 for florbetapir).

[0050] In some embodiments, the subject has been diagnosed with early AD, hi some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely, and / or mild dementia of the Alzheimer's disease type.

[0051] In some embodiments, the treatment method includes measuring p-tau181 levels in a first blood sample obtained from the subject. The terms "p-tau181 level" and "p-tau181 level" are used interchangeably. In some embodiments, the subject is then administered a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. In some embodiments, a second blood sample is obtained after the first sample, and a second p-tau181 level is determined. In some embodiments, the second blood sample is obtained from the subject after treatment has been discontinued or reduced. In some embodiments, the change in p-tau181 level is used to determine a second therapeutically effective dose. In some embodiments, a subject having a second level that is reduced compared to the first level is administered a second therapeutically effective dose comprising an anti-Aβ protofibril antibody in an amount equal to or lower than the first dose for the subject. In some embodiments, subjects with a second level that is higher than the first level are administered a second therapeutically effective dose comprising a higher amount of anti-Aβ protofibril antibody than the first dose. In some embodiments, subjects with a second level that is higher than the first level are administered a different AD treatment. After the first therapeutically effective dose is administered multiple times (e.g., biweekly or monthly for 6-18 months), the patient may be changed to a second therapeutically effective dose or titration regimen after measuring a second p-tau181 level. In some embodiments, the first therapeutically effective dose may be administered for at least 18 months before being switched to a maintenance dose. In some embodiments, the first therapeutically effective dose may be administered until the patient becomes amyloid-negative, after which the patient may be switched to a maintenance dose.In some embodiments, blood biomarkers as measured in serum or plasma (e.g., Aβ1-42 levels, the ratio of two forms of amyloid-β peptide (Aβ1-42 / 1-40 ratio), plasma levels of plasma total tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (P-tau), etc.) are monitored until the patient is amyloid negative (e.g., amyloid or tau positron emission tomography (PET), cerebrospinal fluid Aβ1-42 levels and / or Aβ1-42 / 1-40 ratio, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranin levels, cerebrospinal fluid neurofilament light peptide (NfL) levels, blood biomarkers as measured in serum or plasma (e.g., Aβ1-42 levels, the ratio of two forms of amyloid-β peptide (Aβ1-42 / 1-40 ratio), plasma levels of plasma total tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (P-tau), etc.). After a first therapeutically effective dose is administered, patients may be switched to a maintenance dose (as measured by levels of glial fibrillary acidic protein (GFAP), and / or neurofilament light chain (NfL), including tau phosphorylated at tau 181, 217 (P-tau 217), and 231 (P-tau 231). In some embodiments, patients may be switched to a maintenance dose until they are amyloid-negative, e.g., as measured by an Aβ42 / 40 ratio of 0.092-0.094 or greater (e.g., 0.092 or greater), or have a florbetapir amyloid PET scan of 1.17 or less. The first therapeutically effective dose may be administered until SUVr is negative, followed by a switch to a maintenance dose. In some embodiments, the first therapeutically effective dose may be administered until the patient is amyloid-negative, e.g., as measured by p-tau181 levels below a threshold, or until the patient has a florbetapir amyloid PET SUVr of 1.17 or less, followed by a switch to a maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody biweekly, e.g., at 10 mg / kg intravenously, for at least 18 months, or, e.g., until the patient is amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg).

[0052] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg intravenously until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to an intravenous maintenance dose (e.g., at 10 mg / kg, e.g., every other week or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg intravenously until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a biweekly intravenous maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg intravenously until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a monthly intravenous maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg intravenously until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a monthly intravenous maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg intravenously until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to an intravenous maintenance dose every 8 weeks. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., at 10 mg / kg intravenously until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to an intravenous maintenance dose every 2 months.In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg, for at least 18 months, or until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to an intravenous maintenance dose every quarter year.

[0053] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody subcutaneously weekly, e.g., at 720 mg for at least 18 months, or until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 720 mg), followed by switching to a subcutaneous maintenance dose (e.g., at 720 mg, e.g., weekly, biweekly, or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the maintenance dose is 360 mg weekly.

[0054] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., intravenously at 10 mg / kg until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a weekly subcutaneous maintenance dose (e.g., a 720 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., intravenously at 10 mg / kg for at least 18 months, or e.g., until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a weekly subcutaneous maintenance dose (e.g., a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., intravenously at 10 mg / kg for at least 18 months, or e.g., until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a biweekly subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., intravenously at 10 mg / kg for at least 18 months, or e.g., until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a monthly subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg, for at least 18 months, or until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose) every 6 weeks.In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., for at least 18 months, or e.g., intravenously at 10 mg / kg until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a subcutaneous maintenance dose every 8 weeks (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody every other week, e.g., intravenously at 10 mg / kg for at least 18 months, or e.g., until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a subcutaneous maintenance dose every 2 months (e.g., a 720 mg dose or a 360 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody intravenously every other week, e.g., at 10 mg / kg, for at least 18 months, or until the patient becomes amyloid-negative (e.g., after administering BAN2401 at 10 mg / kg), followed by switching to a subcutaneous maintenance dose (e.g., a 720 mg dose or a 360 mg dose) every quarter year.

[0055] In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody subcutaneously weekly, e.g., for at least 18 months, or, e.g., until the patient becomes amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a switch to a weekly subcutaneous maintenance dose (e.g., the 720 mg dose or the 360 ​​mg dose). In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., for at least 18 months, or, e.g., until the patient becomes amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a switch to a biweekly subcutaneous maintenance dose (e.g., a 720 mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody subcutaneously weekly, e.g., for at least 18 months, or, e.g., until the patient is amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., 720 mg subcutaneous injections comprising sequential injections, followed by a switch to a weekly subcutaneous maintenance dose (e.g., a single 360 ​​mg dose). In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody subcutaneously weekly, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a monthly subcutaneous maintenance dose (e.g., a 720 mg dose).In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., for at least 18 months, or e.g., until the patient is amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a switch to a subcutaneous maintenance dose (e.g., a 720 mg dose) every six weeks. In some embodiments, the first therapeutically effective dose comprises administering an anti-Aβ protofibril antibody subcutaneously weekly, e.g., for at least 18 months, or e.g., until the patient becomes amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a switch to a subcutaneous maintenance dose (e.g., a 720 mg dose) every 8 weeks. In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., for at least 18 months, or, e.g., until the patient becomes amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a switch to a subcutaneous maintenance dose (e.g., a 720 mg dose) every two months. In some embodiments, the first therapeutically effective dose comprises subcutaneous administration of an anti-Aβ protofibril antibody weekly, e.g., for at least 18 months, or e.g., until the patient becomes amyloid-negative, e.g., two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation in a given week, e.g., a 720 mg subcutaneous injection comprising sequential injections, followed by a quarter-yearly subcutaneous maintenance dose (e.g., a 720 mg dose).

[0056] The following are definitions of terms used in this application.

[0057] As used herein, the singular terms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0058] The term "and / or," as used herein, refers to "either or both" of the elements so coordinated, i.e., elements that are present conjunctively in some cases and disjunctively in other cases. Thus, as a non-limiting example, "A and / or B," when used in conjunction with open-ended language such as "comprising," may, in some embodiments, refer to A only (optionally including elements other than B); in other embodiments, it may refer to B only (optionally including elements other than A); in yet other embodiments, it may refer to both A and B (optionally including other elements); and so forth.

[0059] As used herein, "at least one" means one or more of the elements in a list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding any combination of elements in the list of elements. This definition also allows that elements other than those specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether or not related to the specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") may refer, in one embodiment, to at least one, optionally including more than one, A, with no B (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); and so forth.

[0060] As used herein, "about," when used in connection with a dose, amount, or ratio, includes the specified dose, amount, or ratio value or range of doses, amounts, or ratios that one of ordinary skill in the art would recognize as producing a therapeutic effect equivalent to that resulting from the specified dose, amount, or ratio. The term "about" may refer to an acceptable margin of error, as determined by one of ordinary skill in the art for a particular value, depending in part on how the value is measured or determined. The term "about" means within 5% of a given value or range.

[0061] As used herein, "adjusted mean change from baseline" refers to a calculation using statistical analysis of the change in biomarker values ​​over time. In some embodiments, the adjusted mean change from baseline is determined using a linear mixed-effects model (MMRM) to account for at least one additional covariate.

[0062] When a number is recited, whether alone or as part of a numerical range, it should be understood that the number can vary upward and downward from the stated value by up to a variance of ±10% of the stated value.

[0063] When a range of values ​​is recited herein, it is intended to encompass each value and subrange within that range. For example, "2.5 mg / kg to 10 mg / kg" is intended to encompass, for example, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 7.5 mg / kg, 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 2.5 mg / kg to 3 mg / kg, 2.5 mg / kg to 4.5 mg / kg, 3 mg / kg to 4.5 mg / kg, 4.5 mg / kg to 8 mg / kg, 2.5 mg / kg to 9 mg / kg, etc.

[0064] Amyloid beta 1-42 (Aβ42) refers to the amyloid beta monomer from amino acids 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 13). Amyloid beta 1-40 (Aβ1-40) refers to the amyloid beta monomer from amino acids 1 to 42 of the full-length protein (Table 5, SEQ ID NO: 14).

[0065] p-Tau181 is human tau protein phosphorylated at threonine 181.

[0066] Patients with "preclinical AD," "prodromal Alzheimer's disease," or "prodromal AD," as described herein, are cognitively normal individuals with moderate or elevated amyloid levels in the brain, and may be identified by an asymptomatic phase with or without memory complaints, and emerging episodic memory and executive function impairments. Cognitively normal individuals may include those with a CDR of 0 or cognitive test scores within the normal range (e.g., MMSE, International Shopping List Task, Logical Memory). Preclinical AD precedes 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 be indicative of future development of Alzheimer's disease include, but are not limited to, moderate or elevated amyloid or tau amyloid levels in the brain by positron emission tomography (PET) (e.g., on a centiloid scale of about 20-40, e.g., on a scale of about 20-32), cerebrospinal fluid Aβ1-42 levels and / or Aβ1-42 / 1-40 ratio, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranin levels, cerebrospinal fluid neurofilament light peptide (NfL) levels, and blood tau levels as measured in serum or plasma. These may include one or more of the following: fluid biomarkers (e.g., Aβ1-42 levels, the ratio of two forms of amyloid-β peptide (Aβ1-42 / 1-40 ratio, e.g., a ratio of about 0.092 to 0.094, or a ratio below about 0.092), plasma levels of plasma total tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (including tau phosphorylated at 181 (P-tau181), 217 (P-tau217), and 231 (P-tau231)), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL)). For example, subjects treated with the beta-site amyloid precursor protein-cleaving enzyme (BACE) inhibitor elenbecestat (E2609) who had a baseline positron emission tomography (PET) standardized uptake value (SUVr) ratio for amyloid of 1.4 to 1.9 were found to experience the greatest slowing of cognitive decline while on treatment.See Lynch, S.Y. et al., "Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease," Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 did not exhibit sufficient cognitive decline to be detectable, while subjects with SUVr levels above 1.6 appeared to correlate with a plateau effect, where amyloid levels had reached a saturation point and treatment did not result in change in cognitive measures. See Dhadda, S. et al., “Baseline florbetapir amyloid PET standard update value ratio (SUVr) can predict clinical progression in prodromal Alzheimer's disease (pAD).” Poster P4-291, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA.

[0067] "Early AD," "EAD," or "early Alzheimer's disease," as used herein, refers to a continuum of AD severity ranging from mild cognitive impairment due to AD—moderately likely—to mild Alzheimer's disease dementia. Subjects with early AD include subjects with mild Alzheimer's disease dementia, as defined herein, and subjects with moderately likely mild cognitive impairment (MCI) due to AD, as defined herein. In some embodiments, subjects with early AD have an MMSE score of 22-30 and a Clinical Dementia Rating Scale (CDR) global score in the range of 0.5-1.0. Other methods for detecting early AD disease may utilize the tests and assays specified below, including the National Institute on Aging-Alzheimer's Association (NIA-AA) Core Clinical Criteria for probable Alzheimer's disease dementia in McKhann, GM et al., "The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer Dement. 2011;7:263-9. Other methods include the CDR-SB, ADCOMS Total Clinical Score, Mini-Mental State Examination, ADAS-Cog, ADAS MCI-ADL, modified iADRS, Wechsler Memory Scale-IV Logical Memory (Subscale) I (WMS-IV LMI), and Wechsler Memory Scale-IV Logical Memory (Subscale) II (WMS-IV LMII). In some embodiments, the subject with early AD has evidence of elevated amyloid levels or a positive amyloid burden in the brain. In some embodiments, high amyloid levels or positive amyloid burden in the brain are indicated and / or confirmed by PET assessment, hi some embodiments, high amyloid levels or positive amyloid burden in the brain are indicated and / or confirmed by CSF assessment of markers such as Aβ1-42 (e.g., soluble CSF biomarker analysis).In some embodiments, high amyloid levels or positive amyloid burden in the brain are indicated and / or confirmed by measuring p-tau181 levels. In some embodiments, high amyloid levels or positive amyloid burden in the brain are indicated and / or confirmed by MRI. In some embodiments, high amyloid levels or positive amyloid burden in the brain are indicated by retinal amyloid accumulation. In some embodiments, more than one assessment method is used.

[0068] In addition to measuring p-tau181 levels in a sample from a subject, a subject's amyloid levels may alternatively be detected or additionally confirmed by one or more biomarkers, including, but not limited to: (a) amyloid detected by PET scan, either visually or at a semi-quantitative threshold (SUVr or centiloid); (b) cerebrospinal fluid (CSF) Aβ1-42 and / or Aβ1-42 / 1-40 ratio; and / or (c) blood biomarkers (plasma Aβ1-42, tau, and / or total tau (T-tau)). Secondary markers may confirm the primary amyloid determination and include, but are not limited to, markers of neuronal damage, such as neurofilament light peptide (NfL), and markers of neuroinflammation, such as glial fibrillary acidic protein (GFAP).

[0069] "Amyloid" refers to the unbranched, usually extracellular, fibrils found in vivo; in addition, the fibrils bind the dye Congo red, which then exhibit green birefringence when viewed between crossed polarizers. Amyloid-forming proteins have been identified and linked to serious diseases, including amyloid-β peptide (Aβ) associated with Alzheimer's disease (AD), islet amyloid polypeptide (IAPP) associated with type 2 diabetes, and prion protein (PrP) associated with spongiform encephalopathies. As used herein, "amyloid," "cerebral amyloid," and "amyloid-β peptide (Aβ)" are used interchangeably.

[0070] In some embodiments, the subject exhibits "high amyloid" or "intermediate amyloid." As one skilled in the art would recognize, amyloid levels from amyloid PET can be 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). In the centiloid method, the tracer is measured on a scale of 0 CL to 100 CL, where 0 is considered the reference point and corresponds to the mean value of young healthy controls, and 100 CL corresponds to the average amyloid burden found in subjects with mild to moderately severe dementia due to AD (ibid.). As known to one skilled in the art, the centiloid threshold can vary and can be refined, for example, based on new or additional scientific information (see, e.g., http: / / www.gaain.org / centiloid-project). Elevated amyloid levels can be established relative to a baseline threshold for healthy controls, determined according to methods known to those skilled in the art. For example, a centimeter value of 32.5 can be used as a "high amyloid" threshold, with "intermediate amyloid" levels referring to Aβ amyloid PET in the range of 20 to 32.5 CL (e.g., 30 CL). In another example, a centimeter value of 40 can be used as a "high amyloid" threshold, with "intermediate amyloid" levels referring to Aβ amyloid PET in the range of 20 to 40 CL.

[0071] A subject with "mild Alzheimer's disease dementia" or "mild AD dementia," as used herein, is a subject who meets the National Institute on Aging-Alzheimer's Association (NIA-AA) Core Clinical Criteria for probable Alzheimer's disease dementia 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. Also included herein are subjects with a CDR score of 0.5-1.0 and a Memory Box score of 0.5 or greater at screening and baseline, as well as subjects who exhibit a change in the Wechsler Memory Scale-Revised Logical Memory Subscale II (WMS-R LM II) score.

[0072] As used herein, a subject with "moderately probable MCI due to Alzheimer's disease" is one identified as meeting the NIA-AA Core Clinical Criteria for Mild Cognitive Impairment due to Alzheimer's Disease (see McKhann, supra). For example, because the subject is symptomatic but not dementia-affected and has evidence of cerebral amyloid pathology, these subjects are less heterogeneous and more similar to subjects with mild Alzheimer's disease dementia in terms of cognitive and functional decline as measured by the ADCOMS Total Clinical Score, as defined herein. Also included herein are subjects with a CDR score of 0.5 and a Memory Box score of 0.5 or greater at screening and baseline. Also included herein are subjects who report, and whose informants corroborate, a subjective history of slowly progressing, gradually beginning memory decline in the past year prior to screening. Memory decline and / or episodic memory impairment can be assessed in subjects by changes in the Wechsler Memory Scale-Revised Logical Memory Subscale II (WMS-R LM II) score.

[0073] As used herein, "MMSE" refers to the Mini-Mental State Examination, a cognitive function instrument commonly used for screening purposes and often measured longitudinally in AD clinical trials, which has a 30-point scale, with higher scores indicating less impairment and lower scores indicating more impairment, ranging from 0 (mostly impaired) to 30 (no impairment). In some embodiments, seven items measuring orientation to time and place, memorization, recall, attention, language, and drawing may be assessed as part of the MMSE score (Folstein, M.F. et al., "Mini-mental state. A practical method for grading the cognitive state of patients for the clinician." J. Psychiatr. Res. 1975;12:189-98).

[0074] As used herein, "ADAS-Cog" refers to the Alzheimer's Disease Assessment Scale-Cognitive. The ADAS-Cog is a cognitive function measure widely used in Alzheimer's disease testing, and includes structured measures assessing memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational tasks (placing letter paper in an envelope), and constructional tasks (copying geometric patterns) (Rosen, W. Get al., "A new rating scale for Alzheimer's disease." Am. J. Psychiatry 1984;141:1356-64). Ratings of oral language, language comprehension, word-finding difficulties, recall of test instructions, mazes, and digit elimination may also be obtained. In some embodiments, the ADAS-Cog is a measure of cognitive function that is based on the Alzheimer's Disease Assessment Scale-Cognitive subscale. 14The ADAS-Cog14 is a cognitive assessment tool used to assess cognitive impairment. In some embodiments, a modified version may be used herein, which is scored from 0 to 90, with 0 indicating no impairment and 90 indicating the greatest impairment. In some embodiments, the ADAS-Cog14 tasks include memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational tasks (placing letter paper in an envelope), constructional tasks (copying geometric patterns), oral language, language comprehension, word finding difficulties, memory for test instructions, mazes, and digit elimination (Rosen et al, 1984).

[0075] As used herein, "CDR-SB" refers to the Clinical Dementia Scale-Item Total. The CDR is a clinical scale that describes five levels of performance impairment in each of six functional categories, including memory, orientation, judgment and problem-solving, community activities, household and hobbies, and self-care (Berg, L. et al., "Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment." Ann. Neurol. 1988;23:477-84). Impairment ratings obtained in each of the six functional categories are combined to produce a single overall rating, the Dementia CDR score (ranging from 0 to 3). The item total score provides an additional measure of change, with the maximum possible score for each category being 3 points, and the total score being the sum of the category scores, resulting in a possible total score of 0 to 18 points, with higher scores indicating greater functional impairment. This global score can be used as a clinical measure of dementia severity.

[0076] As used herein, "ADCOMS" refers to the Alzheimer's Disease Composite Score, a composite clinical score based on an analysis of four items from the ADAS-Cog (delayed word recall, orientation, word recognition, and word-finding difficulty), two items from the Mini-Mental State Examination (MMSE) (orientation to time and drawing), and all six items from the CDR-SB (personal care, community activities, household and hobbies, memory, orientation, and judgment and problem-solving), as discussed in the present 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).

[0077] In some embodiments, ADCOMS can be calculated using the following formula:

number

[0078] As used herein, "ADCS MCI-ADL" refers to the Alzheimer's Disease Cooperative Study-Mild Cognitive Impairment Activities of Daily Living Scale (ADCS MCI-ADL). The ADCS MCI-ADL is a clinical measure that determines a patient's level of ability in six basic activities of daily living. Further examples are discussed in Kreutzer JS, DeLuca J., Caplan B. (eds) Encyclopedia of Clinical Neuropsychology. Springer, New York, NY.

[0079] As used herein, "modified iADRS" or "iADRS" refers to a comprehensive tool that combines scores from the 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.

[0080] As used herein, "ApoE4-positive" subject and "ApoE4 carrier" refer to a subject harboring the ε4 variant of the apolipoprotein E (APOE) gene. The ε4 variant is one of several major alleles of the apolipoprotein E gene. This gene is generally involved in fat metabolism. Apolipoprotein E ε4 carriers have been found to exhibit significantly increased amyloid deposition rates compared to non-carriers (Drzezga, A. et al., "Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer's disease." Neurology. 2009;72:1487-94). In some embodiments, the subject treated herein is a heterozygote carrier of the apolipoprotein E ε4 gene allele. In some embodiments, the subject is a homozygote carrier of the apolipoprotein E ε4 gene allele. ApoE4 carriers may exhibit a higher therapeutic response than non-ApoE4 carriers when administered a composition containing an anti-Aβ protofibril antibody (i.e., lecanemab). The terms "ApoE4-negative" and "non-ApoE4 carrier" are used interchangeably.

[0081] As used herein, whether an early-stage AD subject is "amyloid positive" or "amyloid negative" may be determined based on whether the subject has a positive amyloid load. In some embodiments, a subject is determined to be amyloid positive or amyloid negative as indicated by longitudinal positron emission tomography (PET) assessment of amyloid imaging agent uptake in the brain. In some embodiments, a subject is "amyloid negative" if the florbetapir amyloid PET SUVr negativity is below 1.17. In some embodiments, a subject is determined to be amyloid positive or amyloid negative by assessment of p-tau181 levels in a sample (e.g., a plasma sample) from the subject, alone or in combination with another method, such as PET measurement of brain amyloid. In some embodiments, a subject is "amyloid negative" if the Aβ42 / 40 ratio of the sample is between 0.092 and 0.094, or approximately above that value, e.g., about 0.092. In some embodiments, a subject is "amyloid-negative" if the Aβ42 / 40 ratio of the sample is greater than 0.092. In some embodiments, a subject is determined to be amyloid-positive or amyloid-negative by CSF assessment of the presence of amyloid pathology using assessment of markers such as p-tau181, alone or in combination with another method, such as PET measurement of brain amyloid. In some embodiments, amyloid-positive and amyloid-negative may be determined using qualitative visual interpretation of PET scans to classify subjects as having "normal" or "abnormal" uptake based on PET image patterns. The reader will be a qualified individual trained to recognize brain PET images with abnormal or normal uptake patterns, or amyloid detection will be performed through semi-quantitative or quantitative methods. In some embodiments, a threshold will be established from biomarkers (e.g., serum or CSF) and / or PET scans to quantitatively determine whether the Aβ brain burden indicates amyloid positivity or negativity in the subject. In some embodiments, the subject is determined to be amyloid positive or amyloid negative by MRI.In some embodiments, a subject is determined to be amyloid positive or amyloid negative by retinal amyloid accumulation, hi some embodiments, a subject is determined to be amyloid positive or amyloid negative by behavioral / cognitive phenotype.

[0082] As one skilled in the art would understand, digital, computerized, and / or traditional (e.g., paper-based) cognitive tests can be used to detect early cognitive changes that may warn of the risk of developing mild cognitive impairment and / or dementia, and thus may be used to identify subjects in need of treatment as disclosed herein. Such tests may, for example, screen for cognitive impairment and potentially identify individuals with MCI. The tests may also use artificial intelligence to analyze cognitive test results and determine whether a case of mild cognitive impairment will progress to Alzheimer's disease within one year. Early diagnosis of a condition, before symptoms begin to appear, may help physicians identify subjects in need of treatment as disclosed herein earlier, potentially delaying the onset or reducing the severity of neurodegenerative diseases.

[0083] As used herein, the term "treatment" refers to any administration or application of a therapeutic agent for a disease or disorder of interest, including inhibiting the disease, slowing the progression of the disease, delaying its progression, halting its onset, halting the progression of the disease (e.g., halting the growth of Aβ fibrils), preventing the onset or development of the disease, alleviating or ameliorating one or more symptoms of the disease or one or more underlying pathologies of the disease, curing the disease, improving one or more clinical metrics, or preventing the recurrence of one or more symptoms of the disease. In some embodiments, treating AD in a subject involves administration, e.g., intravenous infusion, of an anti-amyloid beta (Aβ) protofibril antibody.

[0084] As used herein, the term "infusion" refers to active administration of one or more agents, for example, over an infusion time of about 60 minutes. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibodies described herein are administered systemically to a human subject using an infusion. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibodies are alternatively administered to a human subject, for example, by subcutaneous injection. In some embodiments, the subcutaneous injections are weekly injections. In some embodiments, the subcutaneous injections are biweekly injections. In some embodiments, the anti-amyloid beta (Aβ) protofibril antibodies are administered to a human subject by intravenous infusion.

[0085] In some embodiments, the subject is administered a maintenance dose of treatment. As used herein, the term "maintenance dose" refers to a dosage administered to a subject to maintain a desired therapeutic effect. In some embodiments, the maintenance dose is administered weekly, every two weeks, monthly, every two months, or every three months (quarter-yearly), or every 24 weeks (six months or six months). In some embodiments, the maintenance dose comprises an anti-Aβ protofibril antibody. In some embodiments, the maintenance dose is administered as an intravenous infusion. In some embodiments, the intravenous infusion is administered every two weeks (Q2W). In some embodiments, the intravenous infusion is administered every four weeks (Q4W). In some embodiments, the intravenous infusion is administered every three months (Q3M). In some embodiments, the intravenous infusion is a 10 mg / kg dose of BAN2401. In some embodiments, the intravenous infusion is a 10 mg / kg dose of BAN2401 administered every two weeks. In some embodiments, the maintenance dose is administered subcutaneously, orally, or intranasally. In some embodiments, the maintenance dose is administered subcutaneously.

[0086] In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection. In some embodiments, the maintenance dose is administered as a quarter-yearly subcutaneous injection. In some embodiments, the maintenance dose is administered weekly or less frequently, for example, every two weeks (every other week), every four weeks, every month, every six weeks, every eight weeks (every two months), every three months (every quarter year), or every six months (every six months). In some embodiments, the maintenance dose is provided as a single administration, for example, a single subcutaneous injection of 720 or 1440 mg, or as two or more administrations, for example, two parallel 360 mg administrations totaling 720 mg, or two 720 mg administrations totaling 1440 mg, or four 360 mg administrations totaling 1440 mg. In some embodiments, the maintenance dose is 120 mg. In some embodiments, the maintenance dose is 180 mg. In some embodiments, the maintenance dose is 240 mg. In some embodiments, the maintenance dose is 360 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 480 mg. In some embodiments, the maintenance dose is 540 mg. In some embodiments, the maintenance dose is 440 mg. In some embodiments, the maintenance dose is 580 mg. In some embodiments, the maintenance dose is 600 mg. In some embodiments, the maintenance dose is administered as a single 720 mg dose or two 360 mg doses. In some embodiments, the maintenance dose is 840 mg. In some embodiments, the maintenance dose is 900 mg. In some embodiments, the maintenance dose is 960 mg. In some embodiments, the maintenance dose is 1080 mg. In some embodiments, the maintenance dose is 1200 mg. In some embodiments, the maintenance dose is 1260 mg. In some embodiments, the maintenance dose is 1320 mg. In some embodiments, the maintenance dose is 1440 mg. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection of 720 mg.In some embodiments, the maintenance dose is administered as a weekly 720 mg subcutaneous injection comprising two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation, e.g., sequential injections. In some embodiments, the maintenance dose is administered as a biweekly 720 mg subcutaneous injection. In some embodiments, the maintenance dose is administered as a biweekly 720 mg subcutaneous injection comprising two parallel injections of a 360 mg (2 x 1.8 mL of 400 mg / 2 mL) subcutaneous formulation, e.g., sequential injections. In some embodiments, the maintenance dose is administered as a biweekly 1440 mg subcutaneous injection. In some embodiments, the maintenance dose is provided as a single 1440 mg biweekly administration comprising two parallel, e.g., two sequential 720 mg subcutaneous administrations for a total of 1440 mg, or four sequential 360 mg administrations for a total of 1440 mg.

[0087] In some embodiments, the maintenance dose is administered one or more times, hi some embodiments, the maintenance dose is administered at a lower dose and / or less frequently than during the initial course of treatment.

[0088] In some embodiments, after switching to the maintenance dose, the subject's biomarker level may indicate that the amyloid level in the brain is increasing. In some embodiments, after switching to the maintenance dose, the subject's biomarker level, for example, the plasma Aβ42 / 40 ratio, may begin to decrease, indicating that the amyloid level in the brain is increasing. In some embodiments, the subject on the maintenance dose may show a decrease in the Aβ42 / 40 ratio. In some embodiments, the subject is prescribed a maintenance dose selected so that the subject may exhibit a decrease in the Aβ42 / 40 ratio, but the Aβ42 / 40 ratio may remain above the amyloid positivity threshold, for example, for at least 1 year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0089] In some embodiments, after switching to the maintenance dose, the subject's biomarker levels, e.g., p-tau 181, may begin to increase, indicating increasing amyloid levels in the brain. In some embodiments, the subject on the maintenance dose may exhibit an increase in plasma p-tau 181. In some embodiments, the subject on the maintenance dose may exhibit an increase in p-tau 181, but the p-tau 181 level may remain below the amyloid positivity threshold, for example, for at least one year (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years).

[0090] As used herein, the term "preventing" refers to achieving a beneficial or desired result, including but not limited to a preventative benefit. For preventative benefit, the compositions may be administered to a subject who is at risk of developing Alzheimer's disease even if they have not been clinically diagnosed with Alzheimer's disease, a subject who has one or more preclinical but not clinical symptoms of Alzheimer's disease, or a subject who complains of one or more physiological symptoms of Alzheimer's disease. As used herein, "prevention" may further include a therapeutic benefit, which means the eradication or amelioration of one or more of the underlying condition being treated or of the physiological symptoms associated therewith.

[0091] As used herein, the term "ARIA" refers to amyloid-related imaging abnormalities as assessed using MRI. In some embodiments, ARIA includes amyloid-related imaging abnormalities edema / exudation (ARIA-E). In some embodiments, ARIA includes amyloid-related imaging abnormalities hemorrhage (ARIA-H). In some embodiments, subjects with ARIA experience headache, confusion, and / or seizures, which may be used to identify subjects with ARIA or indicate further evaluation for ARIA. In some embodiments, ARIA is assessed at specified intervals during treatment. In some embodiments, ARIA is assessed when a subject experiences symptoms of ARIA. In some embodiments, the maximum serum concentration (Cmax) of anti-Aβ protofibril antibodies can be used as a predictor of ARIA-E risk. In some embodiments, use of a subcutaneous formulation may result in a reduced risk of ARIA-E (e.g., due to a lower Cmax) compared to IV administration.

[0092] As used herein, the term "clinical decline" refers to a worsening of one or more clinical symptoms of AD. Methods for measuring clinical decline may use the tests and assays specified herein. In some embodiments, clinical decline is determined by a worsening of ADCOMS. In some embodiments, clinical decline is determined by a worsening of MMSE. In some embodiments, clinical decline is determined by a worsening of ADAS-Cog. In some embodiments, clinical decline is determined by a worsening of FAQ. In some embodiments, clinical decline is determined by a worsening of CDR-SB. In some embodiments, clinical decline is determined by a worsening of Wechsler Memory Scale-IV Logical Memory (Subscale) I and / or (Subscale) II. In some embodiments, clinical decline is determined by a worsening of CDR score. In some embodiments, clinical decline refers to a worsening of one or more AD biomarkers or brain measures (e.g., by PET or MRI), such as brain measures of brain atrophy and / or amyloid accumulation.

[0093] As used herein, the term "blood sample" or "blood" refers to a sample of blood, including serum and / or plasma, from a human subject. In some embodiments, blood will be collected from the subject to assess potential AD biomarkers, which may include amyloid fragments and isoforms, tau, and other protein biomarkers (e.g., NFL), for association with AD diagnosis, amyloid or tau burden, or disease modification. In some embodiments, subjects are asked to fast, if possible, prior to collection at weeks 96 and 216. In other embodiments, and / or at other time points, subjects are not required to fast. Precursor AD biomarker levels that may indicate the onset of Alzheimer's disease include, but are not limited to, brain amyloid levels, cerebrospinal fluid Aβ1-42 levels, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranin levels, and cerebrospinal fluid neurofilament light chain (NfL) levels.

[0094] Measurement of p-tau181 levels The disclosures and methods discussed herein rely, in part, on the surprising discovery that treatments involving anti-Aβ protofibril antibodies, such as BAN2401, can lead to decreases in p-tau181 levels, which correlate with reduced cerebral amyloid burden and improved cognitive outcomes in subjects. Changes in levels can therefore, in various embodiments, be used as a minimally invasive measure of treatment efficacy, enabling monitoring and treatment decision-making, such as whether to increase or decrease the amount of antibody administered, increase or decrease the frequency of administration, introduce additional therapeutic agents, and / or discontinue treatment with the anti-Aβ protofibril antibody.

[0095] p-tau181 levels can be measured using immunoassays (e.g., the Quanterix™ Simoa® p-tau assay) and / or mass spectrophotometric (IP / LC-MS / MS)-based techniques. Plasma p-tau181 is elevated in early stages of AD (I-II) as determined by the Braak staging system and continues to increase as the disease progresses to Braak stages V-VI (Janelidze et al., "Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology, and longitudinal progression to Alzheimer's dementia," Nat. Med., 26(3):379-386 (2020)). The biomarker has been demonstrated to be highly correlated with amyloid PET and tau PET, with a moderate increase in MCI compared to controls but a 3.5-fold increase in AD, and also appears to distinguish patients with clinically diagnosed AD from other tauopathies (Thijssen et al., “Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration,” Nat. Med., 26(3):387-397 (2020); Janelidze et al.).

[0096] Measuring p-tau181 levels may be used alone to assess treatment efficacy, or may be used in conjunction with one or more additional criteria, such as PET measurement of Aβ radiotracer uptake update, MRI assessment of Aβ plaques, and / or behavioral measures, as discussed herein. Such assays may also be used to diagnose patients eligible for treatment (e.g., by measuring p-tau181 levels and determining, alone or in conjunction with measuring one or more additional AD pathology markers in the subject, that the subject is suitable for treatment because the levels are higher than those observed in healthy control subjects or control subjects not diagnosed with AD, including EAD). In some embodiments, measuring p-tau181 levels may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine whether a subject is suitable for treatment. In some embodiments, measuring p-tau181 levels may be used in place of another method of measuring brain amyloid levels, such as a PET scan, to determine treatment efficacy and / or to make treatment decisions, such as whether to continue treatment or switch to a maintenance dose. Determining the efficacy of treatment or making treatment decisions may be performed by comparing the level of p-tau181 with a control level, which may be obtained from a healthy subject or a subject not diagnosed with AD, including EAD.

[0097] In some embodiments, the measurement of p-tau181 levels may utilize a relative change from a baseline measurement. In some embodiments, the change in p-tau181 levels may be used to assess treatment efficacy. In some embodiments, a decrease in p-tau181 levels indicates treatment efficacy, e.g., a decrease in brain amyloid levels. In some embodiments, the measurement of p-tau181 levels may utilize a set threshold to determine the change in brain amyloid levels, e.g., to identify and / or select patients suitable for treatment, e.g., with an anti-Aβ protofibril antibody, or to determine whether to continue treatment, or to switch to a maintenance dose, or to conclude that the patient is amyloid-negative. In some embodiments, the threshold may be assessed in conjunction with another measure of brain amyloid burden, such as a PET scan, to assist in determining whether a subject is suitable for treatment or whether to continue treatment. In some embodiments, the p-tau181 level threshold may be used in place of another method of measuring brain amyloid levels, such as a PET scan. In some embodiments, a p-tau 181 level threshold of about 2.2-2.3 pg / mL or 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 about 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 about 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, p-tau 181 levels are measured using the Quanterix™ Simoa® p-tau assay. In some embodiments, the threshold is about 2.3 pg / mL. In some embodiments, the threshold is about 2.2 pg / mL. In some embodiments, an increase in p-tau 181 levels above the threshold may indicate the need to continue treatment or to select an increased titration regimen.In some embodiments, a decrease in p-tau181 levels below a threshold may be used to indicate that treatment may be terminated (e.g., in favor of a maintenance regimen) and / or to determine a decrease in the titration regimen or discontinuation of treatment in other cases. In some embodiments, an increase in p-tau181 levels above a threshold may be used to determine whether to discontinue a maintenance dosing regimen and, for example, return to a previous treatment regimen.

[0098] Anti-Aβ protofibril antibody In some embodiments, any anti-Aβ protofibril antibody can be used in the methods disclosed herein. In some embodiments, the antibody comprises one or more of the sequences listed in Tables 1-4, including, for example, the complete set of six complementarity-determining regions (CDRs) and / or the complete set of variable regions and / or the complete set of heavy and light chain sequences from these tables. In some embodiments, the anti-Aβ protofibril antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO:3 (HCDR3); and three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3). In some embodiments, an anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, an anti-Aβ protofibril antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. As used herein in the context of an antibody sequence or structure, "CDR" refers to a complementarity-determining region (CDR) that provides the primary determinant of antigen binding. Generally, an antigen-binding site has six CDRs: three in the VH (HCDR1, HCDR2, HCDR3) and three in the VL (LCDR1, LCDR2, LCDR3). CDRs may be determined according to the Kabat numbering scheme (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991, hereinafter referred to as the "Kabat report").

[0099] In some embodiments, at least one anti-Aβ protofibril antibody comprises a human constant region. In some embodiments, the human constant region of at least one anti-Aβ protofibril antibody comprises a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allelic variants thereof, as disclosed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region is selected from IgG1 and allelic variants thereof. The amino acid sequence of a human IgG1 constant region is known in the art and is set forth in SEQ ID NO: 11.

[0100] In some embodiments, the human constant region of at least one anti-Aβ antibody comprises a light chain constant region selected from the κ-λ chain constant regions and any allelic variants thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region is selected from κ and allelic variants thereof. The amino acid sequence of a human κ chain constant region is known in the art and is set forth in SEQ ID NO: 12.

[0101] In some embodiments, at least one anti-Aβ protofibril antibody comprises human heavy and light chain variable region frameworks. In some embodiments, at least one anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, at least one anti-Aβ protofibril antibody comprises a human IgG1 heavy chain constant region and a human Igκ light chain constant region. In some embodiments, at least one anti-Aβ protofibril antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 11 and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 12.

[0102] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401, also known as lecanemab. The terms "BAN2401" and "lecanemab" are used interchangeably and refer to a humanized IgG1 monoclonal version of mAb158, a murine monoclonal antibody produced to target protofibrils and disclosed in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO:1 (HCDR1), SEQ ID NO:2 (HCDR2), and SEQ ID NO:3 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:4 (LCDR1), SEQ ID NO:5 (LCDR2), and SEQ ID NO:6 (LCDR3), as described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 comprises (i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO:8. The full-length sequences of the heavy and light chains of BAN2401 are shown in SEQ ID NOs: 9 and 10 and are described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015).

[0103] Other non-limiting examples of antibodies suitable for use as the at least one anti-Aβ protofibril antibody in the present disclosure include aducanumab and those disclosed in WO 2002 / 003911, WO 2005 / 123775, WO 2007 / 108756, WO 2011 / 001366, WO 2011 / 104696, and WO 2016 / 005466.

[0104] In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 80 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 100 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 200 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration of at least 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration ranging from 80 mg / mL to 300 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 85 mg / mL to 275 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 90 mg / mL to 250 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 95 mg / mL to 225 mg / mL. In some embodiments, the isolated anti-Aβ protofibril antibody is present at a concentration ranging from 100 mg / mL to 200 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, or 300 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 100 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 200 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 250 mg / mL. In some embodiments, the isolated antibody or fragment thereof is present at a concentration of 300 mg / mL. In some embodiments, the isolated antibody or fragment thereof is BAN2401.

[0105] As used herein, a "fragment" of an antibody includes a portion of an antibody, such as a portion comprising its antigen-binding 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.

[0106] a therapeutically effective amount of at least one anti-Aβ protofibril antibody In various embodiments, the methods of the present disclosure include administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. As used herein, the term "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition sufficient to produce a desired therapeutic effect. In various embodiments, a therapeutically effective amount is an amount sufficient to reduce p-tau 181 levels when comparing levels in pre- and post-treatment samples, e.g., blood samples. In some embodiments, the therapeutically effective amount is initially 2.5-15 mg / kg, e.g., about 10 mg / kg. In some embodiments, after administering a first therapeutically effective amount for a period of time, e.g., 6-12 months or longer, if a decrease in p-tau 181 levels is observed before and after administering the first therapeutically effective amount, a second therapeutically effective amount is administered at a lower dosage. In some embodiments, the second therapeutically effective amount is accompanied by one or more additional therapies, e.g., a BACE inhibitor and / or an anti-tau antibody therapy. In some embodiments, the at least one additional therapeutic agent comprises one or more of a BACE inhibitor, a gamma-secretase inhibitor, a gamma-secretase modulator, an Aβ peptide production inhibitor other than the at least one anti-Aβ protofibril antibody, an agent that reduces Aβ peptide levels other than the at least one anti-Aβ protofibril antibody, and combinations thereof. In some embodiments, the at least one additional therapeutic agent comprises a BACE inhibitor. In some embodiments, the BACE inhibitor is selected from CNP520, BI-1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat. In some embodiments, the BACE inhibitor is elenbecestat.

[0107] Those skilled in the art will understand that the therapeutically effective amount of at least one anti-Aβ protofibril antibody administered to a subject may depend on several factors, including pharmacodynamic properties, route of administration, frequency of treatment, and the health, age, and weight of the subject to be treated, and will be able to determine the appropriate amount for each subject using the information disclosed herein.

[0108] In some embodiments, a therapeutically effective amount is a dose selected to improve efficacy and / or maintain efficacy and improve at least one of safety and tolerability, hi some embodiments, a therapeutically effective amount is selected to improve efficacy and / or maintain efficacy while reducing at least one side effect.

[0109] In some embodiments, a subject is administered 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg of at least one anti-Aβ protofibril antibody, based on the subject's body weight.

[0110] In some embodiments, a subject is administered 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg of at least one anti-Aβ protofibril antibody, based on the subject's body weight.

[0111] In some embodiments, a subject is administered 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg of at least one anti-Aβ protofibril antibody, based on the subject's body weight.

[0112] In some embodiments, a subject is administered 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg of at least one anti-Aβ protofibril antibody, based on the subject's body weight.

[0113] In some embodiments, a subject is administered at least one anti-Aβ protofibril antibody 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 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg of the subject's body weight. In some embodiments, a subject is administered up to 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[0114] In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 0.5 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 1 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 2 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 2.5 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 3 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 4 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 5 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 6 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 7 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 7.5 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 8 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 9 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 10 mg / kg of the subject's body weight. In some embodiments, the subject is administered at least one anti-Aβ protofibril antibody at 11 mg / kg of the subject's body weight. In some embodiments, the subject is administered 12 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.In some embodiments, the subject is administered 12.5 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 13 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 14 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 15 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is administered 21, 22, 23, 24, or 25 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody.

[0115] In some embodiments, a subject is administered 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 of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[0116] As noted above, in some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. Thus, in some embodiments, a subject is administered 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg of BAN2401, based on the subject's body weight.

[0117] In some embodiments, a subject is administered 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg of BAN2401, based on the subject's body weight.

[0118] In some embodiments, a subject is administered 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg of BAN2401 based on the subject's body weight.

[0119] In some embodiments, a subject is administered 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg of BAN2401, based on the subject's body weight.

[0120] In some embodiments, a subject is administered 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered up to 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg of BAN2401 based on the subject's body weight.

[0121] In some embodiments, a subject is administered 0.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 1 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 2 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 2.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 3 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 4 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 6 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 7 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 7.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 8 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 9 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 10 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 11 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 12 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 12.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 13 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 14 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 15 mg / kg of BAN2401 based on the subject's body weight.In some embodiments, a subject is administered 16, 17, 18, 19, or 20 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 21, 22, 23, 24, or 25 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, a subject is administered 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 of BAN2401 based on the subject's body weight.

[0122] In some embodiments, the subject is administered 2.5 mg / kg to 10 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 5 mg / kg to 10 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 2.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 7.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 10 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, if the initial titration results in a decrease in p-tau181 levels in a sample, e.g., a blood sample, when comparing levels before and after initial treatment, a reduced concentration of BAN2401 is administered.

[0123] In some embodiments, a subject is administered a first dose of an anti-Aβ protofibril antibody without an initial titration step up to a therapeutic dose (e.g., a subject begins treatment at 10 mg / kg with no titration). In some embodiments, a dose of BAN2401 may be used without the need for a preceding titration step. In some embodiments, a subject is switched to a maintenance dose without an initial titration step up to the maintenance dose. In certain instances, providing a therapeutic dose without a titration step may provide additional therapeutic benefit to the patient, for example, may accelerate the shift of plasma biomarkers toward amyloid negativity, or may facilitate earlier identification of patients who do not experience therapeutic changes in plasma biomarkers in response to an anti-Aβ protofibril antibody (non-responders) and would benefit from another treatment.

[0124] Dose-finding regimen for at least one anti-Aβ protofibril antibody In various embodiments, the methods of the present disclosure include administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody on a schedule that may be fixed and / or adjusted over time. Those skilled in the art will understand that any of the therapeutically effective amounts of at least one anti-Aβ protofibril antibody disclosed above can be administered one or more times according to one or more titration regimens. Depending on several factors, including pharmacodynamic properties, route of administration, dosage, and the health, age, and weight of the subject to be treated, and using the information disclosed herein, those skilled in the art will be able to determine the appropriate titration regimen or regimens for each subject.

[0125] In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered to a subject once every 2 to 4 weeks, e.g., 2.5 to 15 mg / kg, e.g., 10 mg / kg, of the subject's body weight. In some embodiments, the composition is administered to a subject once monthly. In various embodiments, the composition is administered, e.g., biweekly or monthly, to reduce p-tau 181 levels when comparing levels in pre-treatment and post-treatment samples, e.g., blood samples. In some embodiments, if a reduction in p-tau 181 levels is observed after administering a first composition, e.g., biweekly or monthly, for a period of time, e.g., 6 to 12 months or more, a reduced frequency is used, e.g., every 3, 4, 5, 6, 7, or 8 weeks, or every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more. In some embodiments, the reduced frequency is accompanied by one or more additional therapies, e.g., BACE inhibitor and / or anti-tau antibody therapy.

[0126] In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered daily, every other day, every three days, once every week, once every two weeks (“biweekly” or “bw”), once every three weeks, once every four weeks (“every four weeks”), once every month (“mo”), once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every eleven weeks, once every twelve weeks, once every three months (quarters of a year), or once every four months (quarters of a year). In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered daily, every other day, every three days, every week, every two weeks ("biweekly"), every four weeks ("four-week interval"), or every month. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks or once every four weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks.

[0127] In some embodiments, the initial treatment is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or more months. In some embodiments, p-tau181 levels are measured in a sample, e.g., a blood sample, from the subject before and after the initial treatment.

[0128] In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once weekly. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every three weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every month.

[0129] In some embodiments, the composition comprising a therapeutically effective amount of BAN2401 is administered once weekly. In some embodiments, the composition comprising a therapeutically effective amount of BAN2401 is administered once every two weeks. In some embodiments, the composition comprising a therapeutically effective amount of BAN2401 is administered once every three weeks. In some embodiments, the composition comprising a therapeutically effective amount of BAN2401 is administered once every four weeks. In some embodiments, the composition comprising a therapeutically effective amount of BAN2401 is administered once monthly.

[0130] In some embodiments, a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to a subject once every week. In some embodiments, a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to a subject once every two weeks. In some embodiments, a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to a subject once every three weeks. In some embodiments, a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to a subject once every four weeks. In some embodiments, a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to the subject once a month.

[0131] In some embodiments, a subject is administered a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of BAN2401 based on the subject's body weight once weekly. In some embodiments, a subject is administered a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of BAN2401 based on the subject's body weight once every two weeks. In some embodiments, a subject is administered a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of BAN2401 based on the subject's body weight once every three weeks. In some embodiments, a subject is administered a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of BAN2401 based on the subject's body weight once every four weeks. In some embodiments, a composition comprising 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of BAN2401 based on the subject's body weight is administered to the subject once a month.

[0132] In some embodiments, a composition comprising 10 mg / kg of BAN2401 based on the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition comprising 10 mg / kg of BAN2401 based on the subject's body weight is administered to the subject once monthly. In some embodiments, if initial titration (e.g., every two or four weeks for 6-12 months or more) results in a decrease in p-tau181 levels when comparing pre- and post-initial treatment levels in a sample, e.g., a blood sample, then a reduced dosing frequency and / or reduced concentration of BAN2401 is administered.

[0133] Compositions Comprising at Least One Anti-Aβ Protofibril Antibody In some embodiments, at least one anti-Aβ protofibril antibody is included in a composition. In some embodiments, the composition consists of at least one anti-Aβ protofibril antibody. In some embodiments, the antibody is present at a concentration of 50-250 mg / mL, e.g., 100-200 mg / mL. In some embodiments, the composition comprises at least one anti-Aβ protofibril antibody and further comprises at least one additional active and / or inactive ingredient. In some embodiments, the at least one additional ingredient may comprise one or more physiologically acceptable excipients suitable for human and / or veterinary use.

[0134] The compositions of the present disclosure may be in the form of tablets, pills, capsules, solutions, and / or any other suitable form deemed appropriate by those skilled in the art. The route of administration of the compositions of the present disclosure may be any suitable route, including intravenous, subcutaneous, oral, and nasal. In some embodiments, the compositions are formulated as sterile, nonpyrogenic liquids for intravenous administration. In some embodiments, the compositions are saline solutions.

[0135] In some embodiments, at least one additional component in the composition comprises one or more buffers. In some embodiments, at least one additional component comprises one or more emulsifiers. In some embodiments, at least one additional component comprises sodium citrate, sodium chloride, histidine, arginine, arginine hydrochloride, and / or polysorbate 80. In some embodiments, sodium citrate may be present at a concentration ranging from 1 mM to 150 mM. In some embodiments, sodium citrate may be present at a concentration of 25 mM. In some embodiments, sodium citrate may be present at a concentration of 50 mM. In some embodiments, sodium chloride may be present at a concentration ranging from 25 mM to 250 mM. In some embodiments, arginine may be present at a concentration ranging from 240 mM to 360 mM. In some embodiments, arginine hydrochloride may be present at a concentration ranging from 100 mM to 250 mM. In some embodiments, histidine may be present at a concentration ranging from 10 mM to 50 mM. In some embodiments, sodium citrate may be present at a concentration of 125 mM. In some embodiments, polysorbate 80 may be present at a concentration ranging from 0.001% (w / v) to 2% (w / v). In some embodiments, polysorbate 80 may be present at a concentration of 0.02% (w / v). In some embodiments, polysorbate 80 may be present at a concentration of 0.05% (w / v).

[0136] In some embodiments, the composition is a liquid dosage form comprising at least one anti-Aβ protofibril antibody, such as BAN2401, and further comprising, for example, sodium citrate, sodium chloride, and polysorbate 80. In some embodiments, the composition is a liquid dosage form comprising 50 mmol / L citrate, 350 mmol / L arginine, and 0.05% polysorbate 80.

[0137] In some embodiments, the composition is in a liquid dosage form comprising at least one anti-Aβ protofibril antibody, such as BAN2401, and further comprising, for example, arginine hydrochloride, histidine, and polysorbate 80. In some embodiments, the composition is in a liquid dosage form comprising 25 mmol / L histidine, 200 mmol / L arginine, 0.05% polysorbate 80. PCT / IB2021 / 000155 (WO 2021 / 186245) is incorporated herein by reference for suitable intravenous and subcutaneous formulations.

[0138] Concomitant administration of at least one anti-Aβ protofibril antibody and at least one Alzheimer's disease medication other than BAN2401 In some embodiments, provided herein are methods of treating a subject, e.g., a subject with prodromal AD or early Alzheimer's disease, comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody, such as BAN2401, in combination with a therapeutically effective amount of at least one Alzheimer's disease medication other than BAN2401. In some embodiments, provided herein are methods of reducing and / or slowing clinical decline in a subject, e.g., a subject with prodromal AD or early Alzheimer's disease, comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody, such as BAN2401, in combination with a therapeutically effective amount of at least one Alzheimer's disease medication other than BAN2401. The at least one additional therapy may include an additional anti-Aβ antibody, such as aducanumab. In some embodiments, the at least one additional therapy may include a BACE inhibitor and / or an anti-tau antibody. In some embodiments, the additional therapy is given in place of the anti-Aβ protofibril antibody, such as BAN2401, if initial treatment with the first antibody does not lead to a decrease in p-tau 181 levels, or the additional therapy is given in combination with an increased dosage or frequency of administration of the first antibody. In some embodiments, the additional therapy is given in combination with a reduced dosage or frequency of administration of the anti-Aβ protofibril antibody, such as BAN2401, if initial treatment with the first antibody leads to a decrease in p-tau 181 levels.

[0139] In some embodiments, provided herein are methods of treating a subject with prodromal AD or a patient symptomatic for Alzheimer's disease (e.g., early Alzheimer's disease), comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody, such as BAN2401, in combination with a therapeutically effective amount of an anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau, e.g., the anti-tau antibody or antigen-binding fragment comprises E2814 or an antigen-binding fragment thereof. E2814 is disclosed in U.S. Patent Application Publication No. 2019 / 0112364 A1 as clone 7G6-HCzu25 / LCzu18, the sequence of which is incorporated herein by reference. In some embodiments, provided herein are methods of reducing and / or slowing clinical decline in a subject, e.g., a subject with prodromal AD or a patient symptomatic for Alzheimer's disease (e.g., early Alzheimer's disease), comprising administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody, such as BAN2401, in combination with a therapeutically effective amount of an anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau, e.g., the anti-tau antibody or antigen-binding fragment comprises E2814 or an antigen-binding fragment thereof. E2814 is disclosed in U.S. Patent Application Publication No. 2019 / 0112364 A1 as clone 7G6-HCzu25 / LCzu18, the sequence of which is incorporated herein by reference. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO: 15 (HCDR1), SEQ ID NO: 16 (HCDR2), SEQ ID NO: 17 (HCDR3), SEQ ID NO: 18 (LCDR1), SEQ ID NO: 19 (LCDR2), and SEQ ID NO: 20 (LCDR3). See, for example, Table 11. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) from the heavy chain variable region of SEQ ID NO: 21 and the light chain variable region of SEQ ID NO: 22.In some embodiments, an anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau comprises a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22. See, e.g., Table 12. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 23. In some embodiments, the heavy chain constant region comprises SEQ ID NO: 24. See, e.g., Table 13.

[0140] In some embodiments, a patient symptomatic for Alzheimer's disease is administered an anti-Aβ protofibril antibody (e.g., BAN2401) for at least 24 weeks, and then an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau (e.g., E2814) is administered in combination with the isolated anti-Aβ protofibril antibody. In some embodiments, a patient symptomatic for Alzheimer's disease is administered an anti-Aβ protofibril antibody, for example, for 24 weeks or until the patient's p-tau181 levels drop below a certain threshold, and then an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered in combination with the isolated anti-Aβ protofibril antibody. In some embodiments, a patient symptomatic for Alzheimer's disease is administered an anti-Aβ protofibril antibody for 24 weeks or until the patient becomes amyloid-negative, and then an isolated anti-tau antibody, or antigen-binding fragment thereof, capable of binding to human tau is administered in combination with the isolated anti-Aβ protofibril antibody.

[0141] In some embodiments, the patient is asymptomatic for Alzheimer's disease (pre-AD) and is first administered an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau (e.g., E2814) for, e.g., 52 weeks, followed by administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau in combination with an isolated anti-Aβ protofibril antibody (e.g., BAN2401). In some embodiments, the patient is asymptomatic for Alzheimer's disease and is administered an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau for 52 weeks, or until the patient's p-tau181 levels fall below a certain threshold, and then is administered an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau in combination with an isolated anti-Aβ protofibril antibody. In some embodiments, a patient who is asymptomatic with respect to Alzheimer's disease is administered an isolated anti-tau antibody, or antigen-binding fragment thereof, capable of binding to human tau for 52 weeks or until the patient becomes amyloid-negative, and then the isolated anti-tau antibody, or antigen-binding fragment thereof, capable of binding to human tau is administered in combination with an isolated anti-Aβ protofibril antibody.

[0142] In some embodiments, the at least one Alzheimer's disease medication is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's disease medication is a combination of donepezil and memantine. In some embodiments, the at least one additional therapeutic agent comprises one or more of a BACE inhibitor, a gamma-secretase inhibitor, a gamma-secretase modulator, an Aβ peptide production inhibitor other than the at least one anti-Aβ protofibril antibody, an agent that reduces Aβ peptide levels other than the at least one anti-Aβ protofibril antibody, and combinations thereof. In some embodiments, the at least one additional therapeutic agent is a BACE inhibitor. In some embodiments, the BACE inhibitor is selected from CNP520, BI-1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat. In some embodiments, the BACE inhibitor is elenbecestat. In some embodiments, the BACE inhibitor is selected from CNP520, BI-1181181, LY2886721, LY3202626, PF-06751979, RG7129, atabecestat, elenbecestat, lanabecestat, and verubecestat.

[0143] In some embodiments, donepezil may be administered at its approved dose. In some embodiments, galantamine may be administered at its approved dose. In some embodiments, memantine may be administered at its approved dose. In some embodiments, rivastigmine may be administered at its approved dose.

[0144] In some embodiments, elenbecestat may be administered at a dose ranging from 5 mg / day to 100 mg / day, from 10 mg / day to 75 mg / day, from 5 mg / day to 50 mg / day, or from 15 mg / day to 50 mg / day. In some embodiments, elenbecestat may be administered at a dose ranging from about 5 mg / day to about 100 mg / day, from about 10 mg / day to about 75 mg / day, from about 5 mg / day to about 50 mg / day, or from about 15 mg / day to about 50 mg / day. In some embodiments, elenbecestat may be administered at a dosage of 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, or 50 mg / day. In some embodiments, elenbecestat may be administered at a dose of 5 mg / day. In some embodiments, elenbecestat may be administered at a dose of 15 mg / day. In some embodiments, elenbecestat may be administered at a dose of 50 mg / day.

[0145] In some embodiments, elenbecestat may be administered at a dose ranging from 5 mg / day to 100 mg / day, from 10 mg / day to 75 mg / day, from 5 mg / day to 50 mg / day, or from 15 mg / day to 50 mg / day. In some embodiments, elenbecestat may be administered at a dose ranging from about 5 mg / day to about 100 mg / day, from about 10 mg / day to about 75 mg / day, from about 5 mg / day to about 50 mg / day, or from about 15 mg / day to about 50 mg / day. In some embodiments, elenbecestat may be administered at a dosage of 5 mg / day, 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, or 50 mg / day. In some embodiments, elenbecestat may be administered at a dose of 5 mg / day. In some embodiments, elenbecestat may be administered at a dose of 15 mg / day. In some embodiments, elenbecestat may be administered at a dose of 50 mg / day.

[0146] Treatment effect In various embodiments, provided herein are methods for reducing clinical decline in a subject with early-stage Alzheimer's disease, comprising administering to the subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein. In some embodiments, the subject with early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderate likelihood—and / or mild Alzheimer's disease dementia. In some embodiments, the subject with early-stage Alzheimer's disease is ApoE4 positive.

[0147] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, dosing regimens therefor, and compositions comprising the same disclosed herein may be used in methods for reducing clinical decline in subjects with early Alzheimer's disease. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, at 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight is administered to the subject once weekly, once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every 4 weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every eight weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every eight ... It is administered once every month (quarter year), once every 14 weeks, once every 16 weeks, once every 4 months, once every 18 weeks, once every 20 weeks, once every 5 months, once every 22 weeks, once every 24 weeks, once every 6 months (every six months), once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, once every 12 months (yearly), once every 13 months, once every 14 months, once every 15 months, once every 16 months, once every 17 months, or once every 18 months. In some embodiments, clinical decline is reduced 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, or at least 46% compared to placebo as determined by ADCOMS.In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0148] In some embodiments, clinical decline is reduced by 20% to 35% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by 20% to 30% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by 27% to 35% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 20% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 35% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 20% as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 30% as determined by ADCOMS. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0149] In some embodiments, clinical decline is reduced by at least 45% compared to placebo as determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 35% compared to placebo as determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 30% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 46% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0150] In some embodiments, the clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27% compared to placebo as determined by ADCOMS. , at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or at least 52%, wherein the subject has been diagnosed with Mild Cognitive Impairment due to Alzheimer's Disease - Moderately Likely. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0151] In some embodiments, clinical decline is reduced by 28% to 33% compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 20%, such as 25% or at least 28%, compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 25%, such as at least 30% or at least 33%, compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 25%, such as at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52%, relative to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately likely. In some embodiments, clinical decline is reduced by at least 52% relative to placebo, as determined by ADCOMS, where the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately likely. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0152] In some embodiments, clinical decline in a subject diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo as determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in a subject diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 25% compared to placebo as determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in a subject diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in subjects diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 52% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0153] In some embodiments, clinical decline is reduced 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, or at least 33% relative to placebo as determined by ADCOMS, wherein the subject has been diagnosed with Mild Cognitive Impairment due to Alzheimer's Disease - Moderately Probable. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0154] In some embodiments, clinical decline is reduced by 28% to 38% compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 20%, such as 25%, at least 28%, or at least 33%, compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 25%, such as at least 30% or at least 33%, compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 33% compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0155] In some embodiments, a subject diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI) with moderate likelihood has a reduction in clinical decline of at least 33% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody, administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0156] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39% less than placebo as determined by ADCOMS. at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, or at least 78%, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0157] In some embodiments, clinical decline is reduced by 20% to 80% compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 35% to 78% compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 35% compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 50%, such as at least 52% or at least 53%, compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 70%, such as at least 75% or at least 78% compared to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0158] In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70% compared to placebo as determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 50% compared to placebo as determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 30% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 52% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0159] In some embodiments, clinical decline is reduced 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% relative to placebo as determined by ADCOMS, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0160] In some embodiments, clinical decline is reduced by 28% to 38% compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 20%, such as 25%, at least 28%, or at least 35%, compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 25%, such as at least 30% or at least 35%, compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 35% compared to placebo, as determined by ADCOMS, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0161] In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 35% compared to placebo as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0162] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39% less than placebo as determined by ADAS-cog. at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0163] In some embodiments, clinical decline is reduced by 40% to 150% compared to placebo as determined by ADAS-cog. In some embodiments, clinical decline is reduced by 45% to 145% compared to placebo as determined by ADAS-cog. In some embodiments, clinical decline is reduced by 45% to 55% compared to placebo as determined by ADAS-cog. In some embodiments, clinical decline is reduced by at least 30% compared to placebo as determined by ADAS-cog. In some embodiments, clinical decline is reduced by at least 35% compared to placebo as determined by ADAS-cog. In some embodiments, clinical decline is reduced by at least 40% as determined by ADAS-cog. In some embodiments, clinical decline is reduced by at least 45% as determined by ADAS-cog. In some embodiments, clinical decline is reduced by at least 47% as determined by ADAS-cog. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0164] In some embodiments, clinical decline is reduced by at least 100%, such as at least 120% or at least 140%, compared to placebo, as determined by ADAS-cog after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-cog after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 40%, such as at least 45%, compared to placebo, as determined by ADAS-cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 47% compared to placebo, as determined by ADAS-cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0165] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least %, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 56%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, or at least 58% reduction in clinical decline, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0166] In some embodiments, clinical decline is reduced by 50% to 70% compared to placebo as determined by ADAS-cog, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI)—moderately severe. In some embodiments, clinical decline is reduced by at least 50%, such as 52%, at least 55%, or at least 58%, compared to placebo as determined by ADAS-cog, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI)—moderately severe. In some embodiments, clinical decline is reduced by at least 58% compared to placebo as determined by ADAS-cog, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI)—moderately severe. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0167] In some embodiments, a subject diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI) - moderately severe - experiences at least a 58% reduction in clinical decline compared to placebo after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADAS-cog. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody, administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0168] In some embodiments, clinical decline is reduced 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, or at least 41% relative to placebo as determined by ADAS-cog, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0169] In some embodiments, clinical decline is reduced by 30% to 50% compared to placebo, as determined by ADAS-cog, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 35%, such as 38%, at least 40%, or at least 41%, compared to placebo, as determined by ADAS-cog, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 41% compared to placebo, as determined by ADAS-cog, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0170] In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 41% compared to placebo as determined by ADAS-cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0171] In some embodiments, clinical decline is reduced 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, or at least 40% compared to placebo as determined by CDR-SB. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0172] In some embodiments, clinical decline is reduced by 20% to 60% compared to placebo as determined by CDR-SB. In some embodiments, clinical decline is reduced by 25% to 60% compared to placebo as determined by CDR-SB. In some embodiments, clinical decline is reduced by 25% to 50% compared to placebo as determined by CDR-SB. In some embodiments, clinical decline is reduced by at least 20% compared to placebo as determined by CDR-SB. In some embodiments, clinical decline is reduced by at least 30% compared to placebo as determined by CDR-SB. In some embodiments, clinical decline is reduced by at least 25% as determined by CDR-SB, such as at least 26% or at least 28%. In some embodiments, clinical decline is reduced by at least 30% as determined by CDR-SB, such as at least 35% or at least 38%. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0173] In some embodiments, clinical decline is reduced by at least 30%, such as at least 35% or at least 40%, compared to placebo, as determined by CDR-SB after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 30%, such as at least 35% or at least 45%, compared to placebo, as determined by CDR-SB after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced by at least 20%, such as at least 25%, compared to placebo, as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0174] In some embodiments, clinical decline is reduced 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%, at least 13%, or at least 14% compared to placebo, as determined by CDR-SB, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0175] In some embodiments, clinical decline is reduced by 10% to 20% compared to placebo as determined by CDR-SB, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately severe. In some embodiments, clinical decline is reduced by at least 5%, such as 10%, at least 12%, or at least 14%, compared to placebo as determined by CDR-SB, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately severe. In some embodiments, clinical decline is reduced by at least 14% compared to placebo as determined by CDR-SB, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately severe. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0176] In some embodiments, a subject diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI) - moderately severe - experiences at least a 14% reduction in clinical decline compared to placebo after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by CDR-SB. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody, administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0177] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least %, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, or at least 51%, wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0178] In some embodiments, clinical decline is reduced by 40% to 60% compared to placebo, as determined by CDR-SB, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 45%, such as 48%, at least 50%, or at least 51%, compared to placebo, as determined by CDR-SB, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 51% compared to placebo, as determined by CDR-SB, and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0179] In some embodiments, clinical decline in a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 51% compared to placebo as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0180] In some embodiments, the reduction in clinical decline is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, 60 months, 63 months, 66 months, and / or 72 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0181] In some embodiments, the reduction in clinical decline is determined after one month of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical decline is determined after six months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical decline is determined after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical decline is determined after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical decline is determined after 60 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the reduction in clinical decline is determined after 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0182] In some embodiments, the reduction in clinical decline is determined after administration of a composition comprising a therapeutically effective amount of BAN2401.

[0183] In some embodiments, the reduction in clinical decline is determined after 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, 60 months, 63 months, 66 months, and / or 72 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 1 month of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 6 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 12 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 18 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 60 months of administration of a composition comprising a therapeutically effective amount of BAN2401. In some embodiments, the reduction in clinical decline is determined after 63 months of administration of a composition comprising a therapeutically effective amount of BAN2401.

[0184] In some embodiments, the subject is ApoE4 positive.

[0185] In some embodiments, the clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, or at least 74%, wherein the subject is ApoE4 positive. In some embodiments, the reduction in clinical decline recited above is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ antibody.

[0186] In some embodiments, clinical decline is reduced by 60% to 80%, such as 63% to 74%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 60%, such as at least 63%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 65%, such as at least 67%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 70%, such as at least 74%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4 positive.

[0187] In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 70% compared to placebo when determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 60% compared to placebo when determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo when determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 63% compared to placebo when determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0188] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 4%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or less At least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, at least 215%, at least The clinical decline is reduced by at least 220%, at least 225%, at least 230%, at least 235%, at least 240%, at least 245%, at least 250%, at least 255%, at least 260%, at least 265%, at least 270%, at least 275%, at least 280%, at least 290%, at least 295%, at least 300%, at least 305%, at least 310%, at least 315%, at least 320%, at least 325%, at least 330%, or at least 331%, wherein the subject is ApoE4 positive. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0189] In some embodiments, clinical decline is reduced by 70% to 400%, such as 80% to 350%, compared to placebo, as determined by ADAS-cog, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-cog, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 80%, such as at least 90% or at least 100%, compared to placebo, as determined by ADAS-cog, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 300%, such as at least 330%, compared to placebo, as determined by ADAS-cog, wherein the subject is ApoE4 positive. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0190] In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 300% compared to placebo as determined by ADAS-cog after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 80%, such as at least 90% or at least 100%, compared to placebo as determined by ADAS-cog after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 70%, such as at least 75%, at least 80%, or at least 84%, compared to placebo as determined by ADAS-cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 84% compared to placebo as determined by ADAS-cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0191] In some embodiments, the clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43% compared to placebo as determined by CDR-SB. , at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, or at least 87%, wherein the subject is ApoE4 positive. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0192] In some embodiments, clinical decline is reduced by 35% to 150%, such as 40% to 100% or 45% to 90%, compared to placebo, as determined by CDR-SB, and wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, and wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, and wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 70%, such as at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, and wherein the subject is ApoE4 positive. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0193] In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by CDR-SB after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 50%, such as at least 55% or at least 60%, compared to placebo, as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects is reduced by at least 60% compared to placebo as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0194] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, or at least 59%, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0195] In some embodiments, clinical decline is reduced by 30% to 70%, such as 38% to 59%, compared to placebo, as determined by ADCOMS, where the subject is ApoE4 positive and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 30%, such as at least 35% or at least 38%, compared to placebo, as determined by ADCOMS, where the subject is ApoE4 positive and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 45%, such as at least 50% or at least 53%, compared to placebo, as determined by ADCOMS, where the subject is ApoE4 positive and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 50%, such as at least 55% or at least 59%, compared to placebo, as determined by ADCOMS, where the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0196] In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately severe mild cognitive impairment due to Alzheimer's disease is reduced by at least 50%, such as at least 55%, compared to placebo, as determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately severe mild cognitive impairment due to Alzheimer's disease is reduced by at least 30%, such as at least 35%, compared to placebo, as determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately severe mild cognitive impairment due to Alzheimer's disease is reduced by at least 45%, such as at least 50% or at least 55%, compared to placebo, as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0197] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least %, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,and / or at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211%, wherein the subject is ApoE4-positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0198] In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, such as at least 110%, compared to placebo, as determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, such as at least 70% or at least 75%, compared to placebo, as determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0199] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 4%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or less At least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, at least 170%, at least 175%, at least 180%, at least 185%, at least 190%, at least 195%, at least 200%, at least 205%, at least 210%, or at least 211%, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the reduction in clinical decline listed above is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0200] In some embodiments, clinical decline is reduced by 40% to 300%, such as 45% to 250% or 50% to 250%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, clinical decline is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, clinical decline is reduced by at least 60%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, clinical decline is reduced by at least 100%, such as at least 150% or at least 200%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0201] In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 100%, such as at least 150% or at least 200%, compared to placebo, as determined by ADAS-cognitive scale after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 40%, such as at least 45% or at least 50%, compared to placebo, as determined by ADAS-cognitive scale after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild cognitive impairment due to Alzheimer's disease (probably mild cognitive impairment) is reduced by at least 50%, such as at least 60%, at least 70%, or at least 75%, compared to placebo, as determined by ADAS-cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0202] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 15% or more compared to placebo as determined by CDR-SB. at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45%, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0203] In some embodiments, clinical decline is reduced by 20% to 90%, such as 25% to 80% or 30% to 75%, compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 25%, such as at least 30%, compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 30%, such as at least 35% or 40%, compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and the subject has been diagnosed with moderately probable mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 35%, such as at least 40% or 45%, compared to placebo, as determined by CDR-SB, where the subject is ApoE4 positive and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0204] In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 35%, such as at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease is reduced by at least 20%, such as at least 25% or at least 30%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild cognitive impairment due to Alzheimer's disease (MCI)—moderately likely—is reduced by at least 35%, such as at least 40%, compared to placebo, as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody, administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0205] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least %, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,and at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, or at least 119%, wherein the subject is ApoE4-positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0206] In some embodiments, clinical decline is reduced by 76% to 119% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and the subject is diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 76% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and the subject is diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 113% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and the subject is diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 119% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and the subject is diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0207] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 4%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or less At least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173%, at least 174%, at least 175%, at least 176%, at least 177%, at least 178%, at least 179%, at least 180%, at least 190%, at least 200%, at least 210%, at least 220%, at least 230%, at least 240%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 425%, at least 450%, at least 475%, at least 500%, at least 550%, at least 600%, at least 650%, at least 700%, at least 750%, at least 800%, at least 850%, at least 900%, at least 950%,reduced by at least 1000%, at least 1001%, at least 1002%, at least 1003%, at least 1004%, at least 1005%, at least 1006%, at least 1007%, at least 1008%, at least 1009%, at least 1010%, at least 1011%, at least 1012%, at least 1013%, at least 1014%, at least 1015%, at least 1016%, at least 1017%, at least 1018%, at least 1019%, at least 1020%, at least 1021%, at least 1022%, or at least 1023%, wherein the subject is ApoE4 positive, and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the reduction in clinical decline listed above is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0208] In some embodiments, clinical decline is reduced by 58% to 1023% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 58% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 171% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by 1023% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0209] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least %, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143 %, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149%, at least 150%, at least 151%, at least 152%, at least 153%, at least 154%, at least 155%, at least 156%, at least 157%, at least 158%, at least 159%, at least 160%, at least 161%, at least 162%, at least 163%, at least 164%, at least 165%, at least 166%, at least 167%, at least 168%, at least 169%, at least 170%, at least 171%, at least 172%, at least 173%, or at least 174%, wherein the subject is ApoE4 positive, and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the reduction in clinical decline listed above is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0210] In some embodiments, clinical decline is reduced by 70% to 200%, such as 75% to 180% or 82% to 174%, relative to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 70%, such as at least 80%, relative to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 75%, such as at least 80% or at least 85%, relative to placebo, as determined by CDR-SB, wherein the subject is ApoE4 positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 150%, such as at least 160% or 170%, compared to placebo, as determined by CDR-SB, where the subject is ApoE4-positive and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0211] In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 70%, such as at least 75%, at least 80%, or at least 85%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 130%, such as at least 140%, at least 150%, at least 160%, or at least 170%, compared to placebo, as determined by CDR-SB after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-positive subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, such as at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0212] In some embodiments, the subject is ApoE4 negative.

[0213] In some embodiments, clinical decline is reduced 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%, or at least 12% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4-negative. In some embodiments, the above-mentioned reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0214] In some embodiments, clinical decline is reduced by 5% to 15% compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative. In some embodiments, clinical decline is reduced by at least 5%, such as at least 7%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative. In some embodiments, clinical decline is reduced by at least 10%, such as at least 12%, compared to placebo, as determined by ADCOMS, wherein the subject is ApoE4-negative. In some embodiments, the above-listed reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0215] In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least -2% compared to placebo when determined by ADCOMS after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least 10% compared to placebo when determined by ADCOMS after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least 5%, such as at least 7%, compared to placebo when determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least 7% compared to placebo when determined by ADCOMS after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0216] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35% less than placebo as determined by ADAS-cog. at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, or at least 72%, wherein the subject is ApoE4 negative. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0217] In some embodiments, clinical decline is reduced by 40% to 80% compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 negative. In some embodiments, clinical decline is reduced by at least 35%, such as at least 40% or at least 43%, compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 negative. In some embodiments, clinical decline is reduced by at least 40%, such as at least 45% or at least 46%, compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 negative. In some embodiments, clinical decline is reduced by at least 65%, such as at least 70% or at least 72%, compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 negative. In some embodiments, clinical decline is reduced by at least 43% compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 negative. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0218] In some embodiments, clinical decline is increased by 7%, 6%, 5%, 5%, 3%, 2%, or 1% compared to placebo, as determined by CDR-SB, and wherein the subject is ApoE4-negative. In some embodiments, clinical decline is reduced by at least 1%, at least 2%, or at least 3% compared to placebo, as determined by CDR-SB, and wherein the subject is ApoE4-negative. In some embodiments, the above-mentioned reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0219] In some embodiments, clinical decline is reduced by 3% compared to placebo as determined by CDR-SB, and the subject is ApoE4-negative. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline is reduced 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, or at least 26% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4-negative and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0220] In some embodiments, clinical decline is reduced by 15% to 26% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 negative and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by 15% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 negative and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by 26% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 negative and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, the above-mentioned reductions in clinical decline are determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0221] In some embodiments, clinical decline is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 4%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, or less At least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%,and at least 107%, at least 108%, at least 109%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 155%, at least 160%, at least 165%, or at least 166%, where the subject is ApoE4-negative and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0222] In some embodiments, clinical decline is reduced by 50% to 200%, such as 60% to 180% or 65% to 170%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 negative and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 50%, such as at least 55% or at least 65%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 negative and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, where the subject is ApoE4 negative and the subject has been diagnosed with moderately likely mild cognitive impairment due to Alzheimer's disease. In some embodiments, clinical decline is reduced by at least 150%, such as at least 160%, relative to placebo, as determined by ADAS-Cog, where the subject is ApoE4-negative and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0223] In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least 150%, such as at least 160%, compared to placebo, as determined by ADAS-Cog after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least 70%, such as at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, clinical decline in ApoE4-negative subjects is reduced by at least 50%, such as at least 60% or at least 65%, compared to placebo, as determined by ADAS-Cog after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0224] In some embodiments, clinical decline is reduced by at least 1%, at least 2%, at least 3%, at least 4%, or at least 5% compared to placebo as determined by CDR-SB, wherein the subject is ApoE4-negative and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0225] In some embodiments, clinical decline is reduced by at least 5% compared to placebo as determined by CDR-SB, wherein the subject is ApoE4 negative and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0226] In some embodiments, clinical decline is reduced 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%, or at least 12% compared to placebo, as determined by CDR-SB, wherein the subject is ApoE4-negative and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0227] In some embodiments, clinical decline is reduced by at least 10%, such as at least 12%, relative to placebo, as determined by CDR-SB, where the subject is ApoE4-negative and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the above-mentioned reduction in clinical decline is determined after 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0228] Conversion of subjects from amyloid positive to amyloid negative In various embodiments, a subject is administered a composition comprising at least one anti-Aβ protofibril antibody disclosed herein before exhibiting cognitive symptoms of AD (prodromal AD). In some embodiments, prodromal AD patients are amyloid-negative, e.g., as determined by PET SUVr and / or by plasma biomarkers, such as p-tau 181 levels in blood samples. In some embodiments, prodromal AD patients have tau 181 levels below a certain threshold, and optionally, the patient has intermediate amyloid-β, e.g., as measured by PET SUVr before treatment. In some embodiments, prodromal AD patients may be administered a therapeutic regimen comprising an anti-Aβ protofibril antibody (i.e., lecanemab) to prevent amyloid positivity. In some embodiments, prodromal AD patients may be administered a therapeutic regimen comprising an anti-Aβ protofibril antibody (i.e., lecanemab) to delay the onset of amyloid positivity. In some embodiments, prodromal AD patients may be administered a treatment regimen comprising an anti-Aβ protofibril antibody (i.e., lecanemab) to prevent deterioration of one or more AD biomarkers or brain measures (e.g., by PET or MRI), such as brain atrophy and / or brain measures of amyloid accumulation. In some embodiments, amyloid-negative prodromal AD patients are administered a reduced dose or administration frequency compared to the dose or frequency given to amyloid-positive patients (e.g., intravenous infusions of less than 10 mg / kg or less than every other week, or subcutaneous administrations of less than 720 mg or less than weekly). In some embodiments, amyloid-negative prodromal AD patients are transitioned to a maintenance dosing regimen sooner (e.g., in less than 18 months).

[0229] In some embodiments, a prodromal AD patient has p-tau181 levels above a threshold, and administering to the patient a treatment regimen comprising an anti-Aβ protofibril antibody (i.e., lecanemab) reduces the p-tau181 levels to below the threshold. In some embodiments, the patient has intermediate amyloid-β, e.g., as measured by PET SUVr before treatment. In some embodiments, treatment reduces amyloid-β, e.g., as measured by PET SUVr. In some embodiments, treatment converts the patient from an amyloid-positive state to an amyloid-negative state, e.g., as determined by p-tau181 levels and / or PET SUVr.

[0230] In various embodiments, the present disclosure also provides methods for converting an amyloid-positive subject to an amyloid-negative subject. In some embodiments, the method comprises administering to the subject a composition comprising at least one anti-Aβ protofibril antibody disclosed herein. In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease—moderate likelihood—and / or mild Alzheimer's disease dementia. In some embodiments, the method further comprises measuring p-tau 181 levels before administering a first dose of a composition comprising an anti-Aβ protofibril antibody, and assessing the effectiveness of the treatment by measuring again after administering the antibody, for example, after 6 to 12, 18, 24, or 36 months of treatment. In some embodiments, a decrease in p-tau 181 levels after administering a first dose of a composition comprising an anti-Aβ protofibril antibody indicates a change from amyloid-positive to amyloid-negative brain status in the subject. In some embodiments, an increase in the Aβ42 / 40 ratio after administration of a first dose of a composition comprising an anti-Aβ protofibril antibody, e.g., an increase to a ratio greater than 0.092, indicates a change from amyloid-positive to amyloid-negative in the subject's brain. In some embodiments, an increase in the Aβ42 / 40 ratio 6 months, 12 months, 18 months, 24 months, or 36 months after initiation of administration of a composition comprising an anti-Aβ protofibril antibody, e.g., an increase to a ratio of about 0.05 to 0.1, e.g., about 0.08 to 0.1, e.g., about 0.092, indicates a change from amyloid-positive to amyloid-negative in the subject's brain. In some embodiments, a decrease in p-tau181 levels after administration of a first dose of a composition comprising an anti-Aβ protofibril antibody indicates therapeutic efficacy, e.g., a reduction in brain Aβ. In some embodiments, subjects who convert to amyloid-negative are given a reduced dose or frequency of anti-Aβ protofibril antibody, alone or in combination with at least one additional therapy, e.g., a BACE inhibitor and / or an anti-tau antibody.

[0231] Any of the anti-Aβ protofibril antibodies disclosed herein, therapeutically acceptable amounts thereof, dosing regimens therefor, and compositions comprising the same may be used in methods for converting an amyloid-positive subject to an amyloid-negative subject. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, at 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight is administered to the subject once weekly, once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every 4 weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every eight weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 ... It is administered once every month (quarter year), once every 14 weeks, once every 16 weeks, once every 4 months, once every 18 weeks, once every 20 weeks, once every 5 months, once every 22 weeks, once every 24 weeks, once every 6 months (every six months), once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, once every 12 months (yearly), once every 13 months, once every 14 months, once every 15 months, once every 16 months, once every 17 months, or once every 18 months.

[0232] In some embodiments, the method includes measuring p-tau181 levels before administering a first dose of a composition comprising an anti-Aβ protofibril antibody, and measuring again after administering the antibody, e.g., after 6 to 12, 18, or 24 months of treatment. In some embodiments, a decrease in p-tau181 levels indicates a change from amyloid-positive to amyloid-negative in the subject's brain. In some embodiments, an increase in the Aβ42 / 40 ratio, e.g., an increase to a ratio greater than 0.092, indicates a change from amyloid-positive to amyloid-negative in the subject's brain. In some embodiments, subjects who change to amyloid-negative are given a reduced dose or frequency of anti-Aβ protofibril antibody, alone or in combination with at least one additional therapy, e.g., a BACE inhibitor and / or an anti-tau antibody.

[0233] In some embodiments, administration of the composition results in an amyloid PET image of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, or at least 40% amyloid PET image of at least 1 ... , at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, or at least 81% of the subjects are converted from amyloid positive to amyloid negative.

[0234] In some embodiments, administration of the composition results in a conversion from amyloid-positive to amyloid-negative in 50% to 100%, such as 60% to 90%, of subjects, as determined by visual review of amyloid PET images. In some embodiments, administration of the composition results in at least 55%, such as at least 60% or at least 65%, of subjects becoming amyloid-negative after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by visual review of amyloid PET images. In some embodiments, administration of the composition results in at least 70%, such as at least 75% or at least 80%, of subjects becoming amyloid-negative after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by visual review of amyloid PET images. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0235] In some embodiments, administration of the composition results in 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, %, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50% %, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77 %, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the subjects become amyloid negative, wherein these subjects are ApoE4 positive.

[0236] In some embodiments, administration of the composition results in 75% to 100%, such as 80% to 100% or 85% to 100%, of subjects becoming amyloid negative as determined by visual review of amyloid PET images, wherein these subjects are ApoE4 positive. In some embodiments, administration of the composition results in at least 75%, such as at least 80% or at least 85%, of subjects becoming amyloid negative as determined by visual review of amyloid PET images, wherein these subjects are ApoE4 positive. In some embodiments, administration of the composition results in 100% of subjects becoming amyloid negative as determined by visual review of amyloid PET images, wherein these subjects are ApoE4 positive.

[0237] In some embodiments, at least 75%, such as at least 80% or at least 85%, of ApoE4-positive subjects are amyloid-negative after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by visual review of amyloid PET images. In some embodiments, at least 75%, such as at least 80%, at least 85%, at least 90%, or at least 95%, of ApoE4-positive subjects are amyloid-negative after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by visual review of amyloid PET images. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0238] In some embodiments, administration of the composition results in an amyloid PET image of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, or at least At least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, or at least 79% of the subjects will be amyloid negative, wherein these subjects are ApoE4 negative.

[0239] In some embodiments, administration of the composition results in 50% to 100%, such as 55% to 90%, of subjects becoming amyloid negative as determined by visual review of amyloid PET images, where these subjects are ApoE4 negative. In some embodiments, administration of the composition results in at least 50% of subjects becoming amyloid negative as determined by visual review of amyloid PET images, where these subjects are ApoE4 negative. In some embodiments, administration of the composition results in at least 70% of subjects becoming amyloid negative as determined by visual review of amyloid PET images, where these subjects are ApoE4 negative.

[0240] Reduced brain amyloid levels Also provided herein, in various embodiments, are methods for reducing brain amyloid levels in a subject in need thereof. In some embodiments, the methods include measuring p-tau 181 levels before administering a first dose of a composition comprising an anti-Aβ protofibril antibody, and measuring again after administering the antibody, e.g., after 6 to 12 months of treatment. In some embodiments, a decrease in p-tau 181 levels indicates a reduction in amyloid in the brain of the subject. In some embodiments, subjects exhibiting a reduction in brain amyloid as determined by a change in p-tau 181 levels are given a reduced dose or frequency of an anti-Aβ protofibril antibody, alone or in combination with at least one additional therapy, e.g., a BACE inhibitor and / or an anti-tau antibody.

[0241] In some embodiments, the subject has early Alzheimer's disease, hi some embodiments, the subject has Alzheimer's disease, Down's syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, dementia with Lewy bodies, or another brain disease or condition with Aβ peptide-containing soluble and / or insoluble Aβ aggregates.

[0242] Those skilled in the art will understand that, in addition to subjects with Alzheimer's disease, Aβ plaque deposits are present in the brains of subjects with other neurodegenerative diseases and conditions, and therefore, the methods disclosed herein may be beneficial for subjects with such neurodegenerative diseases and / or conditions, including, for example, Down's syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and dementia with Lewy bodies (see, e.g., Catafau et al., "Amyloid PET imaging: applications beyond Alzheimer's disease," Clin. Transl. Imaging 3(1):39-55 (2015); and Banerjee, G. et al., "The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice," J. Neurol. Neurosurg. Psychiatry 88:982-994 (2017)).

[0243] In some embodiments, the subject with early stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderately likely, and / or has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the subject with early stage Alzheimer's disease is ApoE4 positive.

[0244] Any of the anti-Aβ protofibril antibodies disclosed herein, therapeutically acceptable amounts thereof, dosing regimens therefor, and compositions comprising the same may be used in methods for reducing brain amyloid levels in subjects with early Alzheimer's disease. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, at 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight is administered to the subject once weekly, once every two weeks, once every three weeks, once every four weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every 4 weeks, once every month, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months, once every nine weeks, once every ten weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every eight weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, once every 3 weeks, once every eight ... In some embodiments, the at least one anti-Aβ protofibril antibody is administered once every month (quarter year), once every 14 weeks, once every 16 weeks, once every 4 months, once every 18 weeks, once every 20 weeks, once every 5 months, once every 22 weeks, once every 24 weeks, once every 6 months (biannually), once every 7 months, once every 8 months, once every 9 months, once every 10 months, once every 11 months, once every 12 months (yearly), once every 13 months, once every 14 months, once every 15 months, once every 16 months, once every 17 months, or once every 18 months. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0245] In some embodiments, the method results in a reduction in brain amyloid levels after administration compared to brain amyloid levels before said administration. In some embodiments, the brain amyloid level is 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%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 14% or less compared to brain amyloid levels before said administration. at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% reduced.In some embodiments, the reduction in brain amyloid levels listed above is determined by visual reading of amyloid PET images and expressed as PET standard uptake value ratios (SUVr values).

[0246] As used herein, the term "PET" or "amyloid PET" refers to amyloid positron emission tomography imaging. In some embodiments, amyloid pathology is determined by performing PET imaging (also referred to as PET scan). In some embodiments, amyloid PET is determined with a PET tracer, and the same tracer is used in follow-up determinations. In some embodiments, PET imaging uses a florbetapir tracer. In some embodiments, PET imaging uses a flutemetamol tracer.

[0247] Amyloid positron emission tomography (PET) imaging can be used to confirm the presence of amyloid pathology in the brain of early-stage AD subjects during the screening phase of the study, and / or to assess the effect of at least one anti-AB antibody on amyloid levels in the brain by both whole-brain analysis (e.g., an average of five to six cortical regions) and brain-region analysis. In some embodiments, the PET scan uses florbetapir. In some embodiments, amyloid plaque burden can be identified, for example, by visual interpretation of the captured PET images by an experienced radiolog...

Claims

1. 1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. measuring or having measured p-tau181 levels in a blood sample obtained from said subject; and b. if the subject's p-tau181 level is above a threshold, administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. Including, The method, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

2. a. measuring a second p-tau181 level in a second blood sample obtained from the subject after the initial sample collection; and b. if the subject's p-tau 181 level is above a threshold, administering to the subject a second therapeutically effective dose comprising the same amount of the anti-Aβ protofibril antibody as the first dose. The method of claim 1 further comprising:

3. a. measuring a second p-tau181 level in a second blood sample obtained from the subject after the initial sample collection; and b. if the subject's p-tau 181 level is below a threshold, administering to the subject a second therapeutically effective dose comprising the anti-Aβ protofibril antibody in an amount equal to or less than the first dose. The method of claim 1 further comprising:

4. 1. A method for selecting treatment with an anti-amyloid beta (Aβ) protofibril antibody in a subject, comprising: a. measuring or having measured p-tau181 levels in a blood sample obtained from said subject; and b. if said level is above a threshold, selecting said subject for treatment with an anti-amyloid beta (Aβ) protofibril antibody. A method comprising:

5. 1. A method for monitoring therapeutic efficacy in a subject having or suspected of having AD, comprising: administering to the subject a dose of an anti-Aβ protofibril antibody; measuring or having measured post-dose p-tau181 levels in a blood sample obtained from said subject; and comparing the post-dose level of the blood sample to a blood sample obtained from the subject prior to the administration of the first dose of the anti-Aβ protofibril antibody or to a control level, wherein the treatment is deemed efficacious if the post-dose level is lower than the pre-first dose level or the control level. A method comprising:

6. 1. A method for detecting a decrease in brain Aβ levels, comprising: measuring, or having measured, a first level of p-tau181 in a first blood sample obtained from the subject prior to administration of an anti-Aβ protofibril antibody; administering a dose of said anti-Aβ protofibril antibody to said subject; measuring, or has been measured, a second level of p-tau181 in a second blood sample obtained from the subject after administration of the anti-Aβ protofibril antibody; Comparing the first and second levels. Including, A second level lower than the first level indicates a reduction in brain amyloid beta in the subject.

7. The method of any one of claims 1 to 6, wherein the p-tau 181 levels are measured without brain amyloid measurement by PET.

8. The method of any one of claims 1 to 6, further comprising measuring the subject's brain amyloid levels before and / or after treatment.

9. 9. The method of claim 8, wherein a decrease in the PET SUVr value is indicative of a decrease in brain amyloid levels.

10. The method of any one of claims 1 to 9, wherein the subject has Alzheimer's disease.

11. The method of any one of claims 1 to 9, wherein the subject has early Alzheimer's disease.

12. The method of any one of claims 1 to 9, wherein the subject has prodromal Alzheimer's disease (prodromal AD).

13. 10. The method of any one of claims 1 to 9, wherein the subject has Alzheimer's disease, Down's syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, dementia with Lewy bodies, or another brain disease or condition involving Aβ peptide-containing soluble and / or insoluble Aβ aggregates.

14. The object is a. Have been diagnosed with Mild Cognitive Impairment due to Alzheimer's Disease - Moderate Probability and / or Mild Alzheimer's Disease Dementia; b. Mild cognitive impairment due to Alzheimer's disease - moderately probable, as diagnosed by the National Institute on Aging-Alzheimer's Disease Association (NIA-AA) Core Clinical Criteria; c. Mild cognitive impairment due to Alzheimer's disease - moderately probable, diagnosed with a CDR global score of 0.5 and a memory box score of 0.5 or greater before treatment; d. A diagnosis of mild cognitive impairment due to Alzheimer's disease - moderately probable, based on a history of gradual onset and slowly progressive subjective memory decline in the past year prior to treatment; e. Has been diagnosed with mild Alzheimer's disease dementia according to the NIA-AA Core Clinical Criteria for probable Alzheimer's disease dementia; or f. Diagnosed with a pre-treatment CDR score of 0.5-1.0 and a memory box score of 0.5 or more; The method according to any one of claims 1 to 9.

15. The method of any one of claims 1 to 14, wherein the subject is amyloid positive prior to administration.

16. The method of any one of claims 1 to 15, wherein the subject has at least one copy of the ApoE4 gene.

17. The method of any one of claims 1 to 16, wherein the p-tau181 is measured using an LC MS / MS platform.

18. 7. The method of claim 3 or 6, wherein if the second level is lower than the first level, it indicates that the subject has converted from amyloid positive to amyloid negative, or treatment is discontinued if it does not result in a level below a threshold.

19. The method of any one of claims 1 to 18, wherein the anti-Aβ protofibril antibody is administered as an intravenous infusion at a therapeutically effective dose of 10 mg / kg of the subject's body weight.

20. 20. The method of claim 19, wherein the therapeutically effective dose is administered every two weeks.

21. 21. The method of claim 20, wherein the administration frequency is reduced after 18 months of treatment.

22. 22. The method of claim 20 or 21, wherein the therapeutically effective dose is reduced after 18 months of treatment.

23. 21. The method of claim 20, wherein the frequency of administration is reduced after the subject exhibits a p-tau 181 level in the blood sample below the threshold.

24. 24. The method of claim 20 or 23, wherein the therapeutically effective dose is decreased after the subject exhibits a p-tau181 level in the blood sample below a threshold.

25. The method of any one of claims 1 to 18, wherein the anti-Aβ protofibril antibody is administered subcutaneously at a therapeutically effective dose of 720 mg.

26. 26. The method of claim 25, wherein the therapeutically effective dose is administered weekly.

27. 27. The method of claim 26, wherein the administration frequency is reduced after 18 months of treatment.

28. 28. The method of claim 26 or 27, wherein the therapeutically effective dose is reduced after 18 months of treatment.

29. 27. The method of claim 26, wherein the frequency of administration is reduced after the subject exhibits a p-tau 181 level in the blood sample below the threshold.

30. 30. The method of claim 26 or 29, wherein the therapeutically effective dose is decreased after the subject exhibits a p-tau181 level in the blood sample below a threshold.

31. The method of any one of claims 21 to 30, wherein said reduced therapeutically effective dose and / or frequency is increased if the subject presents with a p-tau181 level in the blood sample above a threshold.

32. The method of any one of claims 1 to 31, wherein the anti-Aβ protofibril antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

33. 33. The method of any one of claims 1 to 32, wherein at least one additional AD medication is administered sequentially or simultaneously to the subject.

34. Compared to before treatment, a. a decrease or slowing of increase in cerebrospinal fluid biomarkers; and / or b. A decrease or slowing of increase in plasma or serum biomarkers; The method according to any one of claims 1 to 33, wherein

35. The treatment, a. slow clinical decline as determined by ADCOMS; b. slow clinical decline as determined by ADAS MCI-ADL; c. slow clinical decline as determined by modified iADRS; d. delay clinical decline as measured by CDR-SB; or e. slowing clinical decline as measured by ADAS-Cog; 35. The method according to any one of claims 1 to 34.

36. 36. The method of any one of claims 1 to 35, further comprising monitoring for ARIA.

37. The method of any one of claims 1 to 36, wherein no titration step is required prior to administering to the subject a first therapeutically effective dose of the anti-Aβ protofibril antibody.

38. 1. A method of treating prodromal Alzheimer's disease (prodromal AD) in a subject, comprising: a. measuring or having measured p-tau181 levels in a blood sample obtained from said subject; and b. if the subject's p-tau181 level is above a threshold, administering to the subject a treatment comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody. Including, The method, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

39. 39. The method of claim 38, wherein the subject is switched to a maintenance dosing regimen at or before 18 months of treatment, e.g., when the p-tau 181 levels fall below a threshold.

40. 40. The method of claim 38 or 39, wherein the subject has moderate brain amyloid.

41. 1. A method of treating Alzheimer's disease (AD) in a subject having or suspected of having AD, comprising: a. measuring or having measured a first level of phosphorylated tau 181 (p-tau 181) in a first blood sample obtained from the subject; b. administering to said subject having a p-tau181 level above a threshold a therapeutic dose administration regimen comprising a therapeutically effective dose of an anti-amyloid beta (Aβ) protofibril antibody; and c. determining that a subsequent p-tau181 level in a blood sample from the patient is below a threshold level and switching to a maintenance dosing regimen; Including, The method, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

8.

42. 42. The method of claim 41, wherein the switch to the maintenance dose occurs at least 6 months after initiation of the therapeutic dose administration regimen.

43. 43. The method of claim 41 or 42, wherein the therapeutic dosage regimen comprises administering the anti-Aβ protofibril antibody at a therapeutically effective dose of 10 mg / kg of the subject's body weight as an intravenous infusion every two weeks.

44. 44. The method of any one of claims 41 to 43, wherein the therapeutic dose administration regimen comprises weekly subcutaneous administration of the anti-Aβ protofibril antibody at a therapeutically effective dose of 720 mg.

45. 45. The method of any one of claims 41-44, wherein the maintenance dose administration regimen comprises an intravenous infusion of a therapeutically effective dose of 10 mg / kg of the subject's body weight every two weeks.

46. 45. The method of any one of claims 41-44, wherein the maintenance dose administration regimen comprises subcutaneous administration of a therapeutically effective dose of 720 mg every other week or a dose of 360 mg every week of the anti-Aβ protofibril antibody.

47. The method of any one of claims 41 to 46, wherein a reduction in p-tau181 is detected in a blood sample from the subject prior to switching to a maintenance dose.

48. 48. The method of any one of claims 41-47, wherein brain amyloid negativity as measured by PET SUVr is detected in the subject prior to switching to a maintenance dose.

49. The maintenance dose is a. a p-tau181 level in a blood sample from said patient that is below a threshold; and / or b. Florbetapir PET SUVr level of 1.17 or less 49. The method of any one of claims 41 to 48, wherein the method is administered at a dose and / or frequency selected to maintain

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