Methods of treatment and prevention of alzheimer's disease

Abstract

To provide compositions for reducing brain amyloid levels in a subject having early Alzheimer's disease.SOLUTION: Compositions for reducing brain amyloid levels in a subject having early Alzheimer's disease are provided. The compositions comprise a therapeutically effective amount of at least one anti-Aβ protofibril antibody. The compositions are administered once every 2 weeks at a dose of the at least one anti-Aβ protofibril antibody of 10 mg / kg relative to the weight of the subject, in a sufficient period to observe at least 26% decline of clinical function relative to placebo as determined by CDR-SB.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to methods for treating and preventing Alzheimer's disease. This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 702,659, filed July 24, 2018; U.S. Provisional Patent Application No. 62 / 749,614, filed October 23, 2018; U.S. Provisional Patent Application No. 62 / 824,162, filed March 26, 2019; U.S. Provisional Patent Application No. 62 / 846,902, filed May 13, 2019; and U.S. Provisional Patent Application No. 62 / 874,684, filed July 16, 2019; the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disorder of unknown etiology and the most common form of dementia among older adults. 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 the United States reportedly had over 5 million cases of 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.).

[0003] The disease generally involves a generalized, slowly progressing decline in cognitive function, leading to bedridden status in terminally ill patients. Patients with AD typically survive only 3–10 years after onset, although extreme cases of 2–20 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 leading cause of all deaths in the United States and the fifth leading cause of death among Americans over the age of 65 (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158–94).

[0004] AD poses a significant economic burden throughout industrialized countries, with significant impacts on health care systems and government 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. Summary of the Invention [Problem to be solved by the invention]

[0005] To the best of our knowledge, there is currently no cure for AD, and no way to slow the progression of the disease. Current therapeutic agents for treating AD include symptomatic treatments, such as acetylcholinesterase inhibitors (AChEIs) such as donepezil, and N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine. Although these drugs can improve symptoms of AD, such as cognitive decline and reduced activity of daily living activities, there are no reports that they alter the progression of the disease. Therefore, there is an unmet need for methods to treat the progression of AD and / or prevent AD. [Means for solving the problem]

[0006] In some embodiments, provided herein are methods for reducing clinical decline in a subject with early Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0007] In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, prevents Aβ deposition before plaques begin to form in the brain. In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, reduces protofibrils and existing plaques in the brain. In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, prevents Aβ deposition before plaques begin to form and reduces protofibrils and existing plaques in the brain.

[0008] In some embodiments, provided herein is a method for converting a subject with amyloid-positive early-stage Alzheimer's disease to a subject with amyloid-negative early-stage Alzheimer's disease, the method comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0009] In some embodiments, provided herein is a method for reducing brain amyloid levels in a subject with early Alzheimer's disease, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is an ApoE4 carrier. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0010] In some embodiments, provided herein are methods for preventing Alzheimer's disease in an ApoE4-positive subject. In some embodiments, the method includes determining the subject's pre-administration brain amyloid level, and administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody if the subject's brain amyloid level is above a first predetermined level. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week, as determined by ADCOMS. [Figure 2] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose as determined by ADCOMS. [Figure 3] 1 shows the slowing of cognitive decline compared to placebo over 18 months for a monthly dose of 10 mg / kg BAN2401 and a biweekly dose of 10 mg / kg BAN2401 in subjects with probable mild cognitive impairment due to Alzheimer's disease dementia - moderate, as determined by ADCOMS. [Figure 4] 1 shows slowing of cognitive decline compared to placebo over 18 months for a 10 mg / kg monthly dose of BAN2401 and a 10 mg / kg biweekly dose of BAN2401 in subjects with mild Alzheimer's disease dementia as determined by ADCOMS. [Figure 5] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose in ApoE4 positive subjects as determined by ADCOMS. [Figure 6] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose in ApoE4-negative subjects as determined by ADCOMS. [Figure 7] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week, as determined by ADAS-cog. [Figure 8] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose as determined by ADAS-cog. [Figure 9] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week, as determined by CDR-SB. [Figure 10]1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose as determined by CDR-SB. [Figure 11] Figure 1 shows reduction in amyloid in the brain over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week as determined by PET, averaged across the cortex compared to whole cerebellum reference values. [Figure 12] 1 shows the reduction in amyloid in the brain over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week, as determined by PET-visualized imaging using radioactive tracer binding of brain Aβ amyloid. [Figure 13] 1 shows the conversion of amyloid-positive subjects to amyloid-negative subjects after 12 and 18 months of treatment for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses, as determined by visual reading. [Figure 14] 1 shows the change in cerebrospinal fluid Aβ1-42 levels over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week. [Figure 15] 1 shows the change in cerebrospinal fluid total tau levels over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose. [Figure 16] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-positive subjects as determined by ADCOMS. [Figure 17]Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-positive subjects with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease as determined by ADCOMS. [Figure 18] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly dose of 10 mg / kg BAN2401 and a biweekly dose of 10 mg / kg BAN2401 in ApoE4-positive subjects with mild Alzheimer's disease dementia as determined by ADCOMS. [Figure 19] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4 positive subjects as determined by ADAS-cog. [Figure 20] 1 shows slowing of cognitive decline over 18 months for monthly 10 mg / kg and biweekly 10 mg / kg doses of BAN2401 compared to placebo in ApoE4 positive subjects as determined by ADAS-cog. [Figure 21] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-positive subjects with moderate likelihood of mild cognitive impairment due to Alzheimer's disease as determined by ADAS-cog. [Figure 22] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-positive subjects with mild Alzheimer's disease dementia, as determined by ADAS-cog. [Figure 23]Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-positive subjects as determined by CDR-SB. [Figure 24] 1 shows slowing of cognitive decline over 18 months for monthly 10 mg / kg and biweekly 10 mg / kg doses of BAN2401 compared to placebo in ApoE4-positive subjects as determined by CDR-SB. [Figure 25] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-positive subjects with moderate likelihood of mild cognitive impairment due to Alzheimer's disease as determined by CDR-SB. [Figure 26] FIG. 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-positive subjects with mild Alzheimer's disease dementia, as determined by CDR-SB. [Figure 27] Figure 1 shows brain amyloid reduction over 18 months for BAN2401 at 2.5 mg / kg biweekly, 5 mg / kg monthly, 5 mg / kg biweekly, 10 mg / kg monthly, and 10 mg / kg biweekly doses in ApoE4-positive subjects as cortical-wide average values ​​compared to whole cerebellum reference values, as determined by visual interpretation of amyloid PET images. [Figure 28] 1 shows reduction in brain amyloid over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-positive subjects as determined by PET-visualized imaging using radioactive tracer binding of brain Aβ amyloid. [Figure 29]1 shows the conversion of amyloid-positive ApoE4-positive subjects to amyloid-negative ApoE4-positive subjects after 12 and 18 months of treatment. [Figure 30] 1 shows the change in cerebrospinal fluid Aβ1-42 levels over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week in ApoE4-positive subjects. [Figure 31] 1 shows the change in cerebrospinal fluid total tau levels over 18 months for a monthly 10 mg / kg BAN2401 dose and a biweekly 10 mg / kg BAN2401 dose in ApoE4 positive subjects. [Figure 32] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-negative subjects as determined by ADCOMS. [Figure 33] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-negative subjects with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease as determined by ADCOMS. [Figure 34] 1 shows slowing of cognitive decline compared to placebo over 18 months for a 10 mg / kg monthly dose of BAN2401 and a 10 mg / kg biweekly dose of BAN2401 in ApoE4-negative subjects with mild Alzheimer's disease dementia as determined by ADCOMS. [Figure 35] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-negative subjects as determined by ADAS-cog. [Figure 36]1 shows slowing of cognitive decline over 18 months for monthly 10 mg / kg and biweekly 10 mg / kg doses of BAN2401 compared to placebo in ApoE4-negative subjects as determined by ADAS-cog. [Figure 37] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-negative subjects with moderate likelihood of mild cognitive impairment due to Alzheimer's disease as determined by ADAS-cog. [Figure 38] 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-negative subjects with mild Alzheimer's disease dementia as determined by ADAS-cog. [Figure 39] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-negative subjects as determined by CDR-SB. [Figure 40] 1 shows slowing of cognitive decline over 18 months for 10 mg / kg monthly and 10 mg / kg biweekly doses of BAN2401 compared to placebo in ApoE4-negative subjects as determined by CDR-SB. [Figure 41] Figure 1 shows slowing of cognitive decline compared to placebo over 18 months for a monthly 10 mg / kg dose of BAN2401 and a biweekly 10 mg / kg dose of BAN2401 in ApoE4-negative subjects with moderate likelihood of mild cognitive impairment due to Alzheimer's disease as determined by CDR-SB. [Figure 42]1 shows slowing of cognitive decline compared to placebo over 18 months for a 10 mg / kg monthly dose of BAN2401 and a 10 mg / kg every other week dose in ApoE4-negative subjects with mild Alzheimer's disease dementia as determined by CDR-SB. [Figure 43] Figure 1 shows brain amyloid reduction over 18 months for BAN2401 at 2.5 mg / kg biweekly, 5 mg / kg monthly, 5 mg / kg biweekly, 10 mg / kg monthly, and 10 mg / kg biweekly doses in ApoE4-negative subjects as cortical-wide average values ​​compared to whole cerebellum reference values, as determined by visual interpretation of amyloid PET images. [Figure 44] 1 shows reduction in brain amyloid over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses in ApoE4-negative subjects as determined by PET-visualized imaging using radioactive tracer binding of brain Aβ amyloid. [Figure 45] Conversion of amyloid-positive ApoE4-negative subjects to amyloid-negative ApoE4-negative subjects after 12 and 18 months of treatment is shown. [Figure 46] 1 shows the change in cerebrospinal fluid Aβ1-42 levels over 18 months for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week in ApoE4-negative subjects. [Figure 47] 1 shows the change in cerebrospinal fluid total tau levels over 18 months for the 10 mg / kg monthly dose and the 10 mg / kg biweekly dose in ApoE4 negative subjects. [Figure 48] Figure 1 shows slowing of cognitive decline compared to placebo at 18 months for a biweekly 10 mg / kg BAN2401 dose in ApoE4-positive and ApoE4-negative subjects, and for all subjects regardless of genotype, as determined by ADCOMS, ADAS-Cog, or CDR-SB. [Figure 49]Mild Cognitive Impairment Due to Alzheimer's Disease Dementia - Moderate Probability or Mild Alzheimer's Disease Dementia as Determined by ADCOMS, ADAS-Cog, or CDR-SB. Shows slowing of cognitive decline compared to placebo at 18 months for a biweekly dose of 10 mg / kg BAN2401 in subjects with moderate probable or mild Alzheimer's disease dementia, and for all subjects regardless of disease type or status. [Figure 50] Shows a slowing of cognitive decline compared to placebo at 18 months for a dose of 10 mg / kg BAN2401 every other week in subjects concomitantly receiving at least one Alzheimer's medication other than BAN2401 and in subjects not concomitantly receiving at least one Alzheimer's medication other than BAN2401, and for all subjects regardless of whether they are concomitantly receiving at least one Alzheimer's medication other than BAN2401. [Figure 51] Figure 1 shows brain amyloid clearance compared to placebo at 18 months for a dose of 10 mg / kg BAN2401 every other week in the following subpopulations, as determined by PET: ApoE4-positive subjects; ApoE4-negative subjects; subjects with mild cognitive impairment due to Alzheimer's disease dementia - moderate probability; subjects with mild Alzheimer's disease dementia; subjects concomitantly receiving at least one Alzheimer's medication other than BAN2401; and subjects not concomitantly receiving at least one Alzheimer's medication other than BAN2401. [Figure 52] The study demonstrates a slowing of cognitive decline compared to placebo at 18 months for a biweekly dose of 10 mg / kg BAN2401 in the following subpopulations, as determined by ADCOMS: ApoE4-positive subjects; ApoE4-negative subjects; subjects with mild cognitive impairment due to dementia of the Alzheimer's disease type - moderate likelihood; subjects with mild dementia of the Alzheimer's disease type; subjects concomitantly receiving at least one Alzheimer's medication other than BAN2401; and subjects not concomitantly receiving at least one Alzheimer's medication other than BAN2401. [Figure 53] 1 shows the change in cerebrospinal fluid neurogranin levels at 18 months compared to placebo as a mean value for subjects receiving a dose of 10 mg / kg BAN2401 every two weeks or 10 mg / kg BAN2401 monthly. [Figure 54] 1 shows the change in cerebrospinal fluid phosphotau levels at 18 months compared to placebo as a mean value for subjects receiving a dose of 10 mg / kg BAN2401 every two weeks or 10 mg / kg BAN2401 monthly. [Figure 55] 1 shows the change in cerebrospinal fluid neurofilament light chain levels at 18 months compared to placebo as a mean value for subjects receiving a dose of 10 mg / kg BAN2401 every two weeks or 10 mg / kg BAN2401 monthly. [Figure 56] Figure 1 shows slowing of cognitive decline compared to placebo at 18 months for a dose of 10 mg / kg BAN2401 every other week or 10 mg / kg BAN2401 every month as determined by ADCOMS and PET. [Figure 57] 1 shows the correlation between reduction in brain amyloid and increased clinical improvement as determined by ADCOMS, ADAS-Cog, and CDR-SB. [Figure 58] 1 shows that ApoE4-positive and ApoE4-negative subjects who did not receive BAN2401 exhibited similar rates of disease progression. [Figure 59] 1 shows the impact of various factors on disease progression as determined by ADCOMS. [Figure 60] 1 shows the change in BAN2401 concentrations as a function of time following administration of a monthly dose of 10 mg / kg BAN2401 and a biweekly dose of 10 mg / kg BAN2401. [Figure 61] 1 depicts the preferential binding of BAN2401 to large Aβ protofibrils compared to Aβ peptide monomers, dimers, and oligomers. [Figure 62] 1 shows the proportion of subjects experiencing an ARIA-E event as a function of peak plasma concentration of BAN2401. [Figure 63]Administration of BAN2401 significantly reduced amyloid PET levels at all doses. [Figure 64] This paper outlines research designs for early intervention and prevention of Alzheimer's disease. [Figure 65] Figure 1 shows the adjusted mean change from baseline (least squares mean, "LSM") in cerebrospinal fluid phospho-tau levels over 18 months compared to placebo for BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week. [Figure 66] Figure 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurogranin levels over 18 months compared to placebo for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses. [Figure 67] Figure 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurofilament light chain levels over 18 months for BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every month, 5 mg / kg every other week, 10 mg / kg every month, and 10 mg / kg every other week doses compared to placebo. [Figure 68] 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid phospho-tau levels over 18 months for the combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo. [Figure 69] FIG. 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid phospho-tau levels over 18 months for a combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-positive subjects. [Figure 70] FIG. 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid phospho-tau levels over 18 months for a combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-negative subjects. [Figure 71] 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurogranin levels over 18 months for the combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo. [Figure 72] FIG. 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurogranin levels over 18 months for a combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-positive subjects. [Figure 73] FIG. 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurogranin levels over 18 months for a combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-negative subjects. [Figure 74] Figure 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurofilament light chain levels over 18 months for the combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo. [Figure 75] FIG. 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurofilament light chain levels over 18 months for a combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-positive subjects. [Figure 76] FIG. 1 shows the adjusted mean change from baseline (LSM) in cerebrospinal fluid neurofilament light chain levels over 18 months for a combined 10 mg / kg dose of BAN2401 (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-negative subjects. [Figure 77]Correlation between change from baseline in PET standardized uptake ratio (normalized to whole cerebellum mask) and cognitive outcomes at 12 and 18 months for placebo and BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every other week, 5 mg / kg every other week, 10 mg / kg every other week, and 10 mg / kg every other week doses, as determined by ADCOMS. [Figure 78] Correlations between change from baseline in PET standardized uptake ratio (normalized to whole cerebellum mask) and cognitive outcomes at 12 and 18 months for placebo and BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every other week, 5 mg / kg every other week, 10 mg / kg every other week, and 10 mg / kg every other week doses, as determined by CDR-SB. [Figure 79] Correlations between change from baseline in PET standardized uptake ratio (normalized to whole cerebellum mask) and cognitive outcomes at 12 and 18 months for placebo and BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every other week, 5 mg / kg every other week, 10 mg / kg every other week, and 10 mg / kg every other week doses, as determined by ADAS-Cog. [Figure 80] Correlation between change from baseline in PET standardized uptake ratio (normalized to subcortical white matter) and cognitive outcomes at 12 and 18 months for placebo and BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every other week, 5 mg / kg every other week, 10 mg / kg every other week, and 10 mg / kg every other week doses, as determined by ADCOMS. [Figure 81] Correlations between change from baseline in PET standardized uptake ratio (normalized to subcortical white matter) and cognitive outcomes at 12 and 18 months for placebo and BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every other week, 5 mg / kg every other week, 10 mg / kg every other week, and 10 mg / kg every other week doses, as determined by CDR-SB. [Figure 82]Correlations between change from baseline in PET standardized uptake ratio (normalized to subcortical white matter) and cognitive outcomes at 12 and 18 months for placebo and BAN2401 at 2.5 mg / kg every other week, 5 mg / kg every other week, 5 mg / kg every other week, 10 mg / kg every other week, and 10 mg / kg every other week doses, as determined by ADAS-Cog. DETAILED DESCRIPTION OF THE INVENTION

[0012] "Amyloid hypothesis" 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 range of conformational states, with species tending to progress from monomeric Aβ to soluble Aβ aggregates (which range from low-molecular-weight oligomers to higher-molecular-weight protofibrils) and ultimately to insoluble fibrils (plaques). Several immunotherapies have been developed to reduce the amount of insoluble Aβ fibrils deposited in the brain. However, a simple correlation between the amount and progressive accumulation of insoluble amyloid plaques and the clinical course of AD remains to be determined. Although 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 characteristics 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).

[0013] It was hypothesized that BAN2401 and other anti-Aβ protofibril antibodies could be used to slow AD progression in subjects with early-stage disease, when amyloid has been deposited in the brain but the downstream neurodegenerative cascade believed to be caused by amyloid deposition is still relatively early in its course (i.e., limited brain tissue loss has occurred and associated clinical impairment is minimal). As disclosed herein, the inventors have discovered a novel method for reducing brain amyloid levels in amyloid-positive, early-stage AD subjects using BAN2401 as an exemplary anti-Aβ protofibril antibody. Also disclosed herein is a novel method for converting amyloid-positive, early-stage AD subjects to amyloid-negative status, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. Also disclosed herein is a method for reducing clinical decline in amyloid-positive, early-stage AD subjects, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. As will be discussed, unexpectedly beneficial results were obtained when subjects were ApoE4 positive.

[0014] Surprisingly and unexpectedly, the inventors have also discovered a method for preventing and / or delaying the onset of AD in a subject with early-stage AD, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subject is ApoE4-positive. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0015] definition The following are definitions of terms used in this application.

[0016] As used herein, the singular terms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0017] The phrase "and / or," as used herein, means "either or both" of the elements so connected, i.e., elements that are present in some cases as a coordinate conjunction and in other cases as a disjunctive conjunction. Thus, as a non-limiting example, "A and / or B," when used in conjunction with open-ended language such as "comprising," in some embodiments refers to A only (optionally including elements other than B); in other embodiments refers to B only (optionally including elements other than A); in yet other embodiments refers to both A and B (optionally including other elements), and so on.

[0018] As used herein, "at least one" means one or more of the elements in a list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than those specifically identified in the list of elements to which the phrase "at least one" refers can optionally be present, whether related or not to the elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B" or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one, optionally including more than one, A, and no B (and optionally including elements other than B); in another embodiment to at least one, optionally including more than one, B, and 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 on.

[0019] When a number is recited alone or as part of a range, it should be understood that the number can vary above and below the stated value by a variance of 10% of the stated value.

[0020] When a range of values ​​is recited herein, it is intended to encompass each value and sub-range 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.

[0021] "Early stage AD" or "early stage Alzheimer's disease," as used herein, refers to a continuum of AD severity ranging from mild cognitive impairment attributable to AD—moderate probability to mild Alzheimer's disease dementia. Subjects with early stage AD include subjects with mild Alzheimer's disease dementia, as defined herein, and subjects with MCI attributable to AD—moderate probability, as defined herein. In some embodiments, subjects with early stage AD have an MMSE score of 22-30 and a CDR composite in the range of 0.5-1.0.

[0022] As used herein, a subject with "mild Alzheimer's disease dementia" refers to a subject who meets the 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.

[0023] As used herein, a subject with "moderate likelihood of MCI due to AD" is one identified as such according to the NIA-AA Core Clinical Criteria for Mild Cognitive Impairment attributable to Alzheimer's Disease (see McKhann, supra). For example, a symptomatic but non-demented AD subject with evidence of cerebral amyloid pathology (and therefore cognitive and functional decline less distinct from and more similar to subjects with mild Alzheimer's disease dementia, as measured by the ADCOMS composite clinical score, as defined herein). Also included 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 a subjective history of memory decline with gradual onset and slow progression over the past year prior to screening, which is corroborated by informants.

[0024] As used herein, "MMSE" refers to the Mini-Mental State Examination, a 30-point cognitive measure commonly used for screening purposes but often used longitudinally in AD clinical trials, with higher scores indicating lower impairment and lower scores indicating higher impairment. As used herein, seven items measuring orientation to time and place, memorization, recall, attention, language, and drawing were assessed (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).

[0025] 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 clinical trials and includes structured measures assessing memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational execution (placing a letter in an envelope), and constructive execution (copying a geometric design) (Rosen, W. Get al., A new rating scale for Alzheimer's disease. Am. J. Psychiatry 1984;141:1356-64). Scores were also obtained for spoken language, language comprehension, word-finding difficulty, ability to recall test instructions, mazes, and digit elimination. The modified version used herein is scored from 0 to 90, with 0 indicating no impairment and 90 indicating maximal impairment.

[0026] As used herein, "CDR-SB" refers to the Clinical Dementia Rating-Sum of Boxes. The CDR is a clinical scale that describes a five-point scale of impairment in executive abilities across six functional categories, including memory, orientation, judgment and problem-solving, community activities, household and hobbies, and personal care (Berg, L. et al., Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment. Ann. Neurol. 1988;23:477-84). The impairment ratings obtained for each of the six functional categories are combined to produce a single overall score (ranging from 0 to 3) for the Dementia CDR score. The item sum score provides an additional measure of change, with each category having a maximum possible score of 3 and the total score being the sum of the category scores, resulting in a total possible score ranging from 0 to 18, with higher scores indicating greater impairment. This overall score can be used as a clinical measure of dementia severity.

[0027] As used herein, "ADCOMS" refers to the Alzheimer's Disease Composite Score, which is a composite clinical score based on an analysis of four ADAS-Cog items (delayed word recall, orientation, word recognition, and word-finding difficulties), two MMSE items (orientation to time and drawing), and all six CDR-SB items (personal care, community activities, home and hobbies, memory, orientation, and judgment and problem solving), as discussed in this example and in Wang, J. et al., ADCOMS: a composite clinical outcome for prodromal Alzheimer's disease trials. J. Neurol. Neurosurg. Psychiatry. 2016;87:993-999. ADCOMS was developed specifically to detect disease progression in early, i.e., prodromal, and mild AD.

[0028] As used herein, "ApoE4-positive" subject and "ApoE4 carrier" refer to a subject who has the ε4 variant of the apolipoprotein E 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 have significantly higher amyloid burden compared to non-carriers (Drzezga, A. et al., Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology. 2009;72:1487-94). In some embodiments, the subject is a heterozygous carrier of the apolipoprotein E ε4 gene allele. In some embodiments, the subject is a homozygous carrier of the apolipoprotein E ε4 gene allele.

[0029] As used herein, whether an early stage AD subject is "amyloid positive" or "amyloid negative" is determined by longitudinal PET assessment of amyloid imaging agent uptake in the brain and / or Aβ 1-42 The determination of amyloid status is based on whether the patient has a positive amyloid burden as indicated by CSF assessment of the presence of amyloid pathology using assessment of markers such as soluble CSF biomarker analysis. In some embodiments, amyloid positivity and amyloid negativity are determined using qualitative visual interpretation of the PET scan by classifying subjects as having either "normal" or "abnormal" uptake based on the PET image pattern. The reader is a qualified individual trained to recognize brain PET images with abnormal or normal uptake patterns, or amyloid detection is performed using semi-quantitative or quantitative techniques.

[0030] As used herein, the term "treat" refers to achieving a beneficial or desired result, including but not limited to a therapeutic benefit (meaning the eradication or amelioration of the underlying condition under treatment or one or more of the physiological symptoms associated therewith).

[0031] As used herein, the term "preventing" refers to achieving a beneficial or desired result, including but not limited to, a preventative benefit. For a preventative benefit, the compositions may be administered to a subject at risk of developing Alzheimer's disease, even if they have not been clinically diagnosed with Alzheimer's disease, to a subject who has one or more pre-symptomatic symptoms of Alzheimer's disease but does not have clinical symptoms, or to a subject who experiences one or more physiological symptoms of Alzheimer's disease. As used herein, "prevention" may also include a therapeutic benefit, which refers to the eradication or amelioration of the underlying condition being treated or one or more physiological symptoms associated therewith.

[0032] Pre-symptomatic AD biomarker levels that may indicate the onset of Alzheimer's disease include, but are not limited to, brain amyloid levels, cerebrospinal fluid Aβ 1-42These include cerebrospinal fluid (CSF) levels, cerebrospinal fluid total tau levels, cerebrospinal fluid neurogranin levels, and cerebrospinal fluid neurofilament light chain levels. For example, subjects with a baseline amyloid PET standardized uptake value ratio (SUVr) of 1.4 to 1.9 treated with the BACE inhibitor elenbecestat (E2609) exhibited the greatest slowing of cognitive decline during treatment. See Lynch, S.Y. et al., "Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease." Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 have not shown sufficient cognitive decline to be detectable, while subjects with SUVr levels above 1.6 appear to correlate with a plateau effect (amyloid levels reach a saturation point and treatment does not change 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.

[0033] As used herein, the term "serious adverse event" or "SAE" means an event observed after administration of a composition described herein that is (1) an event resulting in death; (2) a life-threatening event; (3) an event requiring inpatient hospitalization or extension of an existing hospitalization; (4) an event resulting in persistent or significant disability / incapacity; and / or (5) a congenital anomaly / birth defect.

[0034] The severity of a serious adverse event may be assessed based on an equivalent scale used in the art. For example, the severity of a subject's serious adverse event may be determined according to the National Cancer Institute's "Common Terminology Criteria for Adverse Events" or "CTCAE." A description of the various CTCAE adverse event grades is provided below: Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic findings only; no intervention required. Grade 2: Moderate; minimal local or non-invasive intervention required; age-appropriate limitations in instrumental activities of daily living. - Grade 3: Severe or medically significant but not immediately life-threatening; requiring hospitalization or prolonged hospitalization; disabling; limiting self-care activities of daily living. Grade 4: Life-threatening consequences; urgent intervention required. -Grade 5: Death related to an adverse event.

[0035] As used herein, the term "elenbecestat" refers to the compound N-[3-((4aS,5R,7aS)-2-amino-5-methyl-4a,5,7,7a-tetrahydro-4H-fluro[3,4-d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-difluoromethylpyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof. Elenbecestat is an amyloid precursor protein beta-site cleaving enzyme 1 (BACE1) inhibitor (see, e.g., U.S. Pat. Nos. 8,158,620 and 8,426,584), and is also known as E2609. [ka]

[0036] At least one anti-Aβ protofibril antibody As used herein, the at least one anti-Aβ protofibril antibody is selected from monoclonal antibodies (mAbs) that preferentially bind to large soluble amyloid-β (Aβ) oligomers and / or aggregates (also referred to as protofibrils), e.g., compared to Aβ monomers. See, e.g., Figure 61. As used herein, the term "preferentially binds" refers to a binding potency that is at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, at least 200-fold, at least 225-fold, at least 250-fold, at least 275-fold, or at least "Aβ" refers to an antibody that binds to Aβ oligomers and / or protofibrils with 300-fold, at least 325-fold, at least 350-fold, at least 375-fold, at least 400-fold, at least 425-fold, at least 450-fold, at least 475-fold, at least 500-fold, at least 550-fold, at least 600-fold, at least 650-fold, at least 700-fold, at least 750-fold, at least 800-fold, at least 850-fold, at least 900-fold, at least 950-fold, at least 1000-fold, or at least 1050-fold greater potency. Binding potency to various forms of Aβ can be determined by methods well known in the art, such as ELISA assays and surface plasmon resonance (SPR).

[0037] In some embodiments, the selectivity of the at least one anti-Aβ protofibril antibody is measured by an ELISA assay. In some embodiments, the preferential binding of the at least one anti-Aβ protofibril antibody is measured by surface plasmon resonance.

[0038] In some embodiments, the preferential binding of BAN2401 is measured by an ELISA assay. In some embodiments, the selectivity of BAN2401 is measured by surface plasmon resonance.

[0039] For example, BAN2401 has been shown to bind to Aβ protofibrils with 200-1000 times greater potency than to Aβ monomers, and to bind to Aβ protofibrils with over 40 times greater potency than to Aβ fibrils (see also WO 2007 / 108756 A1, p. 13 and Figure 2; Lord, A. et al., An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease. 2009;26:425-34; and Swanson, CJ et al., Pharmacology of BAN2401: A Monoclonal Antibody Selective for Aβ Protofibrils. Poster P4-286, Alzheimer's Association International Conference, July 13-18, 2013). This potency difference was determined by a sandwich ELISA assay, in which BAN2401 was coated onto wells of a microtiter plate, and increasing concentrations of different Aβ forms were added to the wells. Id. Measurement of bound Aβ forms was performed by adding biotinylated mAb158 and HRP-conjugated streptavidin, and color development was measured according to the manufacturer's protocol. Similarly, BAN2401 was found to have weak affinity for the N-terminal portion of Aβ peptides and Aβ monomers, and no binding to the C-terminal fragment of Aβ was observed. Id. Affinity was determined using a competitive ELISA assay, in which ELISA plates were coated with human Aβ protofibrils and BAN2401, followed by incubation with increasing amounts of different Aβ forms. Id. This incubation mixture was added to microtiter plate wells, allowing free antibody to bind to the immobilized protofibrils within the wells, and bound BAN2401 antibody was measured with a secondary antibody. Id.

[0040] In some embodiments, at least one anti-Aβ protofibril antibody comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3) comprising the amino acid sequences of SEQ ID NO:5 (HCDR1), SEQ ID NO:6 (HCDR2), and SEQ ID NO:7 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:8 (LCDR1), SEQ ID NO:9 (LCDR2), and SEQ ID NO:10 (LCDR3).

[0041] The assignment of amino acids to each domain generally follows the definitions in SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (Kabat et al., 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242, hereinafter referred to as the "Kabat report").

[0042] 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 its allelic variants. The amino acid sequence of a human IgG1 constant region is known in the art and is set forth in SEQ ID NO: 3.

[0043] In some embodiments, the human constant region of at least one anti-Aβ antibody comprises a light chain constant region selected from a κ-λ chain constant region 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:4.

[0044] 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: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. 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: 3 and a light chain constant region comprising the amino acid sequence of SEQ ID NO: 4.

[0045] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. BAN2401 is a humanized IgG1 monoclonal version of mAb158, a murine monoclonal antibody developed to target protofibrils and disclosed in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015). BAN2401 is at least one anti-Aβ protofibril antibody that exhibits low affinity for Aβ monomers but high selectivity for soluble Aβ aggregate species. For example, BAN2401 has been reported to exhibit approximately 1000-fold and 5- to 10-fold higher selectivity for soluble Aβ protofibrils than for Aβ monomers or insoluble Aβ fibrils, respectively.

[0046] BAN2401 comprises (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 2. The full-length sequence of BAN2401 is set forth in SEQ ID NO: 11 and is described in WO 2007 / 108756 and Journal of Alzheimer's Disease 43:575-588 (2015).

[0047] Other non-limiting examples of antibodies suitable for use as the at least one anti-Aβ protofibril antibody in the present disclosure include those disclosed in WO 2002 / 003911, WO 2005 / 123775, WO 2007 / 108756, WO 2011 / 001366, WO 2011 / 104696, and WO 2016 / 005466.

[0048] A therapeutically effective amount of at least one anti-Aβ protofibril antibody The disclosed methods include administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. As used herein, the term "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition sufficient to produce the desired therapeutic effect.

[0049] 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.

[0050] In some embodiments, a therapeutically effective amount is a dose selected to improve and / or maintain efficacy and improve at least one of safety and tolerability, hi some embodiments, a therapeutically effective amount is selected to improve and / or maintain efficacy while reducing at least one side effect.

[0051] In some embodiments, 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 is administered to a subject, based on the subject's body weight.

[0052] In some embodiments, 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 is administered to a subject, based on the subject's body weight.

[0053] In some embodiments, 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 is administered to the subject, based on the subject's body weight.

[0054] In some embodiments, 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 is administered to the subject, based on the subject's body weight.

[0055] In some embodiments, 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 at least one anti-Aβ protofibril antibody is administered to the subject based on the subject's body weight. In some embodiments, 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 the subject's body weight of at least one anti-Aβ protofibril antibody is administered to the subject.

[0056] In some embodiments, the subject is administered 0.5 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 1 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 2 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 2.5 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 3 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 4 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 5 mg / kg of at least one anti-Aβ protofibril antibody based on 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, 12.5 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.In some embodiments, the subject is administered 13 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 14 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 15 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered 21, 22, 23, 24, or 25 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight.

[0057] In some embodiments, 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 is administered to the subject based on the subject's body weight.

[0058] As described, in some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. Thus, in some embodiments, 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 is administered to the subject, based on the subject's body weight.

[0059] In some embodiments, 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 is administered to a subject based on the subject's body weight.

[0060] In some embodiments, 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 is administered to a subject based on the subject's body weight.

[0061] In some embodiments, 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 is administered to the subject based on the subject's body weight.

[0062] In some embodiments, 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 BAN2401 based on the subject's body weight is administered to the subject. In some embodiments, 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 is administered to the subject.

[0063] In some embodiments, the subject is administered 0.5 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 1 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 2 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 3 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the subject is administered 4 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 6 mg / kg of BAN2401 based on the subject's body weight. In some embodiments, the 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, hi some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg / kg of BAN2401 based on the subject's body weight.In some embodiments, the subject is administered 21, 22, 23, 24, or 25 mg / kg of BAN2401 based on the subject's body weight, hi some embodiments, the 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.

[0064] 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.

[0065] Dosing regimen for at least one anti-Aβ protofibril antibody The disclosed methods include administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. 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 dosing regimens. Those skilled in the art will be able to determine the appropriate dosing regimen or regimens for each subject, 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.

[0066] In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered daily, every other day, every three days, weekly, every two weeks (“biweekly”), every four weeks (“every four week period”), monthly, every six weeks, every eight weeks, every two months, every ten weeks, every twelve weeks, every three months, every four weeks, every sixteen weeks, every sixteen weeks, every four months, or every fourteen weeks. The composition may be administered once every 8 weeks, 20 weeks, 5 months, 22 weeks, 24 weeks, 6 months, 8 months, 7 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, or 18 months. In some embodiments, a composition comprising at least one anti-Aβ protofibril antibody is administered daily, every other day, every 3 days, weekly, every 2 weeks ("biweekly"), every 4 weeks ("4-week intervals"), or monthly. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered every 2 weeks or every 4 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, hi some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks.

[0067] 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 a month.

[0068] In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once weekly. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once every two weeks. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once every three weeks. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once every four weeks. In some embodiments, a composition comprising a therapeutically effective amount of BAN2401 is administered once a month.

[0069] 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 a 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.

[0070] In some embodiments, a composition comprising 10 mg / kg of the subject's body weight of at least one anti-Aβ protofibril antibody is administered to the subject once every two weeks, or in some embodiments, a composition comprising 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.

[0071] 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 a week. 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.

[0072] 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 a month.

[0073] 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 composition comprises at least one anti-Aβ protofibril antibody and further comprises at least one additional component. The at least one additional component can be selected from physiologically acceptable excipients suitable for human and / or veterinary use.

[0074] 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 administration route 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 a sterile, non-pyrogenic liquid for intravenous administration. In some embodiments, the compositions are saline solutions.

[0075] In some embodiments, at least one additional ingredient in the composition is selected from a buffer. In some embodiments, at least one additional ingredient in the composition is selected from an emulsifier. In some embodiments, at least one additional ingredient in the composition is selected from sodium citrate, sodium chloride, and 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 chloride may be present at a concentration ranging from 25 mM to 250 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).

[0076] 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 comprises 10 mg / mL of at least one anti-Aβ protofibril antibody, such as BAN2401, 25 mM sodium citrate, 125 mM sodium chloride, and 0.2% (w / v) polysorbate 80, and has a pH of 5.7.

[0077] Treatment effect Reduced clinical decline Provided herein are methods for reducing clinical decline in a subject with early-stage Alzheimer's disease, the method 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 attributable to Alzheimer's disease - moderate probability and / or mild Alzheimer's disease dementia. In some embodiments, the subject with early-stage Alzheimer's disease is ApoE4 positive.

[0078] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions comprising the same disclosed herein may be used in methods for reducing clinical decline in a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, is administered to the subject at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. 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 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.

[0079] 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.

[0080] In some embodiments, clinical decline is reduced by at least 45% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 35% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 30% 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 ADCOMS. In some embodiments, clinical decline is reduced by at least 46% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0081] 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%, 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 In some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood, and the clinical decline is reduced by 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%. 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.

[0082] In some embodiments, clinical decline is reduced by 28% to 33% relative to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 20%, e.g., 25% or at least 28%, relative to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 25%, e.g., at least 30% or at least 33%, relative to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, the clinical decline is reduced by at least 25% compared to placebo, e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52%, as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, the clinical decline is reduced by at least 52% compared to placebo, as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0083] In some embodiments, the clinical decline of a subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 25% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo 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 cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 52% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0084] 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 - Moderate 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.

[0085] In some embodiments, clinical decline is reduced by 28% to 38% compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 20%, e.g., 25%, at least 28%, or at least 33%, compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 25%, e.g., at least 30% or at least 33%, compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 33% compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0086] In some embodiments, clinical decline in a subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 33% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0087] 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% 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 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.

[0088] 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%, e.g., 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%, e.g., 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 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.

[0089] In some embodiments, the clinical decline of a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 50% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 30% 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 ADCOMS. In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 52% 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 ADCOMS. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0090] 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 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.

[0091] 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%, e.g., 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%, e.g., 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 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.

[0092] In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 35% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0093] 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%, 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 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 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.

[0094] 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 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.

[0095] In some embodiments, clinical decline is reduced by at least 100%, e.g., at least 120% or at least 140% compared to placebo as determined by ADAS-cognitive scale (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 is reduced by at least 40%, e.g., at least 45%, compared to placebo as determined by ADAS-cognitive scale (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 is reduced by at least 40%, e.g., at least 45%, compared to placebo as determined by ADAS-cognitive scale (ADAS-cognitive scale) 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-cognitive scale (ADAS-cognitive scale) 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 biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0096] 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%, 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 In some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood, and the clinical decline is reduced by 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%. 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.

[0097] 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 - moderate likelihood. In some embodiments, clinical decline is reduced by at least 50%, e.g., 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 - moderate likelihood. 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 - moderate likelihood. 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.

[0098] In some embodiments, clinical decline in a subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 58% 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 and is administered once every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0099] 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 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.

[0100] In some embodiments, clinical decline is reduced by 30% to 50% compared to placebo as determined by ADAS-cog, and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 35%, e.g., 38%, at least 40%, or at least 41%, compared to placebo as determined by ADAS-cog, and 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 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.

[0101] In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 41% 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0102] 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 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.

[0103] 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%, e.g., at least 26% or at least 28%, as determined by CDR-SB. In some embodiments, clinical decline is reduced by at least 30%, e.g., at least 35% or at least 38%, as determined by CDR-SB. 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.

[0104] In some embodiments, clinical decline is reduced by at least 30%, e.g., 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%, e.g., 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%, e.g., 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0105] 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 - likely moderate. 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.

[0106] 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 attributable to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 5%, e.g., 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 attributable to Alzheimer's disease - moderate likelihood. 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 attributable to Alzheimer's disease - moderate likelihood. 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.

[0107] In some embodiments, a subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood - 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0108] 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%, 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 recited 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.

[0109] In some embodiments, clinical decline is reduced by 40% to 60% compared to placebo as determined by CDR-SB, and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 45%, e.g., 48%, at least 50%, or at least 51%, compared to placebo as determined by CDR-SB, and 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 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.

[0110] In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 51% 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0111] 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.

[0112] 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.

[0113] In some embodiments, the reduction in clinical decline is determined after administration of a composition comprising a therapeutically effective amount of BAN2401.

[0114] 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.

[0115] In some embodiments, the subject is ApoE4 positive.

[0116] 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% less than placebo as determined by ADCOMS. 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 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.

[0117] In some embodiments, clinical decline is reduced by 60% to 80%, e.g., 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%, e.g., 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%, e.g., 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%, e.g., at least 74%, compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive.

[0118] In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 70% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 60% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 50%, e.g., at least 55% or at least 60%, 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 ADCOMS. In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 63% 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 ADCOMS. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0119] 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%, 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 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%, 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%, 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 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 protofibril antibody.

[0120] In some embodiments, clinical decline is reduced by 70% to 400%, e.g., 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%, e.g., 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%, e.g., 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%, e.g., at least 330%, compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 positive. 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.

[0121] In some embodiments, the clinical decline of an ApoE4-positive subject 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, the clinical decline of an ApoE4-positive subject is reduced by at least 80%, e.g., 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, the clinical decline of an ApoE4-positive subject is reduced by at least 70%, e.g., 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 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 and is administered once every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0122] 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%, 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 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 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.

[0123] In some embodiments, clinical decline is reduced by 35% to 150%, e.g., 40% to 100% or 45% to 90%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 35%, e.g., at least 40% or at least 45%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 50%, e.g., at least 55% or at least 60%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 70%, e.g., at least 80% or at least 85%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. 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.

[0124] In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 35%, e.g., 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, the clinical decline of an ApoE4-positive subject is reduced by at least 70%, e.g., 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, the clinical decline of an ApoE4-positive subject is reduced by at least 50%, e.g., 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 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0125] 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%, 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 2%, 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0126] In some embodiments, clinical decline is reduced by 30% to 70%, e.g., 38% to 59%, relative to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 30%, e.g., at least 35% or at least 38%, relative to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 45%, e.g., at least 50% or at least 53%, relative to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 50%, e.g., at least 55% or at least 59% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0127] In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 50%, e.g., 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, the clinical decline of an ApoE4-positive subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 30%, e.g., 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, the clinical decline of an ApoE4-positive subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 45%, e.g., 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 biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0128] 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%, 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 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. ,

[0129] In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, e.g., 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, the clinical decline of an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 100%, e.g., 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, the clinical decline of an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, e.g., 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 biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0130] 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%, 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 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%, 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0131] In some embodiments, clinical decline is reduced by 40% to 300%, e.g., 45% to 250%, or 50% to 250%, relative to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 40%, e.g., at least 45% or at least 50%, relative to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 60%, e.g., at least 70%, at least 75%, or at least 80%, relative to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 100%, e.g., at least 150% or at least 200% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0132] In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 100%, e.g., at least 150%, or at least 200%, relative to placebo, after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 40%, e.g., at least 45%, or at least 50%, relative to placebo, 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 - moderate likelihood is reduced by at least 50%, e.g., 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0133] 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%, 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 5%, 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0134] In some embodiments, clinical decline is reduced by 20% to 90%, e.g., 25% to 80%, or 30% to 75%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 25%, e.g., at least 30%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 30%, e.g., at least 35% or 40%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, the clinical decline is reduced by at least 35%, e.g., at least 40% or 45%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0135] In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 35%, e.g., 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, the clinical decline of an ApoE4-positive subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 20%, e.g., 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 an ApoE4-positive subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood, is reduced by at least 35%, e.g., 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0136] 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%, 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 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 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.

[0137] 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 wherein the subject has been 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 wherein the subject has been 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 wherein the subject has been 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 wherein 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.

[0138] 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%, 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 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%, 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 wherein 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.

[0139] 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 wherein the subject has been diagnosed with mild Alzheimer's 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 wherein the subject has been diagnosed with mild Alzheimer's 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 wherein the subject has been diagnosed with mild Alzheimer's 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 wherein the subject has been diagnosed with mild Alzheimer's 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.

[0140] 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%, 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 wherein 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.

[0141] In some embodiments, clinical decline is reduced by 70% to 200%, e.g., 75% to 180% or 82% to 174%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 70%, e.g., at least 80%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 75%, e.g., at least 80% or at least 85%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, the clinical decline is reduced by at least 150%, e.g., at least 160% or 170%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4-positive 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.

[0142] In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70%, e.g., at least 75%, at least 80%, or at least 85%, relative 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, the clinical decline of an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 130%, e.g., at least 140%, at least 150%, at least 160%, or at least 170%, relative to placebo, as determined by CDR-SB. In some embodiments, clinical decline in an ApoE4-positive subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 65%, e.g., 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0143] In some embodiments, the subject is ApoE4 negative.

[0144] 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-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.

[0145] 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%, e.g., 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%, e.g., 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.

[0146] In some embodiments, the clinical decline of an ApoE4-negative subject is reduced by at least -2% 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, the clinical decline of an ApoE4-negative subject is reduced by at least 10% 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, the clinical decline of an ApoE4-negative subject is reduced by at least 5%, e.g., at least 7%, 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 clinical decline of an ApoE4-negative subject is reduced by at least 7% 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 biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0147] 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%, or less compared to 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 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.

[0148] 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%, e.g., 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%, e.g., 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%, e.g., 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 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.

[0149] 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-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.

[0150] In some embodiments, clinical decline is reduced by 3% compared to placebo as determined by CDR-SB, and 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. 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - likely moderate. 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.

[0151] 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by 15% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 negative, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by 26% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 negative, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0152] 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%, 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 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%, 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 / 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%, or at least 166%, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0153] In some embodiments, clinical decline is reduced by 50% to 200%, e.g., 60% to 180% or 65% to 170% compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 50%, e.g., at least 55% or at least 65%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 70%, e.g., at least 75% or at least 80%, compared to placebo as determined by ADAS-Cog, wherein the subject is ApoE4 negative and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, the clinical decline is reduced by at least 150%, e.g., at least 160%, relative to placebo as determined by ADAS-Cog, wherein the subject is ApoE4-negative and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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, the clinical decline of an ApoE4-negative subject is reduced by at least 150%, e.g., 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, the clinical decline of an ApoE4-negative subject is reduced by at least 70%, e.g., 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, the clinical decline of an ApoE4-negative subject is reduced by at least 50%, e.g., 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0155] 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0156] 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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 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 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, the clinical decline is reduced by at least 10%, e.g., at least 12%, compared to placebo as determined by CDR-SB, wherein the subject is ApoE4-negative 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.

[0159] Conversion of an amyloid-positive to amyloid-negative subject Also provided herein are 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 attributable to Alzheimer's disease - moderate probability and / or mild Alzheimer's disease dementia.

[0160] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions comprising the same disclosed herein 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, is administered to a subject at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0161] In some embodiments, administration of the composition may result in an improvement in amyloid PET levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, 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 levels as determined by visual interpretation of amyloid PET images. , 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.

[0162] In some embodiments, administration of the composition results in 50% to 100%, or 60% to 90% of subjects converting from amyloid-positive to amyloid-negative status, as determined by visual review of amyloid PET images. In some embodiments, administration of the composition results in at least 55%, e.g., 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%, e.g., 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 biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0163] In some embodiments, administration of the composition may result in an improvement in amyloid PET levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, 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 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 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 will be amyloid negative, and wherein the subjects are ApoE4 positive.

[0164] In some embodiments, administration of the composition results in 75% to 100%, e.g., 80% to 100%, or 85% to 100% of subjects becoming amyloid negative as determined by visual interpretation of amyloid PET images, wherein the subjects are ApoE4 positive. In some embodiments, administration of the composition results in at least 75%, e.g., at least 80% or at least 85%, of subjects becoming amyloid negative as determined by visual interpretation of amyloid PET images, wherein the subjects are ApoE4 positive. In some embodiments, administration of the composition results in 100% of subjects becoming amyloid negative as determined by visual interpretation of amyloid PET images, wherein the subjects are ApoE4 positive.

[0165] In some embodiments, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, at least 75%, e.g., at least 80%, or at least 85%, of ApoE4-positive subjects are amyloid-negative as determined by visual interpretation of amyloid PET images. In some embodiments, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, at least 75%, e.g., at least 80%, at least 85%, at least 90%, or at least 95% of ApoE4-positive subjects are amyloid-negative as determined by visual interpretation 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0166] 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 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 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 the subjects are ApoE4 negative.

[0167] In some embodiments, administration of the composition results in 50% to 100%, e.g., 55% to 90%, of the subject being amyloid negative as determined by visual review of amyloid PET images, wherein the subject is ApoE4 negative. In some embodiments, administration of the composition results in at least 50% of the subject being amyloid negative as determined by visual review of amyloid PET images, wherein the subject is ApoE4 negative. In some embodiments, administration of the composition results in at least 70% of the subject being amyloid negative as determined by visual review of amyloid PET images, wherein the subject is ApoE4 negative.

[0168] In some embodiments, clinical decline is reduced by 35% to 50% relative to placebo as determined by ADCOMS, wherein the subject is not concurrently administered at least one Alzheimer's medication other than BAN2401. In some embodiments, clinical decline is reduced by at least 35%, e.g., 38%, at least 40%, or at least 41% relative to placebo as determined by ADCOMS, wherein the subject is not concurrently administered at least one Alzheimer's medication other than BAN2401. In some embodiments, clinical decline is reduced by at least 41% relative to placebo as determined by ADCOMS, wherein the subject is not concurrently administered at least one Alzheimer's medication other than BAN2401. 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 other than BAN2401.

[0169] In some embodiments, clinical decline in subjects not receiving at least one concomitant Alzheimer's medication is reduced by at least 41% 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 ADCOMS. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0170] 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 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 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 not concurrently administered at least one Alzheimer's medication. In some embodiments, the recited 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.

[0171] In some embodiments, clinical decline is reduced by 50% to 70% compared to placebo as determined by ADAS-cognitive scale, where the subject is not concurrently receiving at least one Alzheimer's medication. In some embodiments, clinical decline is reduced by at least 50%, e.g., 55%, at least 57%, or at least 59%, compared to placebo as determined by ADAS-cognitive scale, where the subject is not concurrently receiving at least one Alzheimer's medication. In some embodiments, clinical decline is reduced by at least 59% compared to placebo as determined by ADAS-cognitive scale, where the subject is not concurrently receiving at least one Alzheimer's medication. 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.

[0172] In some embodiments, clinical decline in subjects not receiving concomitant administration of at least one Alzheimer's medication is reduced by at least 59% 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-cognitive disorder (ADAS-cog). In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0173] 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% compared to placebo as determined by CDR-SB. , 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%, or at least 45%, wherein the subject is not concurrently administered at least one Alzheimer's medication. 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.

[0174] In some embodiments, clinical decline is reduced by 50% to 70% compared to placebo as determined by ADAS-cog, where the subject is not concurrently administered at least one Alzheimer's medication. In some embodiments, clinical decline is reduced by at least 35%, e.g., 40%, at least 42%, or at least 45%, compared to placebo as determined by CDR-SB, where the subject is not concurrently administered at least one Alzheimer's medication. In some embodiments, clinical decline is reduced by at least 45% compared to placebo as determined by CDR-SB, where the subject is not concurrently administered at least one Alzheimer's medication. 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.

[0175] In some embodiments, clinical decline in subjects not receiving concomitant administration of at least one Alzheimer's medication is reduced by at least 45% 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0176] Coadministration of at least one anti-Aβ protofibril antibody with at least one Alzheimer's disease medication other than BAN2401 In some embodiments, provided herein are methods of reducing clinical decline in a subject with early Alzheimer's disease, comprising simultaneously administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody and a therapeutically effective amount of at least one Alzheimer's medication other than BAN2401. In some embodiments, the 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%, or at least 23% compared to placebo as determined by ADCOMS. 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.

[0177] In some embodiments, clinical decline is reduced by 15% to 30% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 15%, e.g., 20%, at least 21%, or at least 23% compared to placebo as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 23% compared to placebo 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.

[0178] In some embodiments, a subject receiving a therapeutically effective amount of at least one anti-Aβ protofibril antibody concurrently with a therapeutically effective amount of at least one Alzheimer's medication other than BAN2401 experiences at least a 23% reduction in clinical decline compared to placebo after 18 months of administration of the therapeutically effective amount of the at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, 10 mg / kg of the at least one anti-Aβ protofibril antibody is administered once every two weeks or once monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's medication is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's medication is a combination of donepezil and memantine.

[0179] 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.

[0180] 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.

[0181] 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% compared to placebo as determined by ADCOMS. 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 therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0182] 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%, or at least 39% compared to placebo as determined by ADAS-cog, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. 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.

[0183] In some embodiments, clinical decline is reduced by 30% to 50% compared to placebo as determined by ADAS-cognitive scale, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. In some embodiments, clinical decline is reduced by at least 30%, e.g., at least 35%, at least 37%, or at least 39%, compared to placebo as determined by ADAS-cognitive scale, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. In some embodiments, clinical decline is reduced by at least 39% compared to placebo as determined by ADAS-cognitive scale, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. 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.

[0184] In some embodiments, subjects concurrently receiving at least one Alzheimer's medication experience at least a 39% 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-cognitive disorder (ADAS-cognitive scale). In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's medication is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's medication is a combination of donepezil and memantine.

[0185] 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.

[0186] 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.

[0187] 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%, or at least 20% compared to placebo as determined by CDR-SB, wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. In some embodiments, the above-recited 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.

[0188] In some embodiments, clinical decline is reduced by 10% to 30% relative to placebo as determined by CDR-SB, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. In some embodiments, clinical decline is reduced by at least 10%, e.g., at least 15%, at least 17%, or at least 20%, relative to placebo as determined by CDR-SB, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. In some embodiments, clinical decline is reduced by at least 20% relative to placebo as determined by CDR-SB, and wherein the subject is concomitantly administered at least one Alzheimer's medication other than BAN2401. 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.

[0189] In some embodiments, subjects concurrently receiving at least one Alzheimer's medication experience at least a 20% 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's medication is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's medication is a combination of donepezil and memantine.

[0190] 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.

[0191] 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.

[0192] Reduced brain amyloid levels Also provided herein are methods for reducing brain amyloid levels in a subject in need thereof, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein.

[0193] 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 involving Aβ peptide-containing soluble and / or insoluble Aβ aggregates.

[0194] 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 thus the methods disclosed herein may be beneficial to 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)).

[0195] In some embodiments, the subject with early stage Alzheimer's disease has been diagnosed with mild cognitive impairment attributable to Alzheimer's disease - moderate probability and / or mild Alzheimer's disease dementia. In some embodiments, the subject with early stage Alzheimer's disease is ApoE4 positive.

[0196] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions containing the same disclosed herein may be used in methods for reducing brain amyloid levels in subjects with early Alzheimer's disease. For example, in some embodiments, a composition containing at least one anti-Aβ protofibril antibody, such as BAN2401, is administered to a subject at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0197] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0198] In some embodiments, the method reduces brain amyloid levels after administration compared to the brain amyloid levels before administration. In some embodiments, the brain amyloid levels are 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 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 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 interpretation of amyloid PET images and expressed as PET standardized uptake value ratios (SUVr values).

[0199] 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 determine the effect of at least one anti-AB antibody on amyloid levels in the brain, both by whole brain analysis (e.g., an average of five to six cortical regions) and brain regional analysis. In some embodiments, the subject's adjusted mean change from baseline in PET SUVr values ​​is reduced by at least -0.10, at least -0.15, at least -0.20, at least -0.25, at least -0.30, at least -0.35, at least -0.40, at least -0.45, at least -0.50, at least -0.55, at least -0.60, at least -0.65, at least -0.70, at least -0.75, at least -0.80, at least -0.85, at least -0.90, or at least -0.95 compared to baseline. In some embodiments, the subject's adjusted mean change from baseline in PET SUVr value is a decrease of between -0.20 and -0.30.

[0200] In some embodiments, the subject's mean change from baseline in adjusted PET SUVr values, comparing global cortex averages to whole cerebellum reference values, is reduced by at least -0.20, e.g., at least -0.25, 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 subject's mean change from baseline in adjusted PET SUVr values, comparing global cortex averages to whole cerebellum reference values, is reduced by at least -0.25, e.g., at least -0.30, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0201] In some embodiments, the reduction in amyloid in the brain is determined by PET imaging using radioactive tracer binding to brain Aβ amyloid. In some embodiments, the adjusted mean change reduction from baseline is at least −50, e.g., at least −55, or at least −59 centiloids, 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 adjusted mean change reduction from baseline is at least −60, e.g., at least −65, or at least −70 centiloids, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0202] In some embodiments, the method provides for the determination of cerebrospinal fluid Aβ prior to the administration. 1-42 CSF Aβ levels compared with 1-42 In some embodiments, the method reduces the level of cerebrospinal fluid Aβ before the administration. 1-42at 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% less than the level 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 cerebrospinal fluid Aβ 1-42 A reduction in the level occurs.

[0203] In some embodiments, administration of the composition results in a reduction in brain amyloid levels of -0.20 to -0.45, for example -0.25 to -0.35, as determined by visual reading of amyloid PET images, wherein the subject is ApoE4 positive. In some embodiments, administration of the composition results in a reduction in brain amyloid levels of at least -0.25, as determined by visual reading of amyloid PET images, wherein the subject is ApoE4 positive. In some embodiments, administration of the composition results in a reduction in brain amyloid levels of at least 0.30, as determined by visual reading of amyloid PET images, wherein the subject is ApoE4 positive.

[0204] In some embodiments, administration of the composition results in a reduction in brain amyloid levels of at least −0.01, at least −0.02, at least −0.03, at least −0.04, at least −0.05, at least −0.06, at least −0.07, at least −0.08, at least −0.09, at least −0.10, at least −0.11, at least −0.12, at least −0.13, at least −0.14, at least −0.15, at least −0.16, at least −0.17, at least −0.18, at least −0.19, at least −0.20, at least −0.21, at least −0.22, at least −0.23, at least −0.24, at least −0.25, at least −0.26, at least −0.27, at least −0.28, or at least −0.29 compared to placebo as determined by visual interpretation of amyloid PET images, wherein the subject is ApoE4 negative.

[0205] In some embodiments, administration of the composition results in a reduction in brain amyloid levels of -0.10 to -0.40 as determined by visual reading of amyloid PET images, wherein the subject is ApoE4 negative. In some embodiments, administration of the composition results in a reduction in brain amyloid levels of at least -0.20 as determined by visual reading of amyloid PET images, wherein the subject is ApoE4 negative. In some embodiments, administration of the composition results in a reduction in brain amyloid levels of at least -0.25 as determined by visual reading of amyloid PET images, wherein the subject is ApoE4 negative.

[0206] Biomarker changes Cerebrospinal fluid neurogranin levels In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels in the subject, hi some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% compared to baseline.

[0207] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% compared to baseline after 18 months of administration of the composition.

[0208] In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid neurogranin levels by at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL compared to baseline. In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid neurogranin levels by at least about 65 pg / mL compared to baseline.

[0209] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels by at least about 25 pg / mL, at least about 30 pg / mL, at least about 35 pg / mL, at least about 40 pg / mL, at least about 45 pg / mL, at least about 50 pg / mL, at least about 55 pg / mL, at least about 60 pg / mL, or at least about 65 pg / mL relative to baseline after 18 months of administration of the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurogranin levels by at least 65 pg / mL relative to baseline after 18 months of administration of the composition.

[0210] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0211] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered biweekly or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered biweekly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0212] Cerebrospinal fluid neurofilament light chain levels In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid neurofilament light chain levels relative to placebo, hi some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid neurofilament light chain levels by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% relative to placebo.

[0213] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurofilament light chain levels relative to placebo after 18 months of administration of the composition. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid neurofilament light chain levels relative to baseline by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50% relative to placebo after 18 months of administration of the composition.

[0214] In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in the production of cerebrospinal fluid neurofilament light chain levels greater than about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, or about 75 pg / mL relative to baseline. In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in the production of cerebrospinal fluid neurofilament light chain levels of about 75 pg / mL or less relative to baseline.

[0215] In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in the production of cerebrospinal fluid neurofilament light chain levels greater than about 35 pg / mL, about 40 pg / mL, about 45 pg / mL, about 50 pg / mL, about 55 pg / mL, about 60 pg / mL, about 65 pg / mL, about 70 pg / mL, or about 75 pg / mL relative to baseline after 18 months of administration of the composition. In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in the production of cerebrospinal fluid neurofilament light chain levels less than about 75 pg / mL relative to baseline after 18 months of administration of the composition.

[0216] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0217] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is 10 mg / kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered biweekly or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered biweekly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0218] Cerebrospinal fluid phospho-tau levels In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau levels. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline.

[0219] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau levels after 18 months of administration of the composition. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau levels of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0220] In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid phospho-tau levels of at least about 65 pg / mL, at least about 70 pg / mL, at least about 75 pg / mL, at least about 80 pg / mL, at least about 85 pg / mL, at least about 90 pg / mL, or at least about 95 pg / mL compared to baseline. In some embodiments, administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein to a subject results in a reduction in cerebrospinal fluid phospho-tau levels of at least about 95 pg / mL compared to baseline.

[0221] In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau levels by at least about 65 pg / mL, at least about 70 pg / mL, at least about 75 pg / mL, at least about 80 pg / mL, at least about 85 pg / mL, at least about 90 pg / mL, or at least about 95 pg / mL relative to baseline after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, administering to a subject a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein results in a reduction in cerebrospinal fluid phospho-tau levels by at least 95 pg / mL relative to baseline after 18 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody.

[0222] In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0223] In some embodiments, the therapeutically effective amount of at least one anti-Aβ protofibril antibody is 10 mg / kg. In some embodiments, a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein is administered biweekly or monthly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered biweekly. In some embodiments, a composition comprising 10 mg / kg of BAN2401 is administered monthly.

[0224] Treatment for Alzheimer's disease Reduced clinical decline Provided herein are methods for treating 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, wherein the subject's clinical decline is reduced by at least 35% compared to placebo as determined by ADCOMS after 6 months of administration of the composition, at least 30% compared to placebo as determined by ADCOMS after 12 months of administration of the composition, and / or at least 25% compared to placebo as determined by ADCOMS after 18 months of administration of the composition. In some embodiments, the subject with early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment attributable to Alzheimer's disease—moderate probability and / or mild Alzheimer's disease dementia. In some embodiments, the subject with early-stage Alzheimer's disease is ApoE4 positive.

[0225] Any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions comprising the same disclosed herein may be used in methods for reducing clinical decline in a subject with early Alzheimer's disease. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, is administered to the subject at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg of the subject's body weight once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In some embodiments, clinical decline is reduced by 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-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.

[0226] 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.

[0227] In some embodiments, clinical decline is reduced by at least 45% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 35% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, clinical decline is reduced by at least 30% 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 ADCOMS. In some embodiments, clinical decline is reduced by at least 46% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0228] 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%, 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 In some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood, and the clinical decline is reduced by 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%. 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.

[0229] In some embodiments, clinical decline is reduced by 28% to 33% relative to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 20%, e.g., 25% or at least 28%, relative to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 25%, e.g., at least 30% or at least 33%, relative to placebo as determined by ADCOMS, and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, the clinical decline is reduced by at least 25% compared to placebo, e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52%, as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, the clinical decline is reduced by at least 52% compared to placebo, as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0230] In some embodiments, the clinical decline of a subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 25% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo 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 cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 52% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0231] 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 - Moderate 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.

[0232] In some embodiments, clinical decline is reduced by 28% to 38% compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 20%, e.g., 25%, at least 28%, or at least 33%, compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 25%, e.g., at least 30% or at least 33%, compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 33% compared to placebo as determined by ADCOMS, and the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0233] In some embodiments, clinical decline in a subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 33% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0234] 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% 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 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.

[0235] 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%, e.g., 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%, e.g., 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 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.

[0236] In some embodiments, the clinical decline of a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 70% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 50% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of a subject diagnosed with mild Alzheimer's disease dementia is reduced by at least 30% 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 ADCOMS. In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 52% 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 ADCOMS. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0237] 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 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.

[0238] 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%, e.g., 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%, e.g., 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 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.

[0239] In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 35% 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 ADCOMS. 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0240] 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%, 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 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 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.

[0241] 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 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.

[0242] In some embodiments, clinical decline is reduced by at least 100%, e.g., at least 120% or at least 140% compared to placebo as determined by ADAS-cognitive scale (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 is reduced by at least 40%, e.g., at least 45%, compared to placebo as determined by ADAS-cognitive scale (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 is reduced by at least 40%, e.g., at least 45%, compared to placebo as determined by ADAS-cognitive scale (ADAS-cognitive scale) 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-cognitive scale (ADAS-cognitive scale) 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 biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0243] 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%, 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 In some embodiments, the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood, and the clinical decline is reduced by 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%. 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.

[0244] 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 - moderate likelihood. In some embodiments, clinical decline is reduced by at least 50%, e.g., 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 - moderate likelihood. 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 - moderate likelihood. 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.

[0245] In some embodiments, clinical decline in a subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood is reduced by at least 58% 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 and is administered once every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0246] 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 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.

[0247] In some embodiments, clinical decline is reduced by 30% to 50% compared to placebo as determined by ADAS-cog, and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 35%, e.g., 38%, at least 40%, or at least 41%, compared to placebo as determined by ADAS-cog, and 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 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.

[0248] In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 41% 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0249] 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 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.

[0250] 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%, e.g., at least 26% or at least 28%, as determined by CDR-SB. In some embodiments, clinical decline is reduced by at least 30%, e.g., at least 35% or at least 38%, as determined by CDR-SB. 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.

[0251] In some embodiments, clinical decline is reduced by at least 30%, e.g., 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%, e.g., 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%, e.g., 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 a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0252] 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 - likely moderate. 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.

[0253] 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 attributable to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 5%, e.g., 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 attributable to Alzheimer's disease - moderate likelihood. 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 attributable to Alzheimer's disease - moderate likelihood. 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.

[0254] In some embodiments, a subject diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood - 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0255] 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%, 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 recited 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.

[0256] In some embodiments, clinical decline is reduced by 40% to 60% compared to placebo as determined by CDR-SB, and the subject has been diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical decline is reduced by at least 45%, e.g., 48%, at least 50%, or at least 51%, compared to placebo as determined by CDR-SB, and 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 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.

[0257] In some embodiments, a subject diagnosed with mild Alzheimer's disease dementia experiences at least a 51% 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0258] 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.

[0259] 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.

[0260] In some embodiments, the reduction in clinical decline is determined after administration of a composition comprising a therapeutically effective amount of BAN2401.

[0261] 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.

[0262] In some embodiments, the subject is ApoE4 positive.

[0263] 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% less than placebo as determined by ADCOMS. 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 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.

[0264] In some embodiments, clinical decline is reduced by 60% to 80%, e.g., 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%, e.g., 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%, e.g., 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%, e.g., at least 74%, compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive.

[0265] In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 70% compared to placebo after 6 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 60% compared to placebo after 12 months of administration of a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by ADCOMS. In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 50%, e.g., at least 55% or at least 60%, 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 ADCOMS. In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 63% 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 ADCOMS. In some embodiments, the composition comprises 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered biweekly or monthly, hi some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0266] 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%, 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 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%, 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%, 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 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 protofibril antibody.

[0267] In some embodiments, clinical decline is reduced by 70% to 400%, e.g., 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%, e.g., 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%, e.g., 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%, e.g., at least 330%, compared to placebo as determined by ADAS-cog, wherein the subject is ApoE4 positive. 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.

[0268] In some embodiments, the clinical decline of an ApoE4-positive subject 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, the clinical decline of an ApoE4-positive subject is reduced by at least 80%, e.g., 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, the clinical decline of an ApoE4-positive subject is reduced by at least 70%, e.g., 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 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 and is administered once every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0269] 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%, 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 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 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.

[0270] In some embodiments, clinical decline is reduced by 35% to 150%, e.g., 40% to 100% or 45% to 90%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 35%, e.g., at least 40% or at least 45%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 50%, e.g., at least 55% or at least 60%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. In some embodiments, clinical decline is reduced by at least 70%, e.g., at least 80% or at least 85%, relative to placebo as determined by CDR-SB, wherein the subject is ApoE4 positive. 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.

[0271] In some embodiments, the clinical decline of an ApoE4-positive subject is reduced by at least 35%, e.g., 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, the clinical decline of an ApoE4-positive subject is reduced by at least 70%, e.g., 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, the clinical decline of an ApoE4-positive subject is reduced by at least 50%, e.g., 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 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 and is administered biweekly or monthly. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0272] 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%, 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 2%, 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 wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0273] In some embodiments, clinical decline is reduced by 30% to 70%, e.g., 38% to 59%, relative to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 30%, e.g., at least 35% or at least 38%, relative to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 45%, e.g., at least 50% or at least 53%, relative to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. In some embodiments, clinical decline is reduced by at least 50%, e.g., at least 55% or at least 59% compared to placebo as determined by ADCOMS, wherein the subject is ApoE4 positive and wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate likelihood. 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.

[0274] In some embodiments, the clinical decline of an ApoE4-positive subject diagnosed with a moderate likelihood of mild cognitive impairment due to Alzheimer's disease is reduced by at least 50%, e.g., at least 55%, compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition comprising a therapeutically effective amount...

Claims

1. 1. A composition for reducing clinical decline in a subject with early Alzheimer's disease by at least 26% compared to placebo after 18 months of treatment as determined by ADAS-Cog, comprising a therapeutically effective amount of an anti-Aβ protofibril antibody; 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:5 (HCDR1), SEQ ID NO:6 (HCDR2), and SEQ ID NO:7 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:8 (LCDR1), SEQ ID NO:9 (LCDR2), and SEQ ID NO:10 (LCDR3); The composition comprises a dose of 10 mg / kg of the anti-Aβ protofibril antibody based on the subject's body weight and is administered to the subject once every two weeks. composition.

2. 2. The composition of claim 1, wherein the subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate probability, or has been diagnosed with mild Alzheimer's disease dementia.

3. The composition of claim 1 or 2, wherein the anti-Aβ protofibril antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

2.

4. The composition of any one of claims 1 to 3, wherein the anti-Aβ protofibril antibody comprises a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO:

12.

5. Aβ １－４２ , total tau, phosphotau or neurogranin levels are measured; Compared to pre-treatment levels, １－４２ The composition of any one of claims 1 to 4, wherein if levels exceed or total tau, phosphotau or neurogranin levels fall below, a further dose of the anti-Aβ protofibril antibody is administered.

6. The composition according to any one of claims 1 to 5, adapted to be administered without titration.

7. The composition according to any one of claims 1 to 6, used in combination with at least one maintenance therapy.

8. 8. The method of claim 7, wherein the at least one maintenance therapy is administered after 18 months of treatment.

9. The composition of claim 7, wherein the subject is administered the at least one maintenance therapy after becoming amyloid negative.

10. The composition of any one of claims 7 to 9, wherein the at least one maintenance therapy comprises the anti-Aβ protofibril antibody.

11. The method of claim 10, wherein the at least one maintenance therapy is administered subcutaneously.

12. The composition described in claim 11, wherein at least one maintenance therapy is administered once a week.

13. The method of claim 10, wherein the at least one maintenance therapy is administered intravenously.

14. The composition described in claim 13, wherein at least one of the maintenance therapies is administered once every two weeks.

15. 14. The method of claim 13, wherein the at least one maintenance therapy is administered once every four weeks.

16. The composition described in claim 13, wherein at least one maintenance therapy is administered once a month.

17. The composition of any one of claims 13 to 16, wherein the at least one maintenance therapy comprises a dose of 10 mg / kg of the anti-Aβ protofibril antibody based on the subject's body weight.

18. The composition according to any one of claims 1 to 17, comprising sodium chloride.

19. 19. The composition of any one of claims 1 to 18, wherein the clinical decline is reduced by at least 47% compared to placebo as determined by ADAS-Cog 18 months after administration of the composition.

20. A composition described in any one of claims 1 to 19, wherein the clinical decline is reduced by at least 25% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

21. The composition of any one of claims 1 to 20, wherein the clinical decline is reduced by at least 26% compared to placebo as determined by CDR-SB 18 months after administration of the composition.

22. The composition of any one of claims 1 to 20, wherein the clinical decline is reduced by at least 27% compared to placebo as determined by CDR-SB 18 months after administration of the composition.

23. 21. The composition of any one of claims 1 to 20, wherein the clinical decline is reduced by 25-60% compared to placebo as determined by CDR-SB 18 months after administration of the composition.

24. 21. The composition of any one of claims 1 to 20, wherein the clinical decline is reduced by 25-50% compared to placebo as determined by CDR-SB 18 months after administration of the composition.

25. A composition described in any one of claims 1 to 24, wherein the clinical decline is reduced by 24% compared to placebo as determined by ADCOMS 18 months after administration of the composition.

26. A composition described in any one of claims 1 to 24, wherein the clinical decline is reduced by 30% compared to placebo as determined by ADCOMS 18 months after administration of the composition.

27. ​​A composition described in any one of claims 1 to 26, wherein the reduction in clinical decline comprises a reduction in brain amyloid levels as determined by visual interpretation of amyloid PET images and expressed as a PET standard uptake ratio (SUVr value), and the subject's PET SUVr value has an adjusted mean change from baseline of at least -0.

20.

28. A composition described in any one of claims 1 to 27, wherein the reduction in clinical decline comprises a reduction in brain amyloid levels as determined by visual interpretation of amyloid PET images and expressed as a PET standard uptake value ratio (SUVr value), and the subject's PET SUVr value has an adjusted mean change from baseline of at least -0.

25.

29. The composition of any one of claims 1 to 28, wherein the reduction in clinical decline comprises a reduction in brain amyloid levels as determined by visual interpretation of amyloid PET images and expressed as a PET standard uptake ratio (SUVr value), and the subject's PET SUVr value has an adjusted mean change from baseline of at least -0.

30.

30. The composition of any one of claims 1 to 29, wherein the subject is not receiving concomitant administration of a medication for Alzheimer's disease other than the anti-Aβ protofibril antibody.

31. The composition of any one of claims 1-30, wherein the subject is monitored for ARIA-E and ARIA-H.

32. The composition of claim 31, wherein treatment is continued or discontinued if ARIA-E or ARIA-H is detected.

33. 33. The composition of claim 31 or 32, wherein monitoring comprises evaluating the subject three months after administration of the composition.

34. 1. A composition for reducing clinical decline in a subject with early Alzheimer's disease by at least 25% compared to placebo as determined by CDR-SB 18 months after administration of the composition, the composition comprising a therapeutically effective amount of an anti-Aβ protofibril antibody; 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:5 (HCDR1), SEQ ID NO:6 (HCDR2), and SEQ ID NO:7 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:8 (LCDR1), SEQ ID NO:9 (LCDR2), and SEQ ID NO:10 (LCDR3); The composition comprises a dose of the anti-Aβ protofibril antibody of 10 mg / kg based on the body weight of the subject, and is administered to the subject once every two weeks. composition.

35. The composition described in claim 34, wherein the clinical decline is reduced by at least 26% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

36. The composition described in claim 34, wherein the clinical decline is reduced by at least 27% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

37. The composition described in claim 34, wherein the clinical decline is reduced by 25 to 60% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

38. The composition described in claim 34, wherein the clinical decline is reduced by 25 to 50% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

39. A composition for treating a subject having early Alzheimer's disease, comprising a therapeutically effective amount of an anti-Aβ protofibril antibody, 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:5 (HCDR1), SEQ ID NO:6 (HCDR2), and SEQ ID NO:7 (HCDR3); and three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3) comprising the amino acid sequences of SEQ ID NO:8 (LCDR1), SEQ ID NO:9 (LCDR2), and SEQ ID NO:10 (LCDR3); the composition comprises a dose of the anti-Aβ protofibril antibody of 10 mg / kg based on the body weight of the subject and is administered to the subject once every two weeks; The clinical decline on said treatment is reduced by at least 26% compared to placebo as determined by ADAS-Cog after 18 months of treatment; composition.

40. The method of claim 1, wherein Aβ 1-42 , total tau, phosphotau or neurogranin levels are measured; 40. The composition of claim 39, wherein an additional dose of the anti-Aβ protofibril antibody is administered if Aβ 1-42 levels rise above or total tau, phosphotau or neurogranin levels fall below pre-treatment levels.

41. The composition of any one of claims 34 to 38, wherein the subject is a heterozygous carrier of an ApoE4 gene allele.

42. The composition described in any one of claims 1 to 33 and 39, wherein the subject is ApoE4 negative.

43. The composition described in claim 42, wherein the clinical decline is reduced by 41% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

44. The composition described in claim 42 or 43, wherein the clinical decline is reduced by 35% compared to placebo as determined by ADAS-Cog 18 months after administration of the composition.

45. The composition described in claim 42 or 43, wherein the clinical decline is reduced by 43% compared to placebo as determined by ADAS-Cog 18 months after administration of the composition.

46. A composition described in any one of claims 42 to 45, wherein the clinical decline is reduced by 32% compared to placebo as determined by ADCOMS 18 months after administration of the composition.

47. The composition of any one of claims 1 to 46, wherein the composition is administered for at least 18 months.

48. The composition of any one of claims 1 to 47, wherein the composition is administered for at least 24 months.

49. The composition of any one of claims 1 to 48, wherein the composition is administered intravenously.

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