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

[0002] Alzheimer's disease (AD) is a progressive neurodegenerative disorder of unknown etiology and is 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) (Brookmeyer, R., et al., Forecasting the global burden of Alzheimer's Disease. Alzheimer Dement. 2007;3:186-91), while reports indicated that there were over 5 million cases of AD in the United States (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94). By 2050, the total number of Alzheimer's disease (AD) cases worldwide is projected to reach 106.8 million (range: 47.2 million to 221.2 million), while the number of cases in the United States alone is estimated to be between 11 million and 16 million. (Brookmeyer, op. cit., and 2010 Alzheimer's disease facts and figures, op. cit.).

[0003] This disease is generally associated with a general decline in cognitive function, which progresses slowly, leading to a bedridden state in terminal patients. AD patients typically survive for only 3 to 10 years after onset, although extreme cases of 2 to 20 years have been reported (Hebert, LE, et al., Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122). Despite the fact that the mortality rate due to AD is significantly underestimated because it is rare for the cause of death to be listed as AD on death certificates, AD is the 7th leading cause of death among all causes in the United States and the 5th leading cause of death among Americans over 65 years of age (Alzheimer's Association. Alzheimer's Association report. 2010 Alzheimer's disease facts and figures. Alzheimer Dement. 2010;6:158-94).

[0004] Alzheimer's disease (AD) represents a significant economic burden across industrialized nations, profoundly impacting healthcare systems, national treasuries, and patients and their families. In the United States alone, total payments in 2010 were estimated at $172 billion, including $123 billion for Medicare and Medicaid. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] To the best of our knowledge, there is currently no cure for Alzheimer's disease (AD), nor is there any way to slow its progression. Current treatments for AD include symptomatic therapies such as acetylcholinesterase inhibitors (AChEIs) like donepezil and N-methyl-D-aspartate (NMDA) receptor antagonists like memantine. While these drugs can improve symptoms of AD, such as cognitive decline and reduced activity in daily living, there are no reports that they alter the progression of the disease. Therefore, there is a need for a method to treat the progression of AD and / or prevent it, but this has yet to be addressed. [Means for solving the problem]

[0006] In some embodiments, this specification provides a method for reducing clinical functional decline in a subject having 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 plaque formation begins in the brain. In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, reduces protofibril and existing plaque in the brain. In some embodiments, at least one anti-Aβ protofibril antibody, such as BAN2401, prevents Aβ deposition before plaque formation begins and reduces protofibril and existing plaque in the brain.

[0008] In some embodiments, provided herein is a method of converting a subject having amyloid-positive early Alzheimer's disease to a subject having amyloid-negative early 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 of reducing brain amyloid levels in a subject having early 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.

[0010] In some embodiments, provided herein is a method of preventing Alzheimer's disease in an ApoE4-positive subject. In some embodiments, the method comprises determining the pre-administration brain amyloid level of the subject and, if the subject's brain amyloid level exceeds a first predetermined level, administering a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] [Figure 1] Shows the slowing of cognitive decline over 18 months compared to placebo for BAN2401 at doses of 2.5 mg / kg biweekly, 5 mg / kg monthly, 5 mg / kg biweekly, 10 mg / kg monthly, and 10 mg / kg biweekly as determined by ADCOMS. [Figure 2] Shows the slowing of cognitive decline over 18 months compared to placebo for the 10 mg / kg monthly dose and 10 mg / kg biweekly dose of BAN2401 as determined by ADCOMS. [Figure 3] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week in subjects with mild cognitive impairment - moderate likelihood due to Alzheimer's disease - type dementia when determined by ADCOMS. [Figure 4] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week in subjects with mild Alzheimer's disease - type dementia when determined by ADCOMS. [Figure 5] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week in ApoE4 - positive subjects when determined by ADCOMS. [Figure 6] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week in ApoE4 - negative subjects when determined by ADCOMS. [Figure 7] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week of BAN2401 when determined by ADAS - cog. [Figure 8] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week when determined by ADAS - cog. [Figure 9] It shows the slowing of cognitive decline over 18 months compared to placebo for doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week of BAN2401 when determined by CDR - SB. [Figure 10]This shows the slowing of cognitive decline over 18 months compared to placebo for monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401, as determined by CDR-SB. [Figure 11] This shows the reduction of brain amyloid over 18 months for BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, compared to the whole cerebellar reference value as determined by PET. [Figure 12] This shows the reduction of brain amyloid over 18 months for BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by PET imaging using the binding of a radioactive tracer to brain Aβ amyloid. [Figure 13] This shows the conversion from amyloid-positive to amyloid-negative subjects after 12 and 18 months of treatment with BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by visual interpretation. [Figure 14] This shows the changes in cerebrospinal fluid Aβ1-42 levels over 18 months for BAN2401 administered at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week. [Figure 15] This shows the changes in total cerebrospinal fluid tau levels over 18 months for monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 16] This study shows the slowing of cognitive decline over 18 months in ApoE4-positive subjects at doses of BAN2401 of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADCOMS, compared to placebo. [Figure 17]This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-positive subjects with a potential for mild to moderate cognitive impairment due to Alzheimer's disease, as determined by ADCOMS, with monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 18] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-positive subjects with mild Alzheimer's disease, as determined by ADCOMS, with monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 19] This study shows the slowing of cognitive decline over 18 months in ApoE4-positive subjects at doses of BAN2401 of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADAS-cog. [Figure 20] This study shows the slowing of cognitive decline over 18 months in ApoE4-positive subjects receiving BAN2401 at doses of 10 mg / kg monthly and 10 mg / kg every other week, as determined by ADAS-cog. [Figure 21] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-positive subjects with a potential for mild to moderate cognitive impairment due to Alzheimer's disease, as determined by ADAS-cog, with monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 22] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-positive subjects with mild Alzheimer's disease, as determined by ADAS-cog, at doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week. [Figure 23]This shows the slowing of cognitive decline over 18 months in ApoE4-positive subjects at doses of BAN2401 of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by CDR-SB. [Figure 24] This shows the slowing of cognitive decline over 18 months in ApoE4-positive subjects with BAN2401 at doses of 10 mg / kg monthly and 10 mg / kg every other week, as determined by CDR-SB. [Figure 25] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-positive subjects with a potential for mild to moderate cognitive impairment due to Alzheimer's disease, as determined by CDR-SB, with monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 26] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-positive subjects with mild Alzheimer's disease, as determined by CDR-SB, at doses of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week. [Figure 27] This shows the reduction in brain amyloid over 18 months for ApoE4-positive subjects with BAN2401 doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by visual interpretation of amyloid PET images and as a mean value across the entire cortex compared to the whole cerebellar reference value. [Figure 28] This shows the reduction of brain amyloid over 18 months in ApoE4-positive subjects with BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by PET imaging using the binding of a radioactive tracer to brain Aβ amyloid. [Figure 29]This shows the conversion from amyloid-positive ApoE4-positive subjects to amyloid-negative ApoE4-positive subjects after 12 and 18 months of treatment. [Figure 30] This shows the changes in cerebrospinal fluid Aβ1-42 levels over 18 months for BAN2401 administered at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week in ApoE4-positive subjects. [Figure 31] This shows the changes in total cerebrospinal fluid tau levels over 18 months for ApoE4-positive subjects receiving 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week. [Figure 32] This study shows the slowing of cognitive decline over 18 months in ApoE4-negative subjects using BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADCOMS, compared to placebo. [Figure 33] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects with a potential for mild to moderate cognitive impairment due to Alzheimer's disease, as determined by ADCOMS, using monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 34] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects with mild Alzheimer's disease, as determined by ADCOMS, with monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 35] This study shows the slowing of cognitive decline over 18 months in ApoE4-negative subjects with BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, compared to placebo, as determined by ADAS-cog. [Figure 36]This study shows the slowing of cognitive decline over 18 months in ApoE4-negative subjects receiving BAN2401 at doses of 10 mg / kg monthly and 10 mg / kg every other week, as determined by ADAS-cog. [Figure 37] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects with a possible mild to moderate cognitive impairment due to Alzheimer's disease, as determined by ADAS-cog, using monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 38] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects with mild Alzheimer's disease, as determined by ADAS-cog, using monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 39] This shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects at doses of BAN2401 of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by CDR-SB. [Figure 40] This study shows the slowing of cognitive decline over 18 months in ApoE4-negative subjects receiving BAN2401 at doses of 10 mg / kg monthly and 10 mg / kg every other week, as determined by CDR-SB. [Figure 41] This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects with a possible mild to moderate cognitive impairment due to Alzheimer's disease, as determined by CDR-SB, with monthly doses of 10 mg / kg BAN2401 and bi-weekly doses of 10 mg / kg BAN2401. [Figure 42]This study shows the slowing of cognitive decline over 18 months compared to placebo in ApoE4-negative subjects with mild Alzheimer's disease, as determined by CDR-SB, at doses of 10 mg / kg BAN2401 monthly and 10 mg / kg every other week. [Figure 43] This shows the reduction in brain amyloid over 18 months for BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week in ApoE4-negative subjects, as determined by visual interpretation of amyloid PET images, with respect to the whole-cortex mean value compared to the whole-cerebellar reference value. [Figure 44] This shows the reduction of brain amyloid over 18 months in ApoE4-negative subjects with BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by PET imaging using the binding of a radioactive tracer to brain Aβ amyloid. [Figure 45] This shows the conversion from amyloid-positive, ApoE4-negative subjects to amyloid-negative, ApoE4-negative subjects after 12 and 18 months of treatment. [Figure 46] This shows the changes in cerebrospinal fluid Aβ1-42 levels over 18 months for BAN2401 administered at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week in ApoE4-negative subjects. [Figure 47] This shows the changes in total cerebrospinal fluid tau levels over 18 months for subjects with a monthly dose of 10 mg / kg and a bi-weekly dose of 10 mg / kg. [Figure 48] This study shows the slowing of cognitive decline at 18 months compared to placebo with a dose of 10 mg / kg BAN2401 every other week in ApoE4-positive and ApoE4-negative subjects, as determined by ADCOMS, ADAS-Cog, or CDR-SB, and in all subjects regardless of genotype. [Figure 49]This study shows the slowing of cognitive decline at 18 months with a dose of 10 mg / kg BAN2401 every other week, compared to placebo, in subjects with mild to moderate potential cognitive impairment or mild Alzheimer's disease, as determined by ADCOMS, ADAS-Cog, or CDR-SB, and in all subjects regardless of disease type or condition. [Figure 50] This study shows the slowing of cognitive decline at a dose of 10 mg / kg BAN2401 every other week compared to placebo at 18 months, for subjects receiving at least one other Alzheimer's disease medication concurrently, subjects not receiving at least one other Alzheimer's disease medication concurrently, and for all subjects regardless of whether they receive at least one other Alzheimer's disease medication concurrently, as determined by ADCOMS, ADAS-Cog, or CDR-SB. [Figure 51] The following subgroups, as determined by PET, showed brain amyloid removal compared to placebo at 18 months for a dose of 10 mg / kg BAN2401 every other week: ApoE4-positive subjects; ApoE4-negative subjects; subjects with mild to moderate cognitive impairment due to Alzheimer's disease; subjects with mild Alzheimer's disease; subjects receiving at least one other Alzheimer's disease medication concurrently; and subjects not receiving at least one other Alzheimer's disease medication concurrently. [Figure 52] The following subgroups, as determined by ADCOMS, were included: ApoE4-positive subjects; ApoE4-negative subjects; subjects with a potential for mild to moderate cognitive impairment due to Alzheimer's disease; subjects with mild Alzheimer's disease; subjects receiving at least one other Alzheimer's disease medication concurrently; and subjects not receiving at least one other Alzheimer's disease medication concurrently. The study shows the slowing of cognitive decline at 18 months with a dose of 10 mg / kg BAN2401 every other week, compared to placebo. [Figure 53] This shows the change in cerebrospinal fluid neurolanin levels at 18 months, compared to placebo (average value) for subjects who received a dose of 10 mg / kg BAN2401 every other week or 10 mg / kg BAN2401 monthly. [Figure 54] This shows the change in cerebrospinal fluid phosphotau levels at 18 months, compared to placebo, as an average for subjects who received a dose of 10 mg / kg BAN2401 every other week or 10 mg / kg BAN2401 monthly. [Figure 55] This shows the change in cerebrospinal fluid neurofilament light chain levels at 18 months, compared to placebo (average value) for subjects who received 10 mg / kg BAN2401 every other week or 10 mg / kg BAN2401 monthly. [Figure 56] This shows the slowing of cognitive decline at 18 months compared to placebo for doses of 10 mg / kg BAN2401 every other week or 10 mg / kg BAN2401 monthly, as determined by ADCOMS and PET. [Figure 57] This study shows the correlation between a reduction in brain amyloid and increased clinical improvement, as determined by ADCOMS, ADAS-Cog, and CDR-SB. [Figure 58] This indicates that ApoE4-positive and ApoE4-negative subjects who did not receive BAN2401 exhibited similar disease progression rates. [Figure 59] This shows the influence of various factors on disease progression as determined by ADCOMS. [Figure 60] This shows the change in BAN2401 concentration as a function of time after administration of 10 mg / kg BAN2401 monthly and 10 mg / kg BAN2401 every other week. [Figure 61] The diagram illustrates that BAN2401 preferentially binds to large Aβ protofibrils compared to Aβ peptide monomers, dimers, and oligomers. [Figure 62] This shows the proportion of subjects who experienced an ARIA-E event as a function of the peak plasma concentration of BAN2401. [Figure 63]This study demonstrates that administration of BAN2401 significantly reduces amyloid PET levels at all doses. [Figure 64] This paper outlines the research design for early intervention and prevention of Alzheimer's disease. [Figure 65] This shows the mean (least squares mean, "LSM") change from baseline in cerebrospinal fluid phosphotau levels over 18 months compared to placebo for BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week. [Figure 66] This shows the mean, adjusted, long-term changes (LSM) from baseline in cerebrospinal fluid neurogranin levels over 18 months compared to placebo for BAN2401 administered at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week. [Figure 67] This shows the mean, adjusted, long-shortened changes (LSM) from baseline in cerebrospinal fluid neurofilament light chain levels over 18 months compared to placebo for BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week. [Figure 68] This shows the mean, adjusted, long-term change (LSM) from baseline in cerebrospinal fluid phosphotau levels over 18 months compared to placebo for BAN2401 in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week). [Figure 69] This shows the mean, adjusted, long-term change (LSM) from baseline in cerebrospinal fluid phosphotau levels over 18 months compared to placebo for BAN2401 administered in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) in ApoE4-positive subjects. [Figure 70] This shows the mean, adjusted, long-term change (LSM) from baseline in cerebrospinal fluid phosphotau levels over 18 months compared to placebo for BAN2401 administered in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) in ApoE4-negative subjects. [Figure 71] This shows the mean, adjusted, long-term change (LSM) from baseline in cerebrospinal fluid neurolanin levels over 18 months compared to placebo for BAN2401 in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week). [Figure 72] This shows the mean, adjusted, long-term change (LSM) from baseline in cerebrospinal fluid neurogranin levels over 18 months compared to placebo for BAN2401 administered at a combination dose of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) in ApoE4-positive subjects. [Figure 73] This shows the mean, adjusted, long-term change (LSM) from baseline in cerebrospinal fluid neurogranin levels over 18 months compared to placebo for BAN2401 administered in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) in ApoE4-negative subjects. [Figure 74] This shows the mean, adjusted, long-term changes (LSM) from baseline over 18 months for BAN2401 in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo. [Figure 75] This shows the mean, adjusted, long-shortest-scale change (LSM) from baseline over 18 months for BAN2401 administered in combination doses of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-positive subjects. [Figure 76] This shows the mean, adjusted, long-shortest-scale change (LSM) from baseline over 18 months for BAN2401 administered at a combination dose of 10 mg / kg (10 mg / kg monthly and 10 mg / kg every other week) compared to placebo in ApoE4-negative subjects. [Figure 77]This study shows the correlation between the change from baseline in PET standardized uptake ratios (normalized to the whole cerebellar mask) at 12 and 18 months for placebo and BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADCOMS, and cognitive outcomes. [Figure 78] This shows the correlation between the change from baseline in PET standardized uptake ratios (normalized to the whole cerebellar mask) at 12 and 18 months for placebo and BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by CDR-SB, and cognitive outcomes. [Figure 79] This study shows the correlation between the change from baseline in PET standardized uptake ratios (normalized to the whole cerebellar mask) at 12 and 18 months for placebo and BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADAS-Cog, and cognitive outcomes. [Figure 80] This study shows the correlation between the change from baseline in PET standardized uptake ratio (normalized to subcortical white matter) at 12 and 18 months for placebo and BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADCOMS, and cognitive outcomes. [Figure 81] This study shows the correlation between the change from baseline in PET standardized uptake ratio (normalized to subcortical white matter) at 12 and 18 months for placebo and BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by CDR-SB, and cognitive outcomes. [Figure 82]This study shows the correlation between the change from baseline in PET standardized uptake ratio (normalized to subcortical white matter) at 12 and 18 months for placebo and BAN2401 at doses of 2.5 mg / kg every other week, 5 mg / kg monthly, 5 mg / kg every other week, 10 mg / kg monthly, and 10 mg / kg every other week, as determined by ADAS-Cog, and cognitive outcomes. [Modes for carrying out the invention]

[0012] "Amyloid Hypothesis" The "amyloid hypothesis" proposes that amyloid-beta (Aβ) peptides play a central role in the development of Alzheimer's disease (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 tau protein-containing neurofibril entanglements, thus causing neurodegeneration in AD. Aβ peptides generally exist in a dynamic range of conformational states, progressing from monomeric Aβ to soluble Aβ aggregates (ranging from low molecular weight oligomers to higher molecular weight protofibrils) and finally to insoluble fibrils (plaques). Several immunotherapies have been developed to reduce the amount of insoluble Aβ fibrils deposited in the brain. However, the simple correlation between the amount of insoluble amyloid plaques and their progressive accumulation and the clinical course of AD remains undetermined. While treatment strategies continue to focus on removing insoluble amyloid plaques, further therapeutic approaches may include reducing toxic Aβ aggregates such as protofibrils, which may contribute to the neurodegenerative characteristics of AD (see, for example, 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 in subjects in the early stages of the disease, where amyloid is deposited in the brain, but the downstream neurodegenerative cascade thought to be caused by amyloid deposition is still relatively early in its course (i.e., the brain tissue loss that occurs is limited and the associated clinical impairment is minimal), the progression of AD could be slowed using BAN2401 and other anti-Aβ protofibril antibodies. 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, comprising administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody. Also disclosed herein is a method for reducing clinical functional impairment in amyloid-positive early-stage AD subjects, comprising administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody. As we will discuss, unexpectedly beneficial results were obtained when the subjects were ApoE4 positive.

[0014] Surprisingly and unexpectedly, the inventors have also discovered a method for preventing and / or delaying the onset of Alzheimer's disease in early-stage Alzheimer's disease subjects, comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody. In some embodiments, the subjects are 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 references to the plural unless otherwise explicitly indicated by the context.

[0017] When used herein, the phrase "and / or" means "either one or both" of the elements thus connected, that is, elements that exist in some cases in a coordinating connection and in other cases in a disjunctive connection. Thus, as a non-restrictive example, when used in conjunction with open-ended phrases such as "comprising," in some embodiments it may refer to A only (optionally including elements other than B); in other embodiments it may refer to B only (optionally including elements other than A); and in yet another embodiments it may refer to both A and B (optionally including other elements).

[0018] As used herein, “at least one” means one or more elements in the element list, but not necessarily including at least one of every element specifically listed in the element list, and does not exclude any combination of elements in the element list. This definition also allows for the presence of elements other than those specifically identified in the element list referred to by the phrase “at least one,” whether or not they are related to the specifically identified elements, at the discretion of the party. Therefore, as a non-restrictive 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”) could mean, in one embodiment, at least one A comprising two or more of any choice, with no B present (and optionally including elements other than B); in another embodiment, at least one B comprising two or more of any choice, with no A present (and optionally including elements other than A); and in yet another embodiment, at least one A comprising two or more of any choice, and at least one B comprising two or more of any choice (and optionally including other elements), and so on.

[0019] When a number is presented alone or as part of a numerical range, it must be understood that the number can vary up or down from the stated value by a difference of 10%.

[0020] When a range of values ​​is given in this specification, 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 AD" or "early Alzheimer's disease," as used herein, refers to a range of AD severities from mild cognitive impairment (moderate possibility) to mild Alzheimer's disease-type dementia. Subjects with early AD include subjects with mild Alzheimer's disease-type dementia as defined herein and subjects with MCI (moderate possibility) due to AD as defined herein. In some embodiments, subjects with early AD have an MMSE score of 22–30 and a total CDR score in the range of 0.5–1.0.

[0022] When used herein, "subjects with mild Alzheimer's disease-type dementia" refers to subjects who meet the NIA-AA core clinical criteria for presumed Alzheimer's disease-type dementia as described in McKhann, GM et al., The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer Dement. 2011;7:263-9. This specification also includes subjects with a screening and baseline CDR score of 0.5 to 1.0 and a memory box score of 0.5 or higher.

[0023] When used herein, subjects with “AD-related MCI-moderate possibility” are those identified as such according to the NIA-AA Core Clinical Criteria for Mild Cognitive Impairment-moderate possibility due to Alzheimer’s disease (see McKhann, cited above). For example, AD subjects who exhibit symptoms but do not have dementia and have evidence of cerebral amyloid lesions (and therefore show little difference from, and are similar to, subjects with mild Alzheimer’s disease-type dementia in terms of cognitive and functional decline as measured by the ADCOMS composite clinical score as defined herein). Subjects with a CDR score of 0.5 and a Memory Box score of 0.5 or higher at screening and baseline are also included herein. Furthermore, subjects who report a history of subjective memory decline with gradual onset and slow progression over the past year prior to screening, and whose claims are corroborated by the informant, are also included herein.

[0024] As used herein, "MMSE" refers to the Mini-Mental State Examination, a 30-point cognitive scale commonly used for screening purposes but also frequently measured longitudinally in AD clinical trials. A higher score indicates less functional impairment, while a lower score indicates more functional impairment. As used herein, seven items measuring orientation to time and place, memory, recall, attention, language, and drawing were evaluated (Folstein, MF et al., Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 1975;12:189-98).

[0025] As used herein, “ADAS-cog” refers to the Alzheimer's Disease Assessment Scale-Cognitive. The ADAS-cog is a widely used cognitive function scale in Alzheimer's disease clinical trials, comprising structured scales for assessing memory (word recall, delayed word recall, and word recognition), reasoning (following instructions), language (naming, comprehension), orientation, conceptual execution (putting a letter in an envelope), and constructive execution (copying a geometric design) (Rosen, WGet 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 difficulties, ability to recall test instructions, mazes, and number elimination. The modified version used herein is scored on a scale of 0 to 90, where 0 indicates no impairment and 90 indicates maximum 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 functional impairment in terms of executive ability across six functional categories: memory, orientation, judgment and problem-solving, community activities, home 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 functional impairment scores obtained for each of the six functional categories are integrated to form a single overall score (ranging from 0 to 3) of the dementia CDR score. The sum of boxes provides an additional measure of change, where the maximum possible score for each category is 3, and the total score is the sum of the category scores, resulting in a possible total score of 0 to 18, with higher scores indicating greater functional 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, a composite clinical score based on the analysis of four ADAS-Cog items (delayed word recall, orientation, word recognition, and word discovery 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 embodiment 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 to be able to sense disease progression, particularly in the early stages of AD, i.e., the prodromal and mild AD.

[0028] As used herein, “ApoE4-positive” subjects and “ApoE4 carriers” refer to subjects who possess the ε4 variant of the apolipoprotein gene. The ε4 variant is one of several major alleles of the apolipoprotein gene. This gene is generally involved in lipid metabolism. Carriers of apolipoprotein ε4 have been shown to exhibit significantly higher amyloid retention rates compared to non-carriers (Drzezga, A. et al, Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. Neurology. 2009;72:1487-94). In some embodiments, subjects are heterozygous carriers of the apolipoprotein E ε4 gene allele. In some embodiments, subjects are homozygous carriers of the apolipoprotein E ε4 gene allele.

[0029] When used herein, whether an early-stage AD subject is "amyloid-positive" or "amyloid-negative" is determined by longitudinal PET evaluation of amyloid contrast agent uptake into the brain and / or Aβ 1-42 The determination is based on whether the patient has a positive amyloid load as indicated by the CSF assessment for the presence of amyloid lesions, using evaluation of markers such as (soluble CSF biomarker analysis). In some embodiments, amyloid positivity and negativity are determined by qualitative visual interpretation of PET scans, classifying the subject as having either "normal" or "abnormal" uptake based on the PET image pattern. The radiologist is a qualified person trained to recognize abnormal or normal uptake patterns in brain PET images, or amyloid detection is performed using semi-quantitative or quantitative methods.

[0030] As used herein, the term “to treat” means achieving a beneficial or desired outcome, including, but not limited to, a therapeutic benefit (meaning the eradication or improvement of one or more of the underlying medical condition or associated physiological symptoms under treatment).

[0031] As used herein, the term “prevent” means achieving a beneficial or desired outcome, including, but not limited to, a preventive benefit. For a preventive benefit, the composition may be administered to subjects at risk of developing Alzheimer’s disease, subjects with one or more pre-symptomatic symptoms of Alzheimer’s disease but without clinical symptoms, or subjects complaining of one or more physiological symptoms of Alzheimer’s disease, even if they have not been clinically diagnosed with Alzheimer’s disease. As used herein, “prevention” may further include a therapeutic benefit, meaning the eradication or improvement of one or more of the underlying condition or associated physiological symptoms under treatment.

[0032] Pre-symptomatic AD biomarker levels that may suggest the onset of Alzheimer's disease include, but are not limited to, brain amyloid levels and cerebrospinal fluid Aβ levels. 1-42These include levels, total tau levels in cerebrospinal fluid (CSF), neurogranin levels in CSF, and neurofilament light chain levels in CSF. For example, it has been found that subjects with amyloid baseline PET standardized uptake ratio (SUVr) of 1.4-1.9 treated with the BACE inhibitor elenbecestat (E2609) showed the greatest slowing of cognitive decline during treatment. See Lynch, SY et al. Elenbecestat, a BACE inhibitor: results from a Phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease. Poster P4-389, Alzheimer's Association International Conference, July 22-26, 2018, Chicago, IL, USA. Similarly, subjects with baseline florbetapir amyloid PET SUVr levels below 1.2 did not exhibit sufficient cognitive decline to be detectable, while subjects with SUVr levels above 1.6 appeared to correlate with a plateau effect (amyloid levels reached saturation levels, and cognitive function measures did not change with treatment). 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 terms “Serious Adverse Event” or “SAE” mean an event observed after administration of any of the compositions described herein that is (1) fatal; (2) life-threatening; (3) requires hospitalization or extension of an existing hospitalization; (4) results in permanent or significant physical disability / incapacity; and / or (5) results in a birth defect / absence.

[0034] The severity of serious adverse events may be assessed based on equivalence scales used in the relevant technology field. For example, the severity of a serious adverse event may be determined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). Descriptions of various CTCAE adverse event grades are provided below: - Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic findings only; no therapeutic intervention required. - Grade 2: Moderate; requires minimal local or non-invasive therapeutic intervention; age-appropriate limitations in instrumental activities of daily living. - Grade 3: Severe or medically significant but not immediately life-threatening; requires hospitalization or extended hospitalization; physical disability; limitations in daily living activities. - Grade 4: Life-threatening consequences; requires emergency medical intervention. - Grade 5: Death related to an adverse event.

[0035] As used herein, the term “ellenbecestat” 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]thiadin-7a-yl)-4-fluorophenyl]-5-difluoromethylpyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof. Ellenbecestat is an amyloid precursor protein β-site cleavage enzyme 1 (BACE1) inhibitor (see, for example, U.S. Patent Nos. 8,158,620 and 8,426,584), also known as E2609. [ka]

[0036] At least one anti-Aβ protofibril antibody As used herein, at least one anti-Aβ protofibril antibody is selected from monoclonal antibodies (mAbs) that preferentially bind to large soluble amyloid-beta (Aβ) oligomers and / or aggregates (also referred to as protofibrils) compared to, for example, Aβ monomers. See, for example, Figure 61. As used herein, the term “preferentially binds” means at least 10 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, at least 125 times, at least 150 times, at least 175 times, at least 200 times, at least 225 times, at least 250 times, at least 275 times, and less than its potency to bind to other forms of Aβ peptides (e.g., protofibril and monomer, respectively). This refers to antibodies that bind to Aβ oligomers and / or protofibrils with a potency of 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, at least 1000, or at least 1050 times higher. The 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 at least one anti-Aβ protofibril antibody is measured by an ELISA assay. In some embodiments, the preferential binding of 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, it has been shown that BAN2401 binds to Aβ protofibrils with 200 to 1000 times higher potency than Aβ monomers, and that BAN2401 binds to Aβ protofibrils with more than 40 times higher potency than Aβ fibrils. See also page 13 and Figure 2 of International Publication No. 2007 / 108756 A1; 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, C.J et al. Pharmacology of BAN2401: A Monoclonal Antibody Selective for Aβ Protofibrils. Poster P4-286, Alzheimer's Association International Conference, July 13-18, 2013. The difference in potency was determined by a sandwich ELISA assay, in which BAN2401 was coated into the wells of a well plate, and different Aβ forms were added to the wells in increasing concentrations. The bound Aβ forms were measured by adding biotinylated mAb158 and HRP-labeled streptavidin, and the color development was measured according to the manufacturer's procedure. Similarly, BAN2401 was found to have weak affinity for the N-terminal portion of the Aβ peptide and for the Aβ monomer, and no binding to the C-terminal fragment of Aβ was observed. Affinity was determined using a competitive ELISA assay, in which ELISA plates were coated with human Aβ protofibril and BAN2401, and then incubated with increasing amounts of different Aβ forms. This incubation mixture was added to the wells of a microtiter plate, and free antibodies were bound to the protofibril immobilized in the wells, and the bound BAN2401 antibody was measured by a secondary antibody.

[0040] In some embodiments, at least one anti-Aβ protofibril antibody comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3) containing 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) containing 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 definition in SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (Kabat et al., 5th ed., USD 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 includes a human constant region. In some embodiments, the human constant region of at least one anti-Aβ protofibril antibody includes a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE, and any allele variant thereof as disclosed in the Kabat Report. Any one or more of such sequences may be used in this disclosure. In some embodiments, the heavy chain constant region is selected from IgG1 and its allele variants. The amino acid sequence of the human IgG1 constant region is known in the art and is shown in SEQ ID NO: 3.

[0043] In some embodiments, the human constant region of at least one anti-Aβ antibody comprises a κ-λ chain constant region and a light chain constant region selected from any allele variants thereof as discussed in the Kabat report. In this disclosure, any one or more of such sequences may be used. In some embodiments, the light chain constant region is selected from κ and its allele variants. The amino acid sequence of the human κ chain constant region is known in the art and is shown in SEQ ID NO: 4.

[0044] In some embodiments, at least one anti-Aβ protofibril antibody comprises a human heavy chain and light chain variable region framework. 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, at least one anti-Aβ protofibril antibody is BAN2401. BAN2401 is mAb158, a humanized IgG1 monoclonal version, which is a mouse monoclonal antibody produced to target protofibrils, as disclosed in International Publication 2007 / 108756 and the 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 binds with high selectivity to soluble Aβ aggregate species. For example, BAN2401 has been reported to exhibit approximately 1000-fold and 5-10-fold higher selectivity for soluble Aβ protofibrils than for Aβ monomers or Aβ insoluble fibrils, respectively.

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

[0047] Other non-limiting examples of antibodies suitable for use as at least one anti-Aβ protofibril antibody in this disclosure include those disclosed in International Publication No. 2002 / 003911, International Publication No. 2005 / 123775, International Publication No. 2007 / 108756, International Publication No. 2011 / 001366, International Publication No. 2011 / 104696, and International Publication No. 2016 / 005466.

[0048] Therapeutic effective dose of at least one anti-Aβ protofibril antibody The method of this disclosure involves administering a composition comprising a therapeutically effective dose of at least one anti-Aβ protofibril antibody to a target. As used herein, the term “therapeutic dose” means an amount of a compound or pharmaceutical composition sufficient to produce a desired therapeutic effect.

[0049] Those skilled in the art will understand that the therapeutically effective dose 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 that the appropriate dose for each subject can be determined using the information disclosed herein.

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

[0051] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject in doses of 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg, based on the subject's body weight.

[0052] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject in doses of 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg, based on the subject's body weight.

[0053] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject in a dose of 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg based on the subject's body weight.

[0054] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject in doses of 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg, based on the subject's body weight.

[0055] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at concentrations of 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, and 20 mg / kg, based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject in a dose of up to 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg, based on the subject's body weight.

[0056] In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 0.5 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 1 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 2 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 2.5 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 3 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 4 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 5 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 6 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 7 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 7.5 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 8 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 9 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 10 mg / kg based on the subject's body weight. In some embodiments, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 11 mg / kg based on the subject's body weight. In some embodiments, the subject is administered at a dose of 12 mg / kg of at least one anti-Aβ protofibril antibody based on the subject's body weight. In some embodiments, the subject is administered at a dose of 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 at a dose of 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 at a dose of 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 at a dose of 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 at a dose of 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 at a dose of 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, at least one anti-Aβ protofibril antibody is administered to the subject at a dose of 27.5 mg / kg, 30 mg / kg, 32.5 mg / kg, 35 mg / kg, 37.5 mg / kg, 40 mg / kg, 42.5 mg / kg, 45 mg / kg, 47.5 mg / kg, or 50 mg / kg based on the subject's body weight.

[0058] As described, in some embodiments, at least one anti-Aβ protofibril antibody is BAN2401. Accordingly, in some embodiments, BAN2401 is administered to the subject in doses of 0.5 mg / kg to 45 mg / kg, 0.5 mg / kg to 40 mg / kg, 0.5 mg / kg to 35 mg / kg, 0.5 mg / kg to 30 mg / kg, 0.5 mg / kg to 25 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 15 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, or 0.5 mg / kg to 2.5 mg / kg, based on the subject's body weight.

[0059] In some embodiments, BAN2401 is administered to the subject in doses of 2.5 mg / kg to 45 mg / kg, 2.5 mg / kg to 40 mg / kg, 2.5 mg / kg to 35 mg / kg, 2.5 mg / kg to 30 mg / kg, 2.5 mg / kg to 25 mg / kg, 2.5 mg / kg to 20 mg / kg, 2.5 mg / kg to 15 mg / kg, 2.5 mg / kg to 10 mg / kg, or 2.5 mg / kg to 5 mg / kg, based on the subject's body weight.

[0060] In some embodiments, BAN2401 is administered to the subject at doses of 5 mg / kg to 45 mg / kg, 5 mg / kg to 40 mg / kg, 5 mg / kg to 35 mg / kg, 5 mg / kg to 30 mg / kg, 5 mg / kg to 25 mg / kg, 5 mg / kg to 20 mg / kg, 5 mg / kg to 15 mg / kg, or 5 mg / kg to 10 mg / kg, based on the subject's body weight.

[0061] In some embodiments, BAN2401 is administered to the subject in doses of 7.5 mg / kg to 45 mg / kg, 7.5 mg / kg to 40 mg / kg, 7.5 mg / kg to 35 mg / kg, 7.5 mg / kg to 30 mg / kg, 7.5 mg / kg to 25 mg / kg, 7.5 mg / kg to 20 mg / kg, 7.5 mg / kg to 15 mg / kg, or 7.5 mg / kg to 10 mg / kg, based on the subject's body weight.

[0062] In some embodiments, BAN2401 is administered to the subject at doses of 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, and 20 mg / kg, based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a maximum dose of 20 mg / kg, 19 mg / kg, 18 mg / kg, 17 mg / kg, 16 mg / kg, 15 mg / kg, 14 mg / kg, 13 mg / kg, 12 mg / kg, 11 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, or 0.5 mg / kg, based on the subject's body weight.

[0063] In some embodiments, the subject is administered 0.5 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 1 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 2 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 2.5 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 3 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 4 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 5 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 6 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 7 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 7.5 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 8 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 9 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 10 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 11 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 12 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 12.5 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 13 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 14 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 15 mg / kg of BAN2401 based on their body weight. In some embodiments, the subject is administered 16, 17, 18, 19, or 20 mg / kg of BAN2401 based on their body weight.In some embodiments, BAN2401 is administered to the subject at a dose of 21, 22, 23, 24, or 25 mg / kg based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 27.5 mg / kg, 30 mg / kg, 32.5 mg / kg, 35 mg / kg, 37.5 mg / kg, 40 mg / kg, 42.5 mg / kg, 45 mg / kg, 47.5 mg / kg, or 50 mg / kg based on the subject's body weight.

[0064] In some embodiments, BAN2401 is administered to the subject at a dose of 2.5 mg / kg to 10 mg / kg based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 5 mg / kg to 10 mg / kg based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 2.5 mg / kg based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 5 mg / kg based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 7.5 mg / kg based on the subject's body weight. In some embodiments, BAN2401 is administered to the subject at a dose of 10 mg / kg based on the subject's body weight.

[0065] Administration regimen of at least one anti-Aβ protofibril antibody The method disclosed herein involves administering a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody to a subject. Those skilled in the art will understand that any therapeutically effective dose of any of the at least one anti-Aβ protofibril antibody disclosed above may be administered once or more times according to one or more dosing regimens. Those skilled in the art will be able to determine one or more dosing regimens appropriate for each subject, depending on several factors including pharmacodynamic properties, route of administration, dose, 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 may be administered daily, every other day, every three days, once a week, every two weeks ("every other week"), every four weeks ("every four weeks"), once a month, every six weeks, every eight weeks, once every two months, once every ten weeks, once every twelve weeks, once every three months, once every fourteen weeks, once every sixteen weeks, once every four months, and The drug is administered every 8 weeks, every 20 weeks, every 5 months, every 22 weeks, every 24 weeks, every 6 months, every 8 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 12 months, every 13 months, every 13 months, every 14 months, every 15 months, every 16 months, every 17 months, or every 18 months. In some embodiments, the composition containing at least one anti-Aβ protofibril antibody is administered daily, every other day, every 3 days, once a week, every 2 weeks ("every other week"), every 4 weeks ("every 4 weeks"), or once a month. In some embodiments, the composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody is administered every 2 weeks or every 4 weeks. In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks. In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks.

[0067] In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once a week. In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every two weeks. In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every three weeks. In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once every four weeks. In some embodiments, a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody is administered once a month.

[0068] In some embodiments, the composition containing a therapeutically effective dose of BAN2401 is administered once a week. In some embodiments, the composition containing a therapeutically effective dose of BAN2401 is administered once every two weeks. In some embodiments, the composition containing a therapeutically effective dose of BAN2401 is administered once every three weeks. In some embodiments, the composition containing a therapeutically effective dose of BAN2401 is administered once every four weeks. In some embodiments, the composition containing a therapeutically effective dose of BAN2401 is administered once a month.

[0069] In some embodiments, a composition containing at least one anti-Aβ protofibril antibody at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once a week. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once every three weeks. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once every four weeks. In some embodiments, a composition containing at least one anti-Aβ protofibril antibody at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once a month.

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

[0071] In some embodiments, a composition containing BAN2401 at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once a week. In some embodiments, a composition containing BAN2401 at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition containing BAN2401 at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once every three weeks. In some embodiments, a composition containing BAN2401 at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once every four weeks. In some embodiments, a composition containing BAN2401 at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once a month.

[0072] In some embodiments, a composition containing 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 containing 10 mg / kg of BAN2401 based on the subject's body weight is administered to the subject once a month.

[0073] A composition comprising at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains at least one anti-Aβ protofibril antibody. In some embodiments, the composition consists of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 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 use in humans and / or animals.

[0074] The compositions of this disclosure may be in the form of tablets, pills, capsules, solutions, and / or any other suitable form as deemed appropriate by those skilled in the art. The routes of administration of the compositions of this disclosure may be any suitable route, including intravenous, subcutaneous, oral, and nasal. In some embodiments, the compositions are formulated as sterile, non-pyrogenic liquids for intravenous administration. In some embodiments, the compositions are physiological saline.

[0075] In some embodiments, at least one further component in the composition is selected from a buffer. In some embodiments, at least one further component in the composition is selected from an emulsifier. In some embodiments, at least one further component in the composition is selected from sodium citrate, sodium chloride, and polysorbate 80. In some embodiments, sodium citrate may be present at a concentration in the range of 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 in the range of 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 in the range of 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] Therapeutic effect Reduction of clinical functional decline This specification provides a method for reducing clinical functional decline in subjects having early Alzheimer's disease, comprising administering to the subjects a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody disclosed herein. In some embodiments, subjects having early Alzheimer's disease are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease and / or with mild Alzheimer's type dementia. In some embodiments, subjects having early Alzheimer's disease are ApoE4 positive.

[0078] In methods for reducing clinical functional decline in subjects with early-stage Alzheimer's disease, any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions thereof disclosed herein may be used. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In some embodiments, clinical functional 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 of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0079] In some embodiments, clinical functional impairment is reduced by 20% to 35% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by 20% to 30% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by 27% to 35% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 20% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 35% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 20% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by ADCOMS. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0080] In some embodiments, clinical functional impairment is reduced by at least 45% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 6 months. In some embodiments, clinical functional impairment is reduced by at least 35% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months. In some embodiments, clinical functional impairment is reduced by at least 46% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[0081] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, less than placebo. A reduction of 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%, where the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0082] In some embodiments, clinical functional decline was reduced by 28% to 33% compared to placebo, as determined by ADCOMS, and subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 20%, e.g., 25%, or at least 28%, compared to placebo, as determined by ADCOMS, and subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 25%, e.g., at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, and subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 25%, e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52% compared to placebo, as determined by ADCOMS, in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 52% compared to placebo, as determined by ADCOMS, in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0083] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 25% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered 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 functional impairment was 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% compared to placebo, as determined by ADCOMS, where subjects were diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0085] In some embodiments, clinical functional decline was reduced by 28% to 38% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 20%, e.g., 25%, at least 28%, or at least 33%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 25%, e.g., at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 33% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0086] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 33% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0087] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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. The reduction is 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%, and the subjects are diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0088] In some embodiments, clinical functional decline was reduced by 20% to 80% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 35% to 78% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 35% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 50%, for example, at least 52% or at least 53%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 70%, for example, at least 75% or at least 78%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0089] In some embodiments, clinical functional impairment in subjects diagnosed with mild Alzheimer's disease is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in subjects diagnosed with mild Alzheimer's disease is reduced by at least 50% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in subjects diagnosed with mild Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0090] In some embodiments, clinical functional 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% compared to placebo, as determined by ADCOMS, where subjects are diagnosed with mild Alzheimer's disease type dementia. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0091] In some embodiments, clinical functional decline was reduced by 28% to 38% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 20%, e.g., 25%, at least 28%, or at least 35%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 25%, e.g., at least 30%, or at least 35%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 35% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0092] In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0093] In some embodiments, clinical functional decline, as determined by ADAS-cog, was 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 It will be reduced by 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 of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0094] In some embodiments, clinical functional impairment is reduced by 40% to 150% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by 45% to 145% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by 45% to 55% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 35% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 40% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 45% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 47% compared to placebo, as determined by ADAS-cog. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0095] In some embodiments, clinical functional impairment is reduced by at least 100%, for example, at least 120%, or at least 140%, compared to placebo, as determined by ADAS-cog, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment is reduced by at least 40%, for example, at least 45%, compared to placebo, as determined by ADAS-cog, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment is reduced by at least 40%, for example, at least 45%, compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment is reduced by at least 47%, compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0096] In some embodiments, clinical functional decline, as determined by ADAS-cog, was 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%, and at least 30% compared to placebo. A reduction of 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% is achieved, where the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0097] In some embodiments, clinical functional decline is reduced by 50% to 70% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 58% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0098] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 58% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered 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 functional decline was 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 ADAS-cog, and the subjects were diagnosed with mild Alzheimer's disease type dementia. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0100] In some embodiments, clinical functional decline is reduced by 30% to 50% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 41% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0101] In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 41% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0102] In some embodiments, clinical functional impairment 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 of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0103] In some embodiments, clinical functional impairment is reduced by 20% to 60% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by 25% to 60% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by 25% to 50% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 20% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 25%, for example, at least 26% or at least 28%, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 30%, for example, at least 35% or at least 38%, as determined by the CDR-SB. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0104] In some embodiments, clinical functional impairment is reduced by at least 30%, for example, at least 35%, or at least 40%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 6 months. In some embodiments, clinical functional impairment is reduced by at least 30%, for example, at least 35%, or at least 45%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional impairment is reduced by at least 20%, for example, at least 25%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months. In some embodiments, the composition contains at least one anti-Aβ protofibril antibody at a dose of 10 mg / kg and is administered 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 impairment 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, where subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0106] In some embodiments, clinical functional decline is reduced by 10% to 20% compared to placebo, as determined by CDR-SB, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 14% compared to placebo, as determined by CDR-SB, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0107] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 14% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0108] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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%, and at least 26% compared to placebo. The reduction is 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%, where the subjects are diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the reduction in clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0109] In some embodiments, clinical functional decline is reduced by 40% to 60% compared to placebo, as determined by CDR-SB, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 51% compared to placebo, as determined by CDR-SB, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0110] In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 51% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0111] In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 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. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0112] In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for one month. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for six months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for twelve months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for eighteen months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for sixty months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for sixty months.

[0113] In some embodiments, the reduction in clinical functional impairment is determined after administration of a composition containing a therapeutically effective dose of BAN2401.

[0114] In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 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. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 1 month. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 6 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 12 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 18 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 60 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 63 months.

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

[0116] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and less than placebo. All are reduced by 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%, where the subjects are ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0117] In some embodiments, clinical functional impairment was reduced by 60% to 80%, for example, 63% to 74%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive. In some embodiments, clinical functional impairment was reduced by at least 60%, for example, at least 63%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive. In some embodiments, clinical functional impairment was reduced by at least 65%, for example, at least 67%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive. In some embodiments, clinical functional impairment was reduced by at least 70%, for example, at least 74%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive.

[0118] In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 60% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 50%, for example, at least 55% or at least 60%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 63% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0119] In some embodiments, clinical functional decline, as determined by ADAS-cog, was 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%, and 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%, less 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%, small A reduction of 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% is achieved, where the subject is ApoE4 positive. In some embodiments, the reduction in clinical functional impairment listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0120] In some embodiments, clinical functional impairment is reduced by 70% to 400%, for example, 80% to 350%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 70%, for example, at least 75% or at least 80%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 80%, for example, at least 90% or at least 100%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 300%, for example, at least 330%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0121] In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 300% compared to placebo, as determined by ADAS-cog, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 84% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0122] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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% The levels are reduced by 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%, where the subject is ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0123] In some embodiments, clinical functional impairment is reduced by 35% to 150%, e.g., 40% to 100% or 45% to 90%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 35%, e.g., at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 50%, e.g., at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 70%, e.g., at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0124] In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 35%, for example, at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 70%, for example, at least 75% or at least 80%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 50%, for example, at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 60% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0125] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and at least 3% compared to placebo. A reduction of 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 is diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0126] In some embodiments, clinical functional decline was reduced by 30% to 70%, e.g., 38% to 59%, compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 30%, e.g., at least 35% or at least 38%, compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 45%, e.g., at least 50% or at least 53%, compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 50%, e.g., at least 55% or at least 59%, compared to placebo, as determined by ADCOMS, where the subjects are ApoE4 positive and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0127] In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 containing a therapeutically effective dose 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.

[0128] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and at least 24% compared to placebo. %, 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%, and 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%, little 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%,A reduction of 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 is diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months. ,

[0129] In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 100%, for example, at least 110%, compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 100%, for example, at least 110%, compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 65%, for example, at least 70% or at least 75%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0130] In some embodiments, clinical functional decline, as determined by ADAS-Cog, was 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%, and 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%, less 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%,A reduction of 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 is diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of the clinical functional declines described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0131] In some embodiments, clinical functional decline was reduced by 40% to 300%, e.g., 45% to 250%, or 50% to 250%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 40%, e.g., at least 45%, or at least 50%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 60%, e.g., at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 100%, e.g., at least 150%, or at least 200%, compared to placebo, as determined by ADAS-Cog, where the subjects are ApoE4 positive, and where the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0132] In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 100%, e.g., at least 150%, or at least 200%, compared to placebo, as determined by ADAS-cog, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 40%, e.g., at least 45%, or at least 50%, compared to placebo, as determined by ADAS-cog, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0133] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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%, and at least 2% compared to placebo. A reduction of 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 is diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional impairment listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0134] In some embodiments, clinical functional impairment was reduced by 20% to 90%, e.g., 25% to 80% or 30% to 75%, compared to placebo, as determined by CDR-SB, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by at least 25%, e.g., at least 30%, compared to placebo, as determined by CDR-SB, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by at least 30%, e.g., at least 35% or 40%, compared to placebo, as determined by CDR-SB, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 35%, e.g., at least 40% or 45%, compared to placebo, as determined by CDR-SB, where the subjects are ApoE4 positive and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0135] In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0136] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and at least 24% compared to placebo. %, 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%, and 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%, little 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%,A reduction of 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% is observed, wherein the subject is ApoE4 positive and has been diagnosed with mild Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0137] In some embodiments, clinical functional decline was reduced by 76% to 119% compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 76% compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 113% compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 119% compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0138] In some embodiments, clinical functional decline, as determined by ADAS-Cog, was 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%, and 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%, less 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%,A reduction of 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 is diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional declines described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0139] In some embodiments, clinical functional decline was reduced by 58% to 1023% compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 58% compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 171% compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 1023% compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0140] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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%, and at least 24% compared to placebo. %, 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%, and 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%, little 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% , reduced by 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 subjects are ApoE4 positive, and wherein the subjects are diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional declines described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0141] In some embodiments, clinical functional decline was reduced by 70% to 200%, for example, 75% to 180% or 82% to 174%, compared to placebo, as determined by CDR-SB, and the subjects were ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 70%, for example, at least 80%, compared to placebo, as determined by CDR-SB, and the subjects were ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 75%, for example, at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, and the subjects were ApoE4 positive and diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 150%, e.g., at least 160% or 170%, compared to placebo, as determined by CDR-SB, where the subjects are ApoE4 positive and diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0142] In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 70%, e.g., at least 75%, at least 80%, or at least 85%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 130%, e.g., at least 140%, at least 150%, at least 160%, or at least 170%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered 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 subjects are ApoE4 negative.

[0144] In some embodiments, clinical functional impairment 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, where the subjects are ApoE4 negative. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0145] In some embodiments, clinical functional impairment is reduced by 5% to 15% compared to placebo, as determined by ADCOMS, in subjects that are ApoE4 negative. In some embodiments, clinical functional impairment is reduced by at least 5%, e.g., at least 7%, compared to placebo, as determined by ADCOMS, in subjects that are ApoE4 negative. In some embodiments, clinical functional impairment is reduced by at least 10%, e.g., at least 12%, compared to placebo, as determined by ADCOMS, in subjects that are ApoE4 negative. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0146] In some embodiments, clinical functional impairment in ApoE4-negative subjects is reduced by at least 2% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-negative subjects is reduced by at least 10% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-negative subjects is reduced by at least 5%, for example, at least 7%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-negative subjects is reduced by at least 7% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0147] In some embodiments, clinical functional decline, as determined by ADAS-cog, was at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, less than placebo. 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% reduction, where the subjects are ApoE4 negative. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0148] In some embodiments, clinical functional impairment was reduced by 40% to 80% compared to placebo, as determined by ADAS-cog, and the subjects were ApoE4 negative. In some embodiments, clinical functional impairment was reduced by at least 35%, for example, at least 40% or at least 43%, compared to placebo, as determined by ADAS-cog, and the subjects were ApoE4 negative. In some embodiments, clinical functional impairment was reduced by at least 40%, for example, at least 45% or at least 46%, compared to placebo, as determined by ADAS-cog, and the subjects were ApoE4 negative. In some embodiments, clinical functional impairment was reduced by at least 65%, for example, at least 70% or at least 72%, compared to placebo, as determined by ADAS-cog, and the subjects were ApoE4 negative. In some embodiments, clinical functional impairment was reduced by at least 43% compared to placebo, as determined by ADAS-cog, and the subjects were ApoE4 negative. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0149] In some embodiments, clinical impairment was increased by 7%, 6%, 5%, 5%, 3%, 2%, or 1% compared to placebo, as determined by CDR-SB, in subjects that were ApoE4 negative. In some embodiments, clinical impairment was reduced by at least 1%, at least 2%, or at least 3% compared to placebo, as determined by CDR-SB, in subjects that were ApoE4 negative. In some embodiments, the reduction in clinical impairment described above was determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0150] In some embodiments, clinical functional impairment was reduced by 3% compared to placebo, as determined by CDR-SB, in subjects who were ApoE4 negative. In some embodiments, the reduction in clinical functional impairment described above was determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months. In some embodiments, clinical functional impairment 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 subjects are ApoE4 negative and have been diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0151] In some embodiments, clinical functional impairment was reduced by 15% to 26% compared to placebo, as determined by ADCOMS, in subjects who were ApoE4 negative and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by 15% compared to placebo, as determined by ADCOMS, in subjects who were ApoE4 negative and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by 26% compared to placebo, as determined by ADCOMS, in subjects who were ApoE4 negative and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0152] In some embodiments, clinical functional decline, as determined by ADAS-Cog, was 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%, and 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%, less 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%,A reduction of 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% is observed, where the subject is ApoE4 negative and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0153] In some embodiments, clinical functional decline was reduced by 50% to 200%, e.g., 60% to 180% or 65% to 170%, compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 negative and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 50%, e.g., at least 55% or at least 65%, compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 negative and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 70%, e.g., at least 75% or at least 80%, compared to placebo, as determined by ADAS-Cog, with subjects being ApoE4 negative and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by at least 150%, e.g., at least 160%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 negative and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0154] In some embodiments, clinical functional impairment in ApoE4-negative subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-negative subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-negative subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[0155] In some embodiments, clinical functional impairment 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, where subjects are ApoE4 negative and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0156] In some embodiments, clinical functional impairment was reduced by at least 5% compared to placebo, as determined by CDR-SB, where subjects were ApoE4 negative and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0157] In some embodiments, clinical functional decline was 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%, and at least 12% compared to placebo, as determined by CDR-SB, where the subjects were ApoE4 negative and diagnosed with mild Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0158] In some embodiments, clinical functional impairment was reduced by at least 10%, e.g., at least 12%, compared to placebo, as determined by CDR-SB, where the subjects were ApoE4 negative and diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0159] Transition from amyloid-positive to amyloid-negative target Furthermore, this specification also provides a method 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 having early Alzheimer's disease has been diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease and / or has been diagnosed with mild Alzheimer's dementia.

[0160] In a method for converting an amyloid-positive subject to an amyloid-negative subject, any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions thereof disclosed herein may be used. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject 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 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%, and at least 40% of amyloid PET images, as determined by visual interpretation of the 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 subjects are converted from amyloid-positive to amyloid-negative.

[0162] In some embodiments, administration of the composition results in a conversion from amyloid-positive to amyloid-negative in 50% to 100% and 60% to 90% of subjects, as determined by visual interpretation 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 containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by visual interpretation 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 containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody, as determined by visual interpretation of amyloid PET images. In some embodiments, the composition contains 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, at least one anti-Aβ protofibril antibody is BAN2401.

[0163] 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%, and 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%, and 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%, less In all cases, 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of the subjects become amyloid-negative, and in all cases, the subjects are ApoE4-positive.

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

[0165] In some embodiments, after administering a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months, at least 75%, for example, 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 administering a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months, at least 75%, for example, 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 contains 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%, and a small amount. 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 subjects become amyloid-negative, where the subjects are ApoE4-negative.

[0167] In some embodiments, administration of the composition results in 50% to 100%, for example, 55% to 90%, of subjects becoming amyloid-negative as determined by visual interpretation of amyloid PET images, where the subjects are ApoE4-negative. In some embodiments, administration of the composition results in at least 50% of subjects becoming amyloid-negative as determined by visual interpretation of amyloid PET images, where the subjects are ApoE4-negative. In some embodiments, administration of the composition results in at least 70% of subjects becoming amyloid-negative as determined by visual interpretation of amyloid PET images, where the subjects are ApoE4-negative.

[0168] In some embodiments, clinical functional decline is reduced by 35% to 50% compared to placebo, as determined by ADCOMS, and the subjects do not receive concomitant administration of at least one Alzheimer's disease drug other than BAN2401. In some embodiments, clinical functional decline is reduced by at least 35%, e.g., 38%, at least 40%, or at least 41%, compared to placebo, as determined by ADCOMS, and the subjects do not receive concomitant administration of at least one Alzheimer's disease drug other than BAN2401. In some embodiments, clinical functional decline is reduced by at least 41% compared to placebo, as determined by ADCOMS, and the subjects do not receive concomitant administration of at least one Alzheimer's disease drug other than BAN2401. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody other than BAN2401 for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0169] In some embodiments, clinical functional decline in subjects not receiving concomitant administration of at least one Alzheimer's disease drug is reduced by at least 41% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0170] In some embodiments, clinical functional decline, as determined by ADAS-cog, was 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%, and at least 30% compared to placebo. The reduction is 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%, where the subject does not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0171] In some embodiments, clinical functional decline is reduced by 50% to 70% compared to placebo, as determined by ADAS-cog, and the subjects do not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, clinical functional decline is reduced by at least 50%, e.g., 55%, at least 57%, or at least 59%, compared to placebo, as determined by ADAS-cog, and the subjects do not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, clinical functional decline is reduced by at least 59% compared to placebo, as determined by ADAS-cog, and the subjects do not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0172] In some embodiments, clinical functional decline in subjects not receiving concomitant administration of at least one Alzheimer's disease drug is reduced by at least 59% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains at least one anti-Aβ protofibril antibody at a dose of 10 mg / kg and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0173] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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%, and at least 23% compared to placebo. , 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 does not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0174] In some embodiments, clinical functional decline is reduced by 50% to 70% compared to placebo, as determined by ADAS-cog, and the subjects do not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, clinical functional 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, and the subjects do not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, clinical functional decline is reduced by at least 45% compared to placebo, as determined by CDR-SB, and the subjects do not receive concurrent administration of at least one Alzheimer's disease drug. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0175] In some embodiments, clinical functional decline in subjects not receiving concomitant administration of at least one Alzheimer's disease drug is reduced by at least 45% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0176] Concurrent administration of at least one anti-Aβ protofibril antibody and at least one Alzheimer's disease drug other than BAN2401 In some embodiments, the Specified Public provides a method for reducing clinical functional decline in subjects having early Alzheimer's disease, comprising the simultaneous administration of a therapeutically effective dose of at least one anti-Aβ protofibril antibody and at least one Alzheimer's disease drug other than BAN2401. In some embodiments, clinical functional 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 of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0177] In some embodiments, clinical functional impairment is reduced by 15% to 30% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment 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 functional impairment is reduced by at least 23% compared to placebo, as determined by ADCOMS. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0178] In some embodiments, clinical functional decline in subjects receiving a therapeutically effective dose of at least one anti-Aβ protofibril antibody and a therapeutically effective dose of at least one Alzheimer's disease drug other than BAN2401 is reduced by at least 23% compared to placebo, as determined by ADCOMS after 18 months of administration of the therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, at least one anti-Aβ protofibril antibody at 10 mg / kg is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's disease drug is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's disease drug 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 in doses ranging from 5 mg / day to 100 mg / day, 10 mg / day to 75 mg / day, 5 mg / day to 50 mg / day, or 15 mg / day to 50 mg / day. In some embodiments, elenbecestat may be administered in doses ranging from about 5 mg / day to about 100 mg / day, about 10 mg / day to about 75 mg / day, about 5 mg / day to about 50 mg / day, or about 15 mg / day to about 50 mg / day. In some embodiments, elenbecestat may be administered in doses 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 in a dose of 5 mg / day. In some embodiments, elenbecestat may be administered in 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 functional impairment 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 of the clinical functional impairments described above is determined after administering a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0182] In some embodiments, clinical functional 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. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0183] In some embodiments, clinical functional decline is reduced by 30% to 50% compared to placebo, as determined by ADAS-cog, and the subjects are simultaneously administered at least one Alzheimer's disease drug other than BAN2401. In some embodiments, clinical functional decline is reduced by at least 30%, for example, at least 35%, at least 37%, or at least 39%, compared to placebo, as determined by ADAS-cog, and the subjects are simultaneously administered at least one Alzheimer's disease drug other than BAN2401. In some embodiments, clinical functional decline is reduced by at least 39% compared to placebo, as determined by ADAS-cog, and the subjects are simultaneously administered at least one Alzheimer's disease drug other than BAN2401. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0184] In some embodiments, the clinical functional decline in subjects receiving at least one Alzheimer's disease drug concurrently is reduced by at least 39% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains at least one anti-Aβ protofibril antibody at a dose of 10 mg / kg and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's disease drug is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's disease drug 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 in doses ranging from 5 mg / day to 100 mg / day, 10 mg / day to 75 mg / day, 5 mg / day to 50 mg / day, or 15 mg / day to 50 mg / day. In some embodiments, elenbecestat may be administered in doses ranging from about 5 mg / day to about 100 mg / day, about 10 mg / day to about 75 mg / day, about 5 mg / day to about 50 mg / day, or about 15 mg / day to about 50 mg / day. In some embodiments, elenbecestat may be administered in doses 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 in a dose of 5 mg / day. In some embodiments, elenbecestat may be administered in 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 functional 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, where the subject is simultaneously administered at least one Alzheimer's disease drug other than BAN2401. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0188] In some embodiments, clinical functional decline is reduced by 10% to 30% compared to placebo, as determined by CDR-SB, with the subject receiving at least one Alzheimer's disease drug other than BAN2401 concurrently. In some embodiments, clinical functional decline is reduced by at least 10%, e.g., at least 15%, at least 17%, or at least 20% compared to placebo, as determined by CDR-SB, with the subject receiving at least one Alzheimer's disease drug other than BAN2401 concurrently. In some embodiments, clinical functional decline is reduced by at least 20% compared to placebo, as determined by CDR-SB, with the subject receiving at least one Alzheimer's disease drug other than BAN2401 concurrently. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0189] In some embodiments, the clinical functional decline in subjects receiving at least one Alzheimer's disease drug concurrently is reduced by at least 20% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains at least one anti-Aβ protofibril antibody at a dose of 10 mg / kg and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401. In some embodiments, the at least one Alzheimer's disease drug is selected from elenbecestat, donepezil, galantamine, memantine, and rivastigmine. In some embodiments, the at least one Alzheimer's disease drug 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 in doses ranging from 5 mg / day to 100 mg / day, 10 mg / day to 75 mg / day, 5 mg / day to 50 mg / day, or 15 mg / day to 50 mg / day. In some embodiments, elenbecestat may be administered in doses ranging from about 5 mg / day to about 100 mg / day, about 10 mg / day to about 75 mg / day, about 5 mg / day to about 50 mg / day, or about 15 mg / day to about 50 mg / day. In some embodiments, elenbecestat may be administered in doses 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 in a dose of 5 mg / day. In some embodiments, elenbecestat may be administered in a dose of 15 mg / day. In some embodiments, elenbecestat may be administered at a dose of 50 mg / day.

[0192] Reduction of brain amyloid levels Furthermore, this specification also provides a method for reducing brain amyloid levels in a subject in need thereof, which includes 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. In some embodiments, the subject has Alzheimer's disease, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, Lewy body dementia, or another brain disease or condition involving soluble and / or insoluble Aβ aggregates containing Aβ peptides.

[0194] Those skilled in the art will understand that, in addition to subjects with Alzheimer's disease, Aβ plaque deposition is present in the brains of subjects with other neurodegenerative diseases and conditions, and therefore the methods disclosed herein may be beneficial to subjects with such neurodegenerative diseases and / or conditions. Such diseases and conditions are known to include, for example, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and Lewy body dementia (see, for example, 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, subjects with early Alzheimer's disease are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease and / or with mild Alzheimer's dementia. In some embodiments, subjects with early Alzheimer's disease are ApoE4 positive.

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

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

[0198] In some embodiments, the method reduces the brain amyloid level after administration compared to the brain amyloid level before administration. In some embodiments, the brain amyloid level 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%, and less than the brain amyloid level before administration. 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%, less 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%, less Both are reduced by 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%.In some embodiments, the reduction in brain amyloid levels described above is determined by visual interpretation of amyloid PET images and expressed as the PET standard uptake ratio (SUVr value).

[0199] Amyloid positron emission tomography (PET) imaging can be used to confirm the presence of amyloid lesions 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, by both whole-brain analysis (e.g., mean values ​​from 5-6 cortical regions) and brain region analysis. In some embodiments, the mean change from baseline in the subject's adjusted PET SUVr value is a reduction of 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 mean change from the adjusted baseline of the target PET SUVr value is a reduction of -0.20 to -0.30.

[0200] In some embodiments, comparing the cortical mean value to the whole cerebellar reference value, the mean change from baseline of the PET SUVr value in question after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody is at least -0.20, for example, at least -0.25. In some embodiments, the mean change from baseline of the PET SUVr value in question after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody is at least -0.25, for example, at least -0.30.

[0201] In some embodiments, the reduction of amyloid in the brain is determined by imaging visualized by PET using the binding of a radioactive tracer of brain Aβ amyloid. In some embodiments, the mean change reduction from adjusted baseline is at least -50, e.g., at least -55 or at least -59 centoids after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, the mean change reduction from adjusted baseline is at least -60, e.g., at least -65 or at least -70 centoids after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 18 months.

[0202] In some embodiments, the above method is used to administer cerebrospinal fluid Aβ 1-42 Compared to the level of cerebrospinal fluid Aβ 1-42 The level is reduced. In some embodiments, the method reduces the cerebrospinal fluid Aβ before administration. 1-42Compared to the level, 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%, less 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%, less 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% cerebrospinal fluid Aβ 1-42 A reduction in level will occur.

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

[0204] In some embodiments, administration of the composition results in a reduction of 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, where the subjects are ApoE4 negative.

[0205] In some embodiments, administration of this composition results in a reduction of brain amyloid levels of -0.10 to -0.40 as determined by visual interpretation of amyloid PET images, where the subjects are ApoE4 negative. In some embodiments, administration of this composition results in a reduction of brain amyloid levels of at least -0.20 as determined by visual interpretation of amyloid PET images, where the subjects are ApoE4 negative. In some embodiments, administration of this composition results in a reduction of brain amyloid levels of at least -0.25 as determined by visual interpretation of amyloid PET images, where the subjects are ApoE4 negative.

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

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

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

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

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

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

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

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

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

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

[0216] In some embodiments, 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 level 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 level. 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 level of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline.

[0219] 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 level after administering the composition for 18 months. 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 level of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, or at least 13% compared to baseline after administering the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 18 months.

[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, 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 after administering the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 18 months. 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 95 pg / mL compared to baseline after administering the composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 18 months.

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

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

[0224] Treatment methods for Alzheimer's disease Reduction of clinical functional decline This specification provides a method for treating a subject having early 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 functional impairment is reduced by at least 35% compared to placebo after 6 months of administration of the composition as determined by ADCOMS, by at least 30% compared to placebo after 12 months of administration of the composition as determined by ADCOMS, and / or by at least 25% compared to placebo after 18 months of administration of the composition as determined by ADCOMS. In some embodiments, the subject having early Alzheimer's disease is diagnosed with mild to moderate possible cognitive impairment due to Alzheimer's disease, and / or is diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the subject having early Alzheimer's disease is ApoE4 positive.

[0225] In methods for reducing clinical functional decline in subjects with early-stage Alzheimer's disease, any of the anti-Aβ protofibril antibodies, therapeutically acceptable amounts thereof, administration regimens thereof, and compositions thereof disclosed herein may be used. For example, in some embodiments, a composition comprising at least one anti-Aβ protofibril antibody, such as BAN2401, at a dose of 2.5 mg / kg, 5 mg / kg, 7.5 mg / kg, or 10 mg / kg based on the subject's body weight is administered to the subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In some embodiments, clinical functional 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 reduction in clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0226] In some embodiments, clinical functional impairment is reduced by 20% to 35% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by 20% to 30% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by 27% to 35% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 20% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 35% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 20% compared to placebo, as determined by ADCOMS. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by ADCOMS. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0227] In some embodiments, clinical functional impairment is reduced by at least 45% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 6 months. In some embodiments, clinical functional impairment is reduced by at least 35% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months. In some embodiments, clinical functional impairment is reduced by at least 46% compared to placebo, as determined by ADCOMS, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, at least one anti-Aβ protofibril antibody is BAN2401.

[0228] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, less than placebo. A reduction of 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%, where the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0229] In some embodiments, clinical functional decline was reduced by 28% to 33% compared to placebo, as determined by ADCOMS, and subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 20%, e.g., 25%, or at least 28%, compared to placebo, as determined by ADCOMS, and subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 25%, e.g., at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, and subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 25%, e.g., at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 52% compared to placebo, as determined by ADCOMS, in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 52% compared to placebo, as determined by ADCOMS, in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0230] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 25% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered 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 functional impairment was 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% compared to placebo, as determined by ADCOMS, where subjects were diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0232] In some embodiments, clinical functional decline was reduced by 28% to 38% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 20%, e.g., 25%, at least 28%, or at least 33%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 25%, e.g., at least 30%, or at least 33%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 33% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0233] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 33% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0234] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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. The reduction is 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%, and the subjects are diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0235] In some embodiments, clinical functional decline was reduced by 20% to 80% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with Alzheimer's disease. In some embodiments, clinical functional decline was reduced by 35% to 78% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 35% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 50%, for example, at least 52% or at least 53%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 70%, for example, at least 75% or at least 78%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0236] In some embodiments, clinical functional impairment in subjects diagnosed with mild Alzheimer's disease is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in subjects diagnosed with mild Alzheimer's disease is reduced by at least 50% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in subjects diagnosed with mild Alzheimer's disease is reduced by at least 30% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 52% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0237] In some embodiments, clinical functional 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% compared to placebo, as determined by ADCOMS, where subjects are diagnosed with mild Alzheimer's disease type dementia. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0238] In some embodiments, clinical functional decline was reduced by 28% to 38% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 20%, e.g., 25%, at least 28%, or at least 35%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 25%, e.g., at least 30%, or at least 35%, compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 35% compared to placebo, as determined by ADCOMS, and the subjects were diagnosed with mild Alzheimer's disease. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0239] In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 35% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered 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 functional 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 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% lower when determined by ADAS-cog compared to placebo. In some embodiments, the reduction in the clinical functional decline listed above is determined after administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0241] In some embodiments, clinical functional impairment is reduced by 40% to 150% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by 45% to 145% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by 45% to 55% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 35% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 40% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 45% compared to placebo, as determined by ADAS-cog. In some embodiments, clinical functional impairment is reduced by at least 47% compared to placebo, as determined by ADAS-cog. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0242] In some embodiments, clinical functional impairment is reduced by at least 100%, for example, at least 120%, or at least 140%, compared to placebo, as determined by ADAS-cog, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment is reduced by at least 40%, for example, at least 45%, compared to placebo, as determined by ADAS-cog, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment is reduced by at least 40%, for example, at least 45%, compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment is reduced by at least 47%, compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0243] In some embodiments, clinical functional decline, as determined by ADAS-cog, was 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%, and at least 30% compared to placebo. A reduction of 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% is achieved, where the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0244] In some embodiments, clinical functional decline is reduced by 50% to 70% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 58% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0245] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 58% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered 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 functional decline was 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 ADAS-cog, and the subjects were diagnosed with mild Alzheimer's disease type dementia. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0247] In some embodiments, clinical functional decline is reduced by 30% to 50% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 41% compared to placebo, as determined by ADAS-cog, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0248] In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 41% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0249] In some embodiments, clinical functional impairment 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 of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0250] In some embodiments, clinical functional impairment is reduced by 20% to 60% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by 25% to 60% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by 25% to 50% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 20% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 30% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 25%, for example, at least 26% or at least 28%, as determined by the CDR-SB. In some embodiments, clinical functional impairment is reduced by at least 30%, for example, at least 35% or at least 38%, as determined by the CDR-SB. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0251] In some embodiments, clinical functional impairment is reduced by at least 30%, for example, at least 35%, or at least 40%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 6 months. In some embodiments, clinical functional impairment is reduced by at least 30%, for example, at least 35%, or at least 45%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 12 months. In some embodiments, clinical functional impairment is reduced by at least 20%, for example, at least 25%, compared to placebo, as determined by CDR-SB, after administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody for 18 months. In some embodiments, the composition contains at least one anti-Aβ protofibril antibody at a dose of 10 mg / kg and is administered 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 impairment 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, where subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0253] In some embodiments, clinical functional decline is reduced by 10% to 20% compared to placebo, as determined by CDR-SB, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 14% compared to placebo, as determined by CDR-SB, in subjects diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0254] In some embodiments, clinical functional decline in subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 14% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0255] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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%, and at least 26% compared to placebo. The reduction is 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%, where the subjects are diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the reduction in clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0256] In some embodiments, clinical functional decline is reduced by 40% to 60% compared to placebo, as determined by CDR-SB, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional 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, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, clinical functional decline is reduced by at least 51% compared to placebo, as determined by CDR-SB, in subjects diagnosed with mild Alzheimer's disease. In some embodiments, the reduction in clinical functional decline described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0257] In some embodiments, clinical functional decline in subjects diagnosed with mild Alzheimer's disease is reduced by at least 51% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0258] In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 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. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0259] In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for one month. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for six months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for twelve months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for eighteen months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for sixty months. In some embodiments, the reduction in clinical functional decline is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for sixty months.

[0260] In some embodiments, the reduction in clinical functional impairment is determined after administration of a composition containing a therapeutically effective dose of BAN2401.

[0261] In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 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. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 1 month. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 6 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 12 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 18 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 60 months. In some embodiments, the reduction in clinical functional decline is determined after administering a composition containing a therapeutically effective dose of BAN2401 for 63 months.

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

[0263] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and less than placebo. All are reduced by 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%, where the subjects are ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0264] In some embodiments, clinical functional impairment was reduced by 60% to 80%, for example, 63% to 74%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive. In some embodiments, clinical functional impairment was reduced by at least 60%, for example, at least 63%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive. In some embodiments, clinical functional impairment was reduced by at least 65%, for example, at least 67%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive. In some embodiments, clinical functional impairment was reduced by at least 70%, for example, at least 74%, compared to placebo, as determined by ADCOMS, and the subjects were ApoE4 positive.

[0265] In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 70% compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 60% compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 50%, for example, at least 55% or at least 60%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 63% compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0266] In some embodiments, clinical functional decline, as determined by ADAS-cog, was 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%, and 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%, less 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%, small A reduction of 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% is achieved, where the subject is ApoE4 positive. In some embodiments, the reduction in clinical functional impairment listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0267] In some embodiments, clinical functional impairment is reduced by 70% to 400%, for example, 80% to 350%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 70%, for example, at least 75% or at least 80%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 80%, for example, at least 90% or at least 100%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 300%, for example, at least 330%, compared to placebo, as determined by ADAS-cog, and the subjects are ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0268] In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 300% compared to placebo, as determined by ADAS-cog, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 84% compared to placebo, as determined by ADAS-cog, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0269] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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% The levels are reduced by 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%, where the subject is ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0270] In some embodiments, clinical functional impairment is reduced by 35% to 150%, e.g., 40% to 100% or 45% to 90%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 35%, e.g., at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 50%, e.g., at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, clinical functional impairment is reduced by at least 70%, e.g., at least 80% or at least 85%, compared to placebo, as determined by CDR-SB, and the subjects are ApoE4 positive. In some embodiments, the reduction of the clinical functional impairments described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0271] In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 35%, for example, at least 40% or at least 45%, compared to placebo, as determined by CDR-SB, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 70%, for example, at least 75% or at least 80%, compared to placebo, as determined by CDR-SB, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 50%, for example, at least 55% or at least 60%, compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects is reduced by at least 60% compared to placebo, as determined by CDR-SB, after 18 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0272] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and at least 3% compared to placebo. A reduction of 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 is diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0273] In some embodiments, clinical functional decline was reduced by 30% to 70%, e.g., 38% to 59%, compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 30%, e.g., at least 35% or at least 38%, compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 45%, e.g., at least 50% or at least 53%, compared to placebo, as determined by ADCOMS, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 50%, e.g., at least 55% or at least 59%, compared to placebo, as determined by ADCOMS, where the subjects are ApoE4 positive and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0274] In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 containing a therapeutically effective dose 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.

[0275] In some embodiments, clinical functional decline, as determined by ADCOMS, was 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%, and at least 24% compared to placebo. %, 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%, and 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%, little 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%,A reduction of 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 is diagnosed with mild Alzheimer's disease-type dementia. In some embodiments, the reduction of clinical functional decline listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months. ,

[0276] In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 100%, for example, at least 110%, compared to placebo, as determined by ADCOMS, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 100%, for example, at least 110%, compared to placebo, as determined by ADCOMS, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional impairment in ApoE4-positive subjects diagnosed with mild Alzheimer's disease is reduced by at least 65%, for example, at least 70% or at least 75%, compared to placebo, as determined by ADCOMS, after 18 months of administration of a composition containing a therapeutically effective dose 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.

[0277] In some embodiments, clinical functional decline, as determined by ADAS-Cog, was 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%, and 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%, less 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%,A reduction of 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 is diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of the clinical functional declines described above is determined after administering a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0278] In some embodiments, clinical functional decline was reduced by 40% to 300%, e.g., 45% to 250%, or 50% to 250%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 40%, e.g., at least 45%, or at least 50%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional decline was reduced by at least 60%, e.g., at least 70%, at least 75%, or at least 80%, compared to placebo, as determined by ADAS-Cog, where the subjects were ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 100%, e.g., at least 150%, or at least 200%, compared to placebo, as determined by ADAS-Cog, where the subjects are ApoE4 positive, and where the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0279] In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 100%, e.g., at least 150%, or at least 200%, compared to placebo, as determined by ADAS-cog, after 6 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease is reduced by at least 40%, e.g., at least 45%, or at least 50%, compared to placebo, as determined by ADAS-cog, after 12 months of administration of a composition containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease 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 containing a therapeutically effective dose of at least one anti-Aβ protofibril antibody. In some embodiments, the composition contains 10 mg / kg of at least one anti-Aβ protofibril antibody and is administered every two weeks or once a month. In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401.

[0280] In some embodiments, clinical functional decline, as determined by CDR-SB, was 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%, and at least 2% compared to placebo. A reduction of 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 is diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical functional impairment listed above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0281] In some embodiments, clinical functional impairment was reduced by 20% to 90%, e.g., 25% to 80% or 30% to 75%, compared to placebo, as determined by CDR-SB, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by at least 25%, e.g., at least 30%, compared to placebo, as determined by CDR-SB, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment was reduced by at least 30%, e.g., at least 35% or 40%, compared to placebo, as determined by CDR-SB, with subjects being ApoE4 positive and diagnosed with a possible mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical functional impairment is reduced by at least 35%, e.g., at least 40% or 45%, compared to placebo, as determined by CDR-SB, where the subjects are ApoE4 positive and diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical functional impairment described above is determined after administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 1 month, 6 months, 12 months, 18 months, 60 months, and / or 63 months.

[0282] In some embodiments, clinical functional decline in ApoE4-positive subjects diagnosed with mild to moderate 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 administration of a composition containing a therapeutically effective amount of at least one anti-Aβ protofibril antibody for 12 ...

Claims

1. A composition for reducing clinical functional decline in subjects with early-stage Alzheimer's disease by at least 35% compared to placebo, as determined by ADAS-Cog 18 months after treatment, comprising a therapeutically effective amount of anti-Aβ protofibril antibody, The aforementioned subjects were ApoE4 negative, The anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

2. The composition is administered to the subject once every two weeks at a dose of 10 mg / kg of the anti-Aβ protofibril antibody based on the subject's body weight. composition.

2. The composition according to claim 1, wherein the subject is diagnosed with mild cognitive impairment to moderate possibility due to Alzheimer's disease, or is diagnosed with mild Alzheimer's disease type dementia.

3. The composition according to claim 1 or 2, wherein the anti-Aβ protofibril antibody comprises the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO:

12.

4. Aβ １－４２ Total tau, phosphotau, or neurolanin levels are measured. Aβ levels are higher than before treatment. １－４２ The composition according to any one of claims 1 to 3, wherein if the level is above or the total tau, phosphotau, or neurogranin level is below, a further dose of the anti-Aβ protofibril antibody is administered.

5. A composition according to any one of claims 1 to 4, which is used to be administered without titration.

6. A composition according to any one of claims 1 to 5, to be used in combination with at least one maintenance therapy.

7. The composition according to claim 6, wherein at least one maintenance therapy is administered after 18 months of treatment.

8. The composition according to claim 6, wherein the subject is administered at least one maintenance therapy after becoming amyloid-negative.

9. The composition according to any one of claims 6 to 8, wherein the at least one maintenance therapy comprises the anti-Aβ protofibril antibody.

10. The composition according to claim 9, wherein at least one of the maintenance therapies is administered subcutaneously.

11. The composition according to claim 10, wherein the at least one maintenance therapy is administered once a week.

12. The composition according to claim 9, wherein at least one of the maintenance therapies is administered intravenously.

13. The composition according to claim 12, wherein at least one maintenance therapy is administered once every two weeks.

14. The composition according to claim 12, wherein at least one maintenance therapy is administered once every four weeks.

15. The composition according to claim 12, wherein the at least one maintenance therapy is administered once a month.

16. The composition according to any one of claims 12 to 15, wherein the at least one maintenance therapy is administered at a dose of 10 mg / kg of the anti-Aβ protofibril antibody based on the body weight of the subject.

17. A composition according to any one of claims 1 to 16, comprising sodium chloride.

18. The composition according to any one of claims 1 to 17, wherein the reduction in clinical functional impairment includes a reduction in brain amyloid levels determined by visual interpretation of amyloid PET images and expressed as a PET standard uptake ratio (SUVr value), and the mean change from the adjusted baseline of the PET SUVr value of the subject is at least -0.

20.

19. The composition according to any one of claims 1 to 18, wherein the reduction in clinical functional impairment includes a reduction in brain amyloid levels determined by visual interpretation of amyloid PET images and expressed as a PET standard uptake ratio (SUVr value), and the mean change from the adjusted baseline of the PET SUVr value of the subject is at least -0.

25.

20. The composition according to any one of claims 1 to 19, wherein the reduction in the clinical functional impairment includes a reduction in brain amyloid levels determined by visual interpretation of amyloid PET images and expressed as a PET standard uptake ratio (SUVr value), and the mean change from the adjusted baseline of the PET SUVr value of the subject is at least -0.

30.

21. The composition according to any one of claims 1 to 20, wherein the subject is not simultaneously administered any Alzheimer's disease drug other than the anti-Aβ protofibril antibody.

22. The composition according to any one of claims 1 to 21, wherein the subject is monitored for ARIA-E and ARIA-H.

23. The composition according to claim 22, wherein treatment is continued or discontinued if ARIA-E or ARIA-H is detected.

24. The composition according to claim 22 or 23, wherein monitoring includes evaluating the subject three months after administration of the composition.

25. A composition for treating a subject with early-stage Alzheimer's disease, comprising a therapeutically effective amount of anti-Aβ protofibril antibody, The aforementioned subjects were ApoE4 negative, The anti-Aβ protofibril antibody comprises a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 1 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

2. The composition is administered to the subject once every two weeks at a dose of 10 mg / kg of the anti-Aβ protofibril antibody based on the subject's body weight. The clinical functional decline in the aforementioned treatment, as determined by ADAS-Cog 18 months after treatment, is reduced by at least 35% compared to placebo. composition.

26. Aβ １－４２ Total tau, phosphotau, or neurolanin levels are measured. Aβ levels are higher than before treatment. １－４２ The composition according to claim 25, wherein if the level is above or the total tau, phosphotau, or neurogranin level is below, a further dose of the anti-Aβ protofibril antibody is administered.

27. The composition according to any one of claims 1 to 26, wherein the aforementioned clinical functional decline is reduced by 41% compared to placebo when determined by CDR-SB 18 months after administration of the composition.

28. The composition according to any one of claims 1 to 27, wherein the clinical functional impairment is reduced by 43% compared to placebo when determined by ADAS-Cog 18 months after administration of the composition.

29. The composition according to any one of claims 1 to 28, wherein the aforementioned clinical functional decline is reduced by 32% compared to placebo when determined by ADCOMS 18 months after administration of the composition.

30. The composition according to any one of claims 1 to 29, wherein the composition is administered for at least 18 months.

31. The composition according to any one of claims 1 to 30, wherein the composition is administered for at least 24 months.

32. The composition according to any one of claims 1 to 31, wherein the composition is administered intravenously.

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