How to use crenezumab to delay or prevent the onset of Alzheimer's disease

Abstract

Provided herein are methods of treating human patients with familial Alzheimer's disease by administering a humanized monoclonal anti-amyloid beta (Aβ) antibody, resulting in a delay in the onset of symptoms and / or a slowing of cognitive decline.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 351,790, filed June 13, 2022, U.S. Provisional Application No. 63 / 370,100, filed August 1, 2022, and U.S. Provisional Application No. 63 / 385,541, filed November 30, 2022, the disclosures of which are incorporated herein by reference in their entireties.

[0002] Government funding This invention was made with government support, including but not limited to RF1 AG041705 and R01 AG055444.

[0003] Submitting a sequence listing as an ASCII text file The contents of the submission in the following XML file are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 146392062440seqlist.XML, Creation Date: June 12, 2023, Size: (14,016 bytes).

[0004] FIELD OF THE INVENTION The present disclosure relates to methods of delaying the onset of symptoms or slowing cognitive decline by administering crenezumab. [Background technology]

[0005] background Alzheimer's disease (AD) is the most common cause of dementia, affecting an estimated 4.5 million people in the United States and 26.6 million people worldwide (Hebert et al., Arch. Neurol. 2003;60:1119-22; Brookmeyer et al., Alzheimers Dement. 2007;3:186-91). The disease is pathologically characterized by the accumulation of extracellular beta-amyloid ("Aβ") plaques and intracellular neurofibrillary tangles in the brain. Diagnosis is made by clinical evaluation of the neurological and neuropsychiatric signs and symptoms of AD and the exclusion of other causes of dementia. AD is generally classified into stages based on cognitive screening tests such as the Mini-Mental State Examination ("MMSE") or other tests. Currently, there are no known effective treatments approved to modify or prevent disease progression: approved medications, such as those that inhibit acetylcholinesterase ("AChE") activity or antagonize N-methyl-D-aspartate receptors in the brain, may temporarily ameliorate AD symptoms in some patients, but do not modify or prevent disease progression (Cummings, N. Engl. J. Med. 2004;351:56-67).

[0006] The deposition of extracellular amyloid plaques in the brain is a hallmark pathological finding of AD, first described by Alois Alzheimer in 1906. These amyloid plaques are primarily composed of amyloid beta (Aβ) peptides (Haass and Selkoe, Nat. Rev. Mol. Cell Biol. 2007, 8(2):101-112), which are generated by sequential cleavage of the amyloid precursor protein ("APP") via β- and γ-secretase activity. Techniques and tools have been developed to visualize the presence of plaques in patients. For example, to detect Aβ 18 Positron emission tomography ("PET") scans using contrast agents such as F-florbetapir can be used to detect the presence of amyloid in the brain.

[0007] Several genetic factors have been demonstrated in early-onset and late-onset familial AD. Presenilin 1 (PSEN1) alleles are strongly associated with hereditary autosomal dominant AD (ADAD), with clinical onset occurring before age 60 years and Aβ-42 overproduction occurring up to 20 years before symptomatic AD. PET imaging in familial carriers of the PSEN1 E280A mutation provided striking evidence of cerebellar Aβ plaque deposition almost 10 years before ADAD onset (Ghisays et al., NeuroImage: Clinical, 2021;31:102749). Other genetic factors, such as APP and PSEN2, have also been identified and characterized.

[0008] Aβ, particularly in its oligomerized form, is thought to be toxic to neurons and contribute to AD. Therapies that reduce Aβ levels in the brain can alleviate cognitive impairment and block further synaptic loss, axonal degeneration, and neuronal cell death. Aβ can be actively transported across the blood-brain barrier (Deane et al., Stroke, 2004;35(Suppl I):2628-31). In mouse models of AD, systemic delivery of antibodies against Aβ increases plasma Aβ levels while reducing central nervous system (CNS) levels through several proposed mechanisms, including dissolution of brain Aβ plaques, phagocytic clearance of opsonized Aβ, and finally, efflux of Aβ from the brain as a result of an equilibrium shift in Aβ due to circulating antibodies (Morgan (2005), Neurodegener. Dis.;2:261-6).

[0009] Significant failures have marked the development of therapeutic antibodies for the treatment of AD. A large-scale phase 3 clinical trial of bapineuzumab, an IgG1 isotype antibody that specifically binds to the N-terminal portion of Aβ, was halted when administration of the drug failed to halt cognitive decline in treated patients (Miles et al., Scientific Reports. 2013;3:1-4; see also the August 6, 2012, Johnston & Johnson press release, entitled "Johnson & Johnson Announces Discontinuation of Phase 3 Development of Intravenous (IV) Bapineuzumab in Mild-to-Moderate Alzheimer's Disease"). Notably, bapineuzumab appears to stabilize plaque levels and reduce phosphorylated tau levels in the cerebrospinal fluid, suggesting that alterations in these biomarkers alone do not necessarily predict clinical efficacy (Miles et al., Scientific Reports, 2013;3:1-4). Similarly, a phase 3 clinical trial of solanezumab, an antibody specific for monomeric Aβ that binds to the central portion of the peptide, failed to meet its primary cognitive and functional endpoints (Eli Lilly and Company press release, August 24, 2012, "Eli Lilly and Company Announce Topline Results of Phase 3 Solanezumab Clinical Trial in Patients with Alzheimer's Disease"). Safety concerns have also been raised during the investigation of certain immunotherapies for AD: the incidence of amyloid-related imaging abnormalities (ARIA-E and ARIA-H) was greater than 20% among drug-treated patients in a phase 2 clinical trial of bapineuzumab (Sperling et al., The Lancet, 2012;11:241-249). More recently, an IgG1 isotype anti-Aβ antibody that binds to aggregated but not monomeric forms of amyloid beta (aducanumab) was reported to induce ARIA-E, a form of brain edema, in subjects enrolled in a phase 1 clinical trial. In a multiple-dose escalation trial, looking at the subset of subjects carrying the ApoE4 allele, a risk factor for AD, ARIA-E was detected in an increasing percentage of subjects as the dose increased, resulting in an increased percentage of subjects with ARIA-E.Reportedly, 5% of subjects receiving 1 and 3 mg / kg of anti-Aβ antibodies experienced ARIA-E, while 43% and 55% of subjects receiving 6 mg / kg and 10 mg / kg, respectively, experienced ARIA-E. Thus, with increasing dose, the incidence of ARIA-E adverse events also increased. See Gabrielle Strobel's coverage of the 2015 Alzheimer's Association International Conference (Part 4 of 15), www.alzforum.org / news / conference-coverage / aducanumab-solanezumab-gantenerumab-data-lift-crenezumab-well (accessed January 18, 2016). One-third of ARIA-E events were symptomatic in subjects, leading some patients to discontinue or reduce the dose of the anti-amyloid antibody.

[0010] It is estimated that one in nine people over the age of 65 has AD; according to CDC 2020 estimates, 5.8 million people over the age of 65 have AD, a number projected to nearly triple to 14 million by 2060. The CDC has identified AD as the sixth leading cause of death among adults in the United States and the fifth leading cause of death among adults over the age of 65. The total annual costs of health care, long-term care, and hospice care by and on behalf of individuals with AD are estimated to exceed $321 billion in 2022, rising to $1.2 trillion by 2050 (by and on behalf of affected individuals), not considering the combined 12 billion hours spent by 11 million unpaid caregivers, worth an additional $272 billion in 2021 (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures, Alzheimer's and Dementia 18). Currently approved treatments treat only some of the symptoms of AD, but not the underlying degeneration. There is a significant unmet need for safe and effective disease-modifying and disease-preventing therapeutics for AD. Summary of the Invention

[0011] In one aspect, provided herein is a method of delaying the onset of at least one symptom in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody, wherein administering such treatment to a plurality of human patients results in a delay in the onset of at least one symptom in the plurality of human patients compared to a reference onset of the at least one symptom, wherein the reference onset of the at least one symptom is from a plurality of human patients who received a placebo, wherein the antibody comprises six hypervariable regions (HVRs), wherein: (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:8.

[0012] In another aspect, provided herein is a method of slowing cognitive decline in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody, wherein administering such treatment to a plurality of human patients delays cognitive decline in the plurality of human patients compared to reference cognitive decline, wherein the reference cognitive decline is from a plurality of human patients who received a placebo, and wherein the antibody comprises six hypervariable regions (HVRs), wherein (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:8.

[0013] In yet another aspect, provided herein is a method of preventing cognitive impairment in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody, wherein administering such treatment to a plurality of human patients reduces cognitive impairment in the plurality of human patients compared to reference cognitive impairment, wherein the reference cognitive impairment is from a plurality of human patients who received a placebo, and wherein the antibody comprises six hypervariable regions (HVRs), wherein (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO:7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO:8.

[0014] In some embodiments, administering such treatment delays the onset of at least one symptom compared to a reference onset of the at least one symptom after about 5 years or more of treatment.

[0015] In some embodiments, administration of such treatment slows cognitive decline in a plurality of human patients relative to reference cognitive decline after about 5 or more years of treatment.

[0016] In some embodiments, administration of such treatment prevents or reduces cognitive impairment in a plurality of human patients relative to the reference cognitive impairment after about 5 or more years of treatment.

[0017] In some embodiments, delaying the onset of at least one symptom, slowing cognitive decline, or preventing cognitive impairment is measured using the API ADAD cognitive composite test battery, in which administering such a treatment to a plurality of human patients reduces the annualized rate of change in API ADAD composite score for the plurality of human patients relative to a reference annualized rate of change in API ADAD composite score, where the reference annualized rate of change in API ADAD composite score is the annualized rate of change in API ADAD composite score for the plurality of human patients receiving a placebo. In some embodiments, the API ADAD composite cognitive test battery includes Word List Recall, Multilingual Naming Test, Mini-Mental State Examination (MMSE), CERAD Construction Exercise, and Raven's Progressive Matrices. In some embodiments, administering such a treatment reduces the annualized rate of change in API ADAD composite score after about 5 years or more of treatment. In some embodiments, administering such a treatment reduces the annualized rate of change in API ADAD composite score for the plurality of human patients by at least 20% relative to a reference annualized rate of change in API ADAD composite score. In some embodiments, administration of such a treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by at least 30% relative to a reference annual rate of change in API ADAD composite score. In some embodiments, administration of such a treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by 20% to 40% relative to a reference annual rate of change in API ADAD composite score.

[0018] In some embodiments, administering such a treatment to a plurality of human patients reduces the annual rate of change in the Free and Cued Selective Association Task (FCSRT) cue index of the plurality of human patients relative to a reference annual rate of change in the FCSRT cue index, where the reference annual rate of change in the FCSRT cue index is the annual rate of change in the FCSRT cue index of the plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the annual rate of change in the FCSRT cue index of the plurality of human patients compared to the reference annual rate of change in the FCSRT cue index after about 5 years or more of treatment. In some embodiments, administering such a treatment reduces the annual rate of change in the FCSRT cue index of the plurality of human patients by at least 10% relative to the reference annual rate of change in the FCSRT cue index. In some embodiments, administering such a treatment reduces the annual rate of change in the FCSRT cue index of the plurality of human patients by at least 20% relative to the reference annual rate of change in the FCSRT cue index. In some embodiments, administration of such a treatment reduces the annual rate of change in the FCSRT cue index of a plurality of human patients by 10% to about 30% relative to a reference annual rate of change in the FCSRT cue index. In some embodiments, the FCSRT cue index is assessed using controlled learning.

[0019] In some embodiments, administering such a treatment to a plurality of human patients increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in the plurality of human patients relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD, where the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD is the time to progression in the plurality of human patients who received a placebo. In some embodiments, administering such a treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in the plurality of human patients relative to the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD after about 5 years or more of treatment. In some embodiments, administering such a treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in the plurality of human patients by at least 10% compared to the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD. In some embodiments, administering such a treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in a plurality of human patients by at least 20% relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD. In some embodiments, administering such a treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in a plurality of human patients by 10% to 30% relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

[0020] In some embodiments, administering such a treatment to a plurality of human patients increases the time to progression of the Clinical Dementia Rating (CDR) scale global score to non-zero for the plurality of human patients relative to a reference time to progression of the CDR scale global score to non-zero, where the reference time to progression of the CDR scale global score to non-zero is the time to progression for the plurality of human patients who received a placebo. In some embodiments, the CDR scale global score represents impairments in memory, orientation, judgment and problem-solving, social problems, household and hobbies, and personal care. In some embodiments, administering such a treatment increases the time to progression of the CDR scale global score to non-zero for the plurality of human patients by 5% relative to the reference time to progression of the CDR scale global score to non-zero. In some embodiments, administering such a treatment increases the time to progression of the CDR scale global score to non-zero for the plurality of human patients by 10% relative to the reference time to progression of the CDR scale global score to non-zero. In some embodiments, administration of such treatment increases the time to progression of the CDR scale global score to a non-zero score in a plurality of human patients by 5% to 20% relative to a reference time to progression of the CDR scale global score to a non-zero score.

[0021] In some embodiments, administering such a treatment to a plurality of human patients reduces the annualized rate of change in the sum of the boxes on the Clinical Dementia Rating (CDR) scale for the plurality of human patients relative to a reference annualized rate of change in the sum of the boxes on the CDR scale, where the reference annualized rate of change in the sum of the boxes on the CDR scale is the annualized rate of change in the sum of the boxes on the CDR scale in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the annualized rate of change in the sum of the boxes on the CDR scale for a plurality of human subjects compared to the reference annualized rate of change in the sum of the boxes on the CDR scale after about 5 years or more of treatment. In some embodiments, administering such a treatment reduces the annualized rate of change in the sum of the boxes on the CDR scale global score for a plurality of human patients by at least 5% relative to a reference sum of the boxes on the CDR scale global score. In some embodiments, administering such a treatment reduces the annualized rate of change in the sum of the boxes on the CDR scale global score for a plurality of human patients by at least 10% relative to a reference sum of the boxes on the CDR scale global score. In some embodiments, administration of such treatment reduces the annual rate of change in the global sum of boxes score of the CDR measure in a plurality of human patients by 5% to 20% relative to the global sum of boxes score of the reference CDR measure.

[0022] In some embodiments, administering such a treatment to a plurality of human patients reduces the annual rate of change in a measure of global neurocognitive function for the plurality of human patients relative to a reference annual rate of change in the measure of global neurocognitive function, where the reference annual rate of change in the measure of global neurocognitive function is the annual rate of change in the measure of global neurocognitive function for a plurality of human patients receiving a placebo. In some embodiments, the annual rate of change in the measure of global neurocognitive function is determined using a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score. In some embodiments, administering such a treatment reduces the annual rate of change in the RBANS score for the plurality of human patients relative to a reference annual rate of change in the RBANS score, where the reference annual rate of change in the RBANS score is the annual rate of change in the RBANS score for a plurality of human patients receiving a placebo. In some embodiments, administering such a treatment reduces the annual rate of change in the RBANS score for the plurality of human patients relative to the reference annual rate of change in the RBANS score after about 5 years or more of treatment. In some embodiments, administering such a treatment reduces the RBANS score by at least 30% relative to the reference RBANS score. In some embodiments, administration of such a treatment results in a reduction in the RBANS score of at least 40% relative to a reference RBANS score, hi some embodiments, administration of such a treatment results in a reduction in the RBANS score of 30% to 50% relative to a reference RBANS score.

[0023] In some embodiments, administering such a treatment to a plurality of human patients results in an effect on a tau-based CSF biomarker relative to a reference tau-based CSF biomarker, where the reference tau-based CSF biomarker is a tau-based CSF biomarker from a plurality of human patients who received a placebo. In some embodiments, the tau-based CSF biomarker is measured using positron emission tomography. In some embodiments, administering such a treatment reduces the annual rate of change of the tau-based CSF biomarker in the plurality of human patients compared to a reference annual rate of change of the tau-based CSF biomarker, where the reference tau-based CSF biomarker is a tau-based CSF biomarker from a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the annual rate of the tau-based CSF biomarker in the plurality of human patients by at least 30% relative to the reference tau-based CSF biomarker, where the tau-based CSF biomarker is a phospho-tau (ptau)-based CSF biomarker. In some embodiments, administration of such treatment results in a 30% to 50% reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker. In some embodiments, administration of such treatment results in a at least 20% reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau [ttau]-based CSF biomarker. In some embodiments, administration of such treatment results in a 20% to 40% reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau [ttau]-based CSF biomarker.

[0024] In some embodiments, administering such a treatment to a plurality of human patients produces an effect on brain tau load compared to a reference brain tau load, where the reference brain tau load is the brain tau load of a plurality of human patients who received a placebo. In some embodiments, the brain tau load is measured using positron emission tomography (tau PET). In some embodiments, administering such a treatment reduces the annual rate of change in tau PET measurements of a plurality of human patients relative to a reference annual rate of change in tau PET measurements, where the reference annual rate of change in tau PET measurements is the annual rate of change in tau PET measurements of a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the normalized uptake value ratio (SUVR) of entorhinal cortex (ERC) tau PET measurements in a plurality of human patients compared to a reference SUVR for ERC tau PET, where the reference SUVR for ERC tau PET is the SUVR for ERC tau PET of a plurality of human patients who received a placebo. In some embodiments, the tau PET is measured using a [ 18 Tau PET is measured using tau probe 1, which is [F]GTP1. In some embodiments, administration of such a treatment reduces the annual incidence of tau PET in a plurality of human patients by at least 50% relative to a reference tau PET. In some embodiments, administration of such a treatment reduces the annual incidence of tau PET in a plurality of human patients by 40% to 60% relative to a reference tau PET.

[0025] In some embodiments, administering such a treatment to a plurality of human patients reduces the brain fibrillary amyloid burden in a predetermined region of interest of the plurality of human patients relative to a reference brain fibrillary amyloid burden in the predetermined region of interest, where the reference brain fibrillary amyloid burden in the predetermined region of interest is the brain fibrillary amyloid burden in the predetermined region of interest of a plurality of human patients who received a placebo. In some embodiments, the brain fibrillary amyloid burden is measured using florbetapir positron emission tomography (PET). In some embodiments, administering such a treatment reduces the annual rate of change in amyloid burden in the plurality of human patients compared to a reference annual rate of change in amyloid burden, where the reference annual rate of change in amyloid burden is the annual rate of change in amyloid burden in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the annual rate of change in amyloid burden measured by PET in the plurality of human patients by 3% relative to the reference amyloid burden measured by PET. In some embodiments, administration of such a treatment reduces the annual rate of change in amyloid burden measured by PET in a plurality of human patients by 3% to 10% relative to a reference amyloid burden measured by PET. In some embodiments, administration of such a treatment to a plurality of human patients reduces the decline in regional cerebral metabolic rate of glucose (CMRgI) in the plurality of human patients relative to a reference CMRgI, where the reference CMRgI is the CMRgI of a plurality of human patients who received a placebo. In some embodiments, the CMRgI is measured using FDG (fluorodeoxyglucose)-positron emission tomography (PET). In some embodiments, administration of such a treatment reduces FDG PET measurements in the plurality of human patients relative to a reference FDG PET measurement, where the reference FDG PET measurement is the FDG PET measurement of a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment reduces the decline in regional CMRgI in the plurality of human patients relative to the reference CMRgI after about 5 or more years of treatment.In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients relative to a reference annualized SUVR for FDG PET, where the reference annualized SUVR for FDG PET is the SUVR for FDG PET in a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by at least 10% relative to the reference annualized SUVR for FDG PET. In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by 10% to 30% relative to the reference annualized SUVR for FDG PET.

[0026] In some embodiments, administering such a treatment to a plurality of human patients reduces brain atrophy in the plurality of human patients relative to a reference brain atrophy, where the reference brain atrophy is the brain atrophy of a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces brain atrophy in the plurality of human patients relative to the reference brain atrophy after about 5 years or more of treatment.

[0027] In some embodiments, administering such a treatment to a plurality of human patients reduces the annual rate of change in brain atrophy in the plurality of human patients relative to a reference annual rate of change in brain atrophy, where the reference annual rate of change in brain atrophy is the annual rate of change in brain atrophy in the plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the annual rate of change in brain atrophy in the plurality of human patients relative to the reference annual rate of change in brain atrophy after about 5 years or more of treatment. In some embodiments, brain atrophy is measured using volumetric MRI. In some embodiments, the volumetric MRI is measured on the whole brain. In some embodiments, administering such a treatment reduces the annual rate of change in brain atrophy in the plurality of human patients by at least 5% relative to a reference brain atrophy, where the reduction is measured by volumetric MRI of the whole brain. In some embodiments, administering such a treatment reduces the annual rate of change in brain atrophy in the plurality of human patients by 5% to 20% relative to a reference brain atrophy, where the reduction is measured by volumetric MRI of the whole brain.

[0028] In some embodiments, volumetric MRI is measured on both hippocampi. In some embodiments, administration of such treatment results in a reduction in the annual rate of change in brain atrophy of a plurality of human patients by at least 1% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such treatment results in a reduction in the annual rate of change in brain atrophy of a plurality of human patients by 1% to 10% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi.

[0029] In some embodiments, administering such a treatment results in a reduction in change above baseline in a cognitive measure of a plurality of human patients compared to a reference cognitive measure, where the reference cognitive measure is a cognitive measure of a plurality of human patients who received a placebo, and the cognitive measure is selected from the group consisting of: i) a Trial Creation Test, ii) the Mini-Mental State Examination (MMSE), iii) the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) index score, iv) scores on each component of the API ADAD Composite Cognitive Test Battery, v) the Preclinical Alzheimer's Disease Cognitive Composite (PACC), and vi) other clinical endpoints. In some embodiments, administering such a treatment results in a reduction in change above baseline in a cognitive measure of a plurality of human patients compared to the reference cognitive measure after about 5 years or more of treatment.

[0030] In some embodiments, administering such treatment results in a statistically significant reduction in the change above baseline in a neuropsychiatric inventory (NPI) of a plurality of human patients compared to a reference NPI, where the reference NPI is an NPI of a plurality of human patients who received a placebo. In some embodiments, administering such treatment results in a statistically significant reduction in the change above baseline in the NPI after about 5 years or more of treatment.

[0031] In some embodiments, administering such treatment results in a statistically significant reduction in the change above baseline in the Geriatric Depression Scale (GDS) of a plurality of human patients compared to a reference GDS, where the reference GDS is the GDS of a plurality of human patients who received a placebo. In some embodiments, administering such treatment results in a reduction in the change above baseline in the GDS after about 5 years or more of treatment.

[0032] In some embodiments, administering such a treatment reduces the change above baseline in the Functional Assessment of Alzheimer's Disease Staging (FAST) total score for a plurality of human patients compared to a reference FAST total score, where the reference FAST total score is the FAST total score for a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces the change above baseline in the FAST total score after about 5 or more years of treatment.

[0033] In some embodiments, administering such treatment results in a reduction in the change above baseline in a change on the subject memory checklist for a plurality of human patients compared to a reference change on the subject memory checklist, where the reference change on the subject memory checklist is the change on the subject memory checklist for a plurality of human patients who received a placebo. In some embodiments, administering such treatment reduces the change above baseline in the change in subject memory checklist score after about 5 or more years of treatment.

[0034] In some embodiments, the genetic mutation causing familial AD is an autosomal dominant mutation causing autosomal dominant Alzheimer's disease (ADAD). In some embodiments, the ADAD comprises one or more mutations in one or more genes selected from the group consisting of presenilin 1 (PSEN1), presenilin 2 (PSEN2), and / or amyloid precursor protein (APP).

[0035] In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered intravenously.

[0036] In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is administered at a dose of about 60 mg / kg or more; or b) a fixed dose of 4200 mg or more; or c) a fixed dose of about 4200 mg. In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered about every four weeks (Q4W). In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered about Q4W for about 5 years.

[0037] In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered subcutaneously. In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered at a dose of about 720 mg or more. In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered weekly (Q2W). In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered about Q2W for about 5 years. In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered at a dose of about 300 mg.

[0038] In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 11.

[0039] In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:5 and a light chain comprising the amino acid sequence of SEQ ID NO:9.

[0040] In some embodiments, the humanized monoclonal anti-amyloid beta (Aβ) antibody is crenezumab.

[0041] In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients relative to a reference SUVR for amyloid PET, where the reference SUVR for amyloid PET is the SUVR for amyloid PET in a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by at least 3% relative to the reference SUVR for amyloid PET. In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by at least 10% relative to the reference SUVR for amyloid PET. In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by 3% to 10% relative to the reference SUVR for amyloid PET.

[0042] In some embodiments, administration of such a treatment reduces cerebrospinal fluid (CSF) neurofilament light (CSF NfL) in a plurality of human patients relative to a reference CSF NfL, the reference CSF NfL being derived from a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment reduces CSF NfL in a plurality of human patients by at least 10% relative to the reference CSF NfL. In some embodiments, administration of such a treatment reduces CSF NfL in a plurality of human patients by at least 20% relative to the reference CSF NfL. In some embodiments, administration of such a treatment reduces CSF NfL in a plurality of human patients by 10%-20% relative to the reference CSF NfL.

[0043] In some embodiments, administering such treatment to a plurality of human patients produces an effect on plasma biomarkers compared to a reference plasma biomarker, the reference plasma biomarker being a plasma biomarker from a plurality of human patients receiving a placebo. In some embodiments, the plasma biomarker is measured using an immunoassay. In some embodiments, the plasma biomarker is any one of Aβ42, Aβ40, pTau181, pTau217, NfL, GFAP, YKL-40, or sTREM2. In some embodiments, the plasma biomarker is the ratio of Aβ42 to Aβ40.

[0044] In some embodiments, administering such treatment results in an increase in the annualized rate of change of the plasma Aβ42 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma Aβ42 biomarker, wherein the reference plasma Aβ42 biomarker is the annualized rate of change of the plasma Aβ42 biomarker in a plurality of human patients who received a placebo.

[0045] In some embodiments, administering such treatment results in an increase in the annualized rate of change of the plasma Aβ40 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma Aβ40 biomarker, wherein the reference plasma Aβ40 biomarker is the annualized rate of change of the plasma Aβ40 biomarker in a plurality of human patients who received a placebo.

[0046] In some embodiments, administering such treatment results in a reduction in the annualized rate of change of the plasma pTau181 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma pTau181 biomarker, wherein the reference plasma pTau181 biomarker is the annualized rate of change of the plasma pTau181 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such treatment results in a reduction in the annualized rate of change of the plasma pTau181 biomarker in a plurality of human patients by about 6% relative to the reference plasma pTau181 biomarker.

[0047] In some embodiments, administering such treatment results in a reduction in the annualized rate of change of the plasma pTau217 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma pTau217 biomarker, wherein the reference plasma pTau217 biomarker is the annualized rate of change of the plasma pTau217 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such treatment results in a reduction in the annualized rate of change of the plasma pTau217 biomarker in a plurality of human patients by about 9% relative to the reference plasma pTau217 biomarker.

[0048] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma neurofilament light (NfL) biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma NfL biomarker, where the reference plasma NfL biomarker is the annualized rate of change of the plasma NfL biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma NfL biomarker in a plurality of human patients by about 10% relative to the reference plasma NfL biomarker.

[0049] In some embodiments, administering such treatment results in a reduction in the annualized rate of change of the plasma GFAP biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma GFAP biomarker, where the reference plasma GFAP biomarker is the annualized rate of change of the plasma GFAP biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such treatment results in a reduction in the annualized rate of change of the plasma GFAP biomarker in a plurality of human patients by about 17% relative to the reference plasma GFAP biomarker.

[0050] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma YKL-40 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma YKL-40 biomarker, where the reference plasma YKL-40 biomarker is the annualized rate of change of the plasma YKL-40 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma YKL-40 biomarker in a plurality of human patients by about 12% relative to the reference plasma YKL-40 biomarker.

[0051] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma sTREM2 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma sTREM2 biomarker, where the reference plasma sTREM2 biomarker is the annualized rate of change of the plasma sTREM2 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma sTREM2 biomarker in a plurality of human patients by about 23% relative to the reference plasma sTREM2 biomarker.

[0052] In another aspect, provided herein is a kit comprising a humanized monoclonal anti-amyloid beta (Aβ) antibody for treating a human patient in need thereof having a genetic mutation that causes familial Alzheimer's disease (AD), according to the methods described herein.

[0053] In yet another aspect, provided herein are humanized monoclonal anti-amyloid beta (Aβ) antibodies for use in treating a human patient in need thereof, having a genetic mutation that causes familial Alzheimer's disease (AD), according to the methods described herein. [Brief explanation of the drawings]

[0054] [Figure 1A] An overview of the clinical trial treatment groups is shown. [Figure 1B]An overview of the clinical trial design and subsection timeline is provided. [Figure 2A] An overview of the clinical trial treatment groups is shown. [Figure 2B] An overview of the clinical trial design and changes in dosing regimen are provided. [Figure 3] Treatment exposure over the course of the trial is indicated. All participants who received at least one dose of study drug, including both carriers and non-carriers, are included. IV refers to intravenous administration, and SC refers to subcutaneous administration. [Figure 4] Results of the dual primary and key secondary outcomes are shown. Forest plots show the mean annual rate / risk reduction and 95% confidence intervals in the crenezumab carrier group compared with the placebo carrier group. *P values are for tests of differences between the crenezumab and placebo carrier groups and are not corrected for multiple comparisons. [Figure 5] Kaplan-Meier curves for time to MCI or AD dementia are shown, stratified by baseline age, education, CDR global score, and APOE4 carrier status. [Figure 6] Results of the primary outcome by baseline amyloid status are shown. [Figure 7] Baseline AβPET measurements are shown. Abbreviations are as follows: Aβ, amyloid-beta; AD, Alzheimer's disease; PET, positron emission tomography; SUVR, standard uptake value ratio. [Figure 8]Biomarker outcomes in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups are shown. Forest plots show the mean annual percentage / risk reduction and 95% confidence intervals in the crenezumab carrier group compared with the placebo carrier group. Abbreviations are as follows: Aβ, Alzheimer's disease; APOE4, apolipoprotein E4; CI, confidence interval; CSF, cerebrospinal fluid; ERC, entorhinal cortex; FDG, fluorodeoxyglucose; GTP1, Genentech tau probe 1; NfL, neurofilament light chain; PET, positron emission tomography; pTau, phosphorylated tau; RCRM, random coefficient regression model; sROI, statistical region of interest; SUVR, standardized uptake value ratio; tTau, total tau; vMRI, volumetric magnetic resonance imaging. *P values are for testing differences between the crenezumab and placebo carrier groups and are not corrected for multiple comparisons. [Figure 9] Amyloid-β PET changes are shown in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. Florbetapir SUVR is the mean of cortex-white matter florbetapir SUVR. The left plot shows mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 10]FDG PET changes are shown in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. sROI FDG SUVR is the FDG (fluorodeoxyglucose) standardized uptake value ratio (SUVR) in a prespecified statistical region of interest (ROI) that is preferentially associated with a decline in AD-related CMRgl (cerebral metabolic rate of glucose). The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-visit interaction, and treatment-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 11] Figure 1 shows CSF amyloid-β42 changes in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. The left plot shows mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 12] Figure 1 shows CSF Aβ40 changes in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. The left plot shows mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 13]Figure 1 shows CSF pTau181 changes in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. The left plot shows mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 14] Figure 1 shows CSF total tau changes in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. The left plot shows mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 15] Figure 1 shows CSF NfL (neurofilament light) changes (Log10) in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 16]Figure 1 shows MRI brain volume changes in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. The mean annual percent change reflects the mean percent difference between the first and last scans. Hippocampal and ventricular volume changes were calculated using FreeSurfer (version 7.1). Whole brain volume changes were calculated using Banner's iterative principal component analysis (IPCA). [Figure 17] Tau PET changes are shown in crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. Tau PET was introduced later in the study. Due to variability in tau PET visits, only LOESS plots are shown. [Figure 18] Baseline plasma biomarker findings for the study are shown. Included participants received at least one dose of study drug and had at least one plasma measurement. Measurements of Aβ42, Aβ40, and Aβ42 / 40 exclude two outliers within the noncarrier group. YKL-40 is in μg / mL; sTREM2 is in ng / mL; all other Log10 concentrations are in pg / mL. Abbreviations are as follows: Aβ, amyloid-beta; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; pTau, phosphorylated tau; SD, standard deviation; sTREM2, soluble triggering receptor expressed on myeloid cells 2; YKL-40, chitinase 3-like protein 1. [Figure 19] Associations between plasma biomarkers and age are shown. The y-axis shows baseline plasma levels (locally estimated scatterplot smoothing); the x-axis shows participant age; each plot is labeled with the analyzed biomarker. Data exclude plasma Aβ42, Aβ40, and Aβ42 / 40 measurements from two outliers in the non-carrier group. [Figure 20] Long-term plasma biomarker changes in placebo carriers and non-carriers are shown. The y-axis shows change from baseline (locally estimated scatterplot smoothing); the x-axis shows study years; each plot is labeled with the analyzed biomarker. The data exclude two outliers in the non-carrier group: plasma Aβ42, Aβ40, and Aβ42 / 40 measurements. [Figure 21] Changes in plasma Aβ42 in crenezumab- and placebo-treated patients are shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 22] Changes in plasma Aβ40 in crenezumab- and placebo-treated patients are shown. The plot on the left shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the plot on the right shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 23] 1 shows plasma biomarker outcomes in crenezumab- and placebo-treated carriers. Forest plots show the mean reduction and 95% CI of biomarker progression in the crenezumab-carrier group compared to the placebo-carrier group. [Figure 24] Log10 plasma pTau181 change in crenezumab- and placebo-treated carriers is shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 25]Log10 plasma pTau217 change in crenezumab- and placebo-treated carriers is shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 26] Log10 plasma NfL change in crenezumab- and placebo-treated patients is shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 27] Log10 plasma GFAP change in crenezumab- and placebo-treated patients is shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 28]Log10 plasma YKL-40 change in crenezumab- and placebo-treated carriers is shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. [Figure 29] Log10 plasma sTREM2 change in crenezumab- and placebo-treated carriers is shown. The left plot shows a mixed-model repeated measures (MMRM) analysis, with the Y-axis showing least-squares (LS) mean change from baseline, and the right plot shows locally weighted scatterplot smoothing (LOESS). The MMRM analysis was adjusted for baseline score, baseline age, education, APOE4, CDR GS, treatment, visit, baseline-by-visit interaction, and treatment-by-visit interaction to estimate the mean change from baseline; P values are uncorrected for multiple comparisons. DETAILED DESCRIPTION OF THE INVENTION

[0055] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, NY 1992) provide those skilled in the art with a general guide to many of the terms used in this application.

[0056] All references mentioned in this application are incorporated herein by reference in their entirety.

[0057] I. Definition For purposes of interpreting this specification, the following definitions shall apply, and whenever appropriate, terms used in the singular shall also include the plural and vice versa. In the event that any definition set forth below conflicts with any document incorporated herein by reference, the definition set forth below shall control.

[0058] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a protein" or "an antibody" includes a plurality of proteins or antibodies, reference to "a cell" includes a mixture of cells, and so forth.

[0059] Ranges provided in this specification and the appended claims include both endpoints and all points between those endpoints, so for example, a range of 2.0 to 3.0 includes 2.0, 3.0, and all points between 2.0 and 3.0.

[0060] The term "sample" or "test sample" as used herein refers to a composition obtained from or derived from a subject of interest, containing cells and / or other molecular entities to be characterized and / or identified, for example, based on physical, biochemical, chemical, and / or physiological properties. In one embodiment, the definition encompasses blood and other liquid samples of biological origin, as well as tissue samples, such as biopsy specimens or tissue cultures or cells derived therefrom. Sources of tissue samples may include fresh, frozen, and / or preserved organ or tissue samples, or solid tissue from biopsies or aspirates; blood or any blood components; body fluids, including cerebrospinal fluid; and cells from any stage in a subject's pregnancy or development, or plasma. The term "biological sample" as used herein includes, but is not limited to, blood, serum, plasma, sputum, and tissue biopsies (e.g., brain samples).

[0061] The terms "sample," "biological sample," or "test sample" may also include biological samples that have been manipulated in some way after their procurement, such as by treatment with reagents, solubilization or enrichment of specific components such as proteins or polynucleotides, or embedding in a semi-solid or solid matrix for sectioning purposes. For purposes of this specification, a "section" of a tissue sample means a single portion or piece of a tissue sample, e.g., a thin slice of tissue or cells cut from a tissue sample. Samples include, but are not limited to, whole blood, blood-derived cells, serum, plasma, lymph, synovial fluid, cell extracts, and combinations thereof. In one embodiment, the sample is a clinical sample. In another embodiment, the sample is used in a diagnostic assay.

[0062] In one embodiment, the sample is obtained from the subject or patient prior to treatment with an anti-Aβ antibody, hi another embodiment, the sample is obtained from the subject or patient after at least one treatment with an anti-Aβ antibody.

[0063] As used herein, a "reference" or "reference sample" refers to any sample, standard, or level used for comparison purposes. In some embodiments, the reference is a measurement obtained from an individual not treated with an anti-Aβ antibody. In some embodiments, the reference is a measurement obtained from an individual administered a placebo.

[0064] In certain embodiments, the reference sample is a single sample or a combination of multiple samples from the same subject or patient obtained at one or more time points different from when the test sample is obtained. For example, the reference sample is obtained from the same subject or patient at an earlier time point than when the test sample is obtained. In certain embodiments, the reference sample includes all types of biological samples, as defined above under the term "sample," obtained from one or more individuals who are not subjects or patients. In some embodiments, the reference sample is obtained from a subject who has received a placebo. In certain embodiments, the reference sample is obtained from one or more individuals with Alzheimer's disease who are not subjects or patients.

[0065] In certain embodiments, the reference sample is a combination of multiple samples from one or more healthy individuals who are not subjects or patients. In certain embodiments, the reference sample is a combination of multiple samples from one or more individuals who are not subjects or patients and have a disease or disorder (e.g., Alzheimer's disease). In certain embodiments, the reference sample is a pooled RNA sample from normal tissue, or a pooled plasma or serum sample from one or more individuals who are not subjects or patients.

[0066] The term "small molecule" refers to an organic molecule having a molecular weight between 50 and 2500 daltons.

[0067] The terms "antibody" and "immunoglobulin" ("Ig") are used interchangeably in the broadest sense and include, but are not limited to, monoclonal antibodies (e.g., full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, antibodies with polyepitopic specificity, single-chain antibodies, multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies, tetraspecific antibodies), and fragments of antibodies, provided that they exhibit the desired biological activity. Such antibodies may be chimeric, humanized, human, synthetic, and / or affinity matured. Such antibodies and methods of producing them are described in more detail herein.

[0068] An "antibody fragment" preferably comprises only a portion of an intact antibody, which portion retains at least one, and typically most or all, of the functions normally associated with that portion when present in an intact antibody. In one embodiment, an antibody fragment comprises the antigen-binding site of an intact antibody and thus retains the ability to bind to antigen. In another embodiment, an antibody fragment, e.g., an antibody fragment comprising an Fc region, retains at least one of the biological functions normally associated with the Fc region when present in an intact antibody, such as FcRn binding, antibody half-life regulation, ADCC function, and complement fixation. In one embodiment, an antibody fragment is a monovalent antibody with an in vivo half-life substantially similar to that of an intact antibody. For example, such an antibody fragment may comprise an antigen-binding arm attached to an Fc sequence, which may confer in vivo stability to the fragment. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0069] As used herein, the term "target" refers to any native molecule from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses "full-length" unprocessed targets, as well as any form of target resulting from processing within a cell. The term also encompasses naturally occurring variants of the target, such as splice variants or allelic variants.

[0070] The terms "amyloid beta," "beta-amyloid," "Abeta," "amyloid β," and "Aβ," used interchangeably herein, refer to a fragment of amyloid precursor protein ("APP") produced upon β-secretase 1 ("BACE1") cleavage of APP, as well as modifications, fragments, and any functional equivalents thereof, including, but not limited to, Aβ1-40 and Aβ1-42. Aβ is known to exist in a monomeric form and to associate to form oligomeric and fibrillar structures, which can be found as constituent members of amyloid plaques. The structure and sequence of such Aβ peptides are well known to those skilled in the art, and methods for producing the peptides or extracting them from brain and other tissues are described, for example, in Glenner and Wong, Biochem Biophys Res. Comm. 129:885-890 (1984). Furthermore, Aβ peptides are also commercially available in various forms. An exemplary amino acid sequence of human Aβ1-42 is DAEFRHDSGYEVHHQKLVFFAED VGSNKGAIIGLMVGGVVIA (SEQ ID NO: 1).

[0071] "Anti-Aβ immunoglobulin," "anti-Aβ antibody," and "antibody that binds to Aβ" are used interchangeably herein and refer to an antibody that specifically binds to human Aβ. A non-limiting example of an anti-Aβ antibody is crenezumab.

[0072] The terms "crenezumab" and "MABT5102A" are used interchangeably herein and refer to a specific anti-Aβ antibody that binds to monomeric, oligomeric, and fibrillar forms of Aβ and is related to CAS Registry Number 1095207. Crenezumab comprises: (1) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO:2; (2) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO:3; (3) an HVR-H3 sequence comprising the amino acid sequence of SEQ ID NO:4; (4) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO:6; (5) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO:7; and (6) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the specific anti-Aβ antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:5 and a light chain comprising the amino acid sequence of SEQ ID NO:9. In another such embodiment, the specific anti-Aβ antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO:10 and a VL domain comprising the amino acid sequence of SEQ ID NO:11. In another embodiment, the antibody is an IgG4 antibody. In another such embodiment, the IgG4 antibody comprises a mutation in its constant domain such that serine 228 is replaced by proline.

[0073] The term "familial AD" refers to Alzheimer's disease in which the patient has a family history of AD and / or is a carrier of a genetic mutation that causes AD and / or influences the progression of AD.

[0074] The term "autosomal dominant AD" or "ADAD" refers to AD in which the genetic mutation is an autosomal dominant mutation, such that being a carrier of the mutation is associated with a higher likelihood of developing AD and / or AD progression in the carrier.

[0075] The term "therapeutic agent" refers to any agent used to treat a disease, including, but not limited to, agents that treat the symptoms of the disease.

[0076] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to a clinical intervention aimed at altering the natural history of the individual being treated and may occur during the clinical pathology process. Desirable effects of treatment include, but are not limited to, alleviation or amelioration of one or more symptoms, reduction or delay in the appearance or worsening of any direct or indirect pathological consequence of the disease, reduction in the rate of disease progression, and improvement or palliation of the disease state. In some embodiments, antibodies are used to delay disease onset or slow the progression of a disease such as AD.

[0077] As used herein, the term "treatment-emergent" refers to an event that occurs after the first dose of a therapeutic agent is administered. For example, a "treatment-emergent adverse event" is an event that is identified during or after the first dose of treatment in a clinical study.

[0078] A "treatment regimen" refers to a combination of dosages, frequency of administration, or duration of treatment, with or without the addition of a second drug.

[0079] An "effective treatment regimen" refers to a treatment regimen that results in a beneficial response in the patient receiving the treatment.

[0080] "Modifying treatment" refers to changes in the treatment regimen, including changing the dosage, frequency of administration, or duration of treatment, and / or adding a second drug.

[0081] An "effective amount" or "effective dose" of a drug refers to an amount or dose effective for a period of time necessary to achieve a desired result. For example, a "therapeutically effective amount" is an amount effective for a period of time necessary to treat the indicated disease, condition, clinical pathology, or symptom, i.e., to modify the course of AD and / or alleviate and / or prevent one or more symptoms of AD.

[0082] "Affinity" or "binding affinity" refers to the total strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen-binding arm). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein, any of which can be used for purposes of the present invention. Specific illustrative, exemplary embodiments for measuring binding affinity are described herein.

[0083] An "affinity matured" antibody refers to an antibody that has one or more changes in one or more hypervariable regions (HVRs) compared to a parent antibody that does not have such modifications, and such changes improve the affinity of the antibody for antigen.

[0084] As used herein, the term "patient" refers to any single subject for whom treatment is desired. In certain embodiments, a patient herein is a human.

[0085] The term "subject" as used herein typically refers to a human. Typically, the subject is eligible for treatment and has a genetic mutation associated with AD, such as a mutation that causes or is predicted to cause familial AD. A qualified subject or patient is at risk of developing AD based on a genetic mutation. The subject may not have signs or symptoms of AD, such as MCI. The diagnosis of AD or the risk of developing AD can be based on medical history, clinical examination, established imaging modalities, and / or genetic testing. The term "patient" or "subject" as used herein includes any single human subject who is eligible for treatment and has a genetic mutation that causes familial AD. The subject is intended to include any subject involved in a clinical research trial, or a subject involved in an epidemiological study, or a subject who has once been used as a control.

[0086] As used herein, the "lifespan" of a subject refers to the remainder of the subject's life after treatment begins.

[0087] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific for a single antigen. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0088] Monoclonal antibodies herein specifically include "chimeric" antibodies in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Pat. No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci. USA, 1984;81:6851-6855).

[0089] The "class" of an antibody refers to the type of constant domain or constant region carried by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into "subclasses" (or "isotypes"), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0090] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. Most often, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody), such as mouse, rat, rabbit, or non-human primate, possessing the desired specificity, affinity, and capacity. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in either the recipient antibody or the donor antibody. These modifications are made to further refine antibody performance. In general, humanized antibodies comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin lo sequence. The humanized antibody optionally also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 1986; 321:522-525; Riechmann et al., Nature, 1988; 332:323-329; and Presta, Curr. Op. Struct. Biol. 1992; 2:593-596. See also the following reviews and references cited therein: Vaswani and Hamilton,Ann.Allergy,Asthma&Immunol.,1998;1:105-115;Harris,Biochem.Soc.Transactions,1995;23:1035-1038;Hurle and Gross,Curr.Op.Biotech.,1994;5:428-433.

[0091] A "human antibody" is one that contains an amino acid sequence that corresponds to that of an antibody produced by a human or human cell, and / or that contains amino acids that correspond to that of an antibody derived from a non-human source that utilizes the human antibody repertoire or other human antibody-encoding sequences (e.g., produced using any of the techniques for producing human antibodies as disclosed herein). Such techniques include screening combinatorial libraries of human origin, such as phage display (see, e.g., Marks et al., J. Mol. Biol., 1991;222:581-597 and Hoogenboom et al., Nucl. Acids Res., 1991;19:4133-4137); using human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies (see, e.g., Kozbor J. Immunol., 1984;133:3001; Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 55-93 (Marcel Dekker, Inc., New York, 1987); and Boerner et al. al., J. Immunol., 1991;147:86); as well as generating monoclonal antibodies in transgenic animals (e.g., mice) that are capable of producing a full repertoire of human antibodies in the absence of endogenous immunoglobulin production (see, e.g., Jakobovits et al., Proc. Natl. Acad. Sci USA, 1993;90:2551; Jakobovits et al., Nature, 1993;362:255; Bruggermann et al., Year in Immunol., 1993;7:33). This definition of a human antibody specifically excludes humanized antibodies comprising antigen-binding residues from non-human animals.

[0092] An "isolated" antibody is one that has been identified and separated and / or recovered from components of its natural environment. Contaminating components of its natural environment are substances that may interfere with diagnostic and therapeutic uses of the antibody, and these may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, antibodies are purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B, 2007;848:79-87.

[0093] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains of native antibodies (VH and VL, respectively) generally have similar structures, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, for example, Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using the VH or VL domain of an antibody that binds to that antigen, and a library of complementary VL or VH domains, respectively, can be screened. See, e.g., Portolano et al., J. Immunol., 1993;150:880-887; Clarkson et al., Nature, 1991;352:624-628.

[0094] As used herein, the term "hypervariable region," "HVR," or "HV" refers to the region of an antibody variable domain that is hypervariable in sequence and / or forms structurally defined loops. Generally, antibodies contain six hypervariable regions: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Several hypervariable region descriptive methods are in use and are encompassed herein. The Kabat complementarity determining region (CDR) is based on sequence variability and is the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). Chothia instead refers to the location of the structural loops (Chothia and Lesk J. Mol. Biol., 1987;196:901-917). The AbM hypervariable regions are a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. The "contact" hypervariable regions are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below. TIFF2025525331000002.tif47170

[0095] The hypervariable regions may also include "extended hypervariable regions" as follows: 24-36 or 24-34 (L1), 46-56 or 49-56 or 50-56 or 52-56 (L2), and 89-97 (L3) in VL, and 26-35 (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH. The variable domain residues are numbered according to Kabat et al. (see above) for each of these definitions.

[0096] "Framework" or "FR" residues are those variable domain residues other than the hypervariable region residues as defined herein. The FR of a variable domain typically consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences typically appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0097] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0098] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup such as those in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3.

[0099] The term "amyloid-related imaging abnormalities-edema" or "ARIA-E" encompasses cerebral vasogenic edema and sulcal effusion.

[0100] The term "amyloid-related imaging abnormalities-hemorrhage" or "ARIA-H" encompasses central nervous system microhemorrhages and superficial siderosis.

[0101] "Apolipoprotein E4 carrier" or "ApoE4 carrier," used interchangeably herein with "apolipoprotein E4 positive" or "ApoE4 positive," refers to an individual who has at least one apolipoprotein E4 (or "ApoE4") allele. Individuals who have zero ApoE4 alleles are referred to herein as "ApoE4 negative" or "ApoE4 non-carriers." See also Prekumar, et al., Am. J Pathol., 1996;148:2083-95.

[0102] The term "cerebral vasogenic edema" refers to the excessive accumulation of intravascular fluid or protein in the intracellular or extracellular spaces of the brain. Cerebral vasogenic edema can be detected, for example, by brain MRI, including but not limited to FLAIR MRI, and may be asymptomatic ("asymptomatic vasogenic edema") or may be accompanied by neurological symptoms such as confusion, dizziness, vomiting, and lethargy ("symptomatic vasogenic edema") (see Sperling et al. Alzheimer's & Dementia, 2001;7:367).

[0103] The term " cerebral hemorrhage " refers to intracranial or intracerebral hemorrhage of a region that is greater than about 1 cm in diameter.Cerebral hemorrhage can be detected by brain MRI, including but not limited to T2*-weighted GRE MRI, and can be asymptomatic (" silent hemorrhage "), or can be associated with symptoms such as transient or permanent focal motor or sensory disturbance, ataxia, aphasia, and dysarthria (" symptomatic hemorrhage ") (see, for example, Chalela JA, Gomes J. Expert Rev. Neurother. 2004 4:267, 2004 and Sperling et al. Alzheimer's & Dementia, 2011; 7:367).

[0104] The term "cerebral microbleeds" refers to intracranial or intracerebral hemorrhages in the area of less than about 1 cm in diameter.Cerebral microbleeds can be detected by brain MRI, including but not limited to T2*-weighted GRE MRI, and can be asymptomatic ("asymptomatic microbleeds"), or can potentially be associated with symptoms such as transient or persistent focal motor or sensory disturbances, ataxia, aphasia, and dysarthria ("symptomatic microbleeds").See, for example, Greenberg, et al., Lancet Neurol., 2009;8:165-74.

[0105] The term "sulcal effusion" refers to the effusion of fluid in the creases or grooves of the brain. Sulcal effusion can be detected, for example, by brain MRI, including but not limited to FLAIR MRI. See Sperling et al. Alzheimer's & Dementia, 2011; 7: 367.

[0106] The term "superficial siderosis of the central nervous system" refers to bleeding into the subarachnoid space of the brain, detectable by brain MRI, including but not limited to T2*-weighted GRE MRI. Symptoms indicative of superficial siderosis of the central nervous system include sensorineural hearing loss, cerebellar ataxia, and pyramidal signs. See Kumara-N, Am J Neuroradiol., 2010;31:5.

[0107] The term "progression" as used herein refers to the worsening or progression of a disease or symptom over time. For example, progression may refer to a patient or subject with mild cognitive impairment or dementia who did not previously exhibit symptoms characteristic of MCI or who was not classified as having MCI. The "rate of progression" or "progression rate" of a disease refers to how quickly or slowly the disease develops over time in a patient diagnosed with the disease. The rate of disease progression can be expressed by measurable changes in specific disease characteristics over time. A patient with a specific genetic trait is said to have or is likely to have an "increased rate of progression" if the disease state progresses more rapidly than patients without that genetic trait. On the other hand, a patient who responds to treatment is said to have or is likely to have a "decreased rate of progression" if the disease progression slows after treatment compared to the disease state before treatment or other patients who have not received treatment.

[0108] As used herein, "more likely to respond" refers to patients who are most likely to show a slowing or prevention of the progression of AD. With respect to AD, "more likely to respond" refers to patients who are most likely to show a reduction in functional or cognitive loss with treatment. In the context of the present invention, the term "responsive" refers to patients who are suffering from, suspected of suffering from, prone to suffering from, or diagnosed with a disorder described herein, showing a response to anti-Aβ treatment.

[0109] As used herein, the term "benefit(s)" (e.g., benefit(s) of crenezumab treatment) refers to a favorable change in a clinical parameter relative to or compared to baseline (i.e., pre-treatment or no treatment) or placebo treatment. Thus, the benefit(s) of crenezumab treatment can include, but are not limited to, delaying the onset of at least one symptom of Alzheimer's disease (AD), slowing cognitive decline, or preventing cognitive impairment in AD patients or individuals who do not show symptoms of AD or show early symptoms but are considered to be at risk for AD, relative to or compared to baseline (i.e., pre-treatment or no treatment) or placebo treatment.

[0110] As used herein, the phrases "selecting a patient" or "identifying a patient" refer to using information or data generated related to the presence of an allele in a patient's sample to identify or select a patient who is likely to benefit from a treatment comprising an anti-Aβ antibody. This information or data used or generated can be in any form, such as written, oral, or electronic. In some embodiments, using the generated information or data includes communicating, presenting, reporting, storing, transmitting, transferring, providing, disseminating, enforcing, or a combination thereof. In some embodiments, communicating, presenting, reporting, storing, transmitting, transferring, providing, disseminating, enforcing, or a combination thereof is performed by a computer device, an analyzer unit, or a combination thereof. In some further embodiments, communicating, presenting, reporting, storing, transmitting, transferring, providing, disseminating, enforcing, or a combination thereof is performed by a researcher or medical professional. In some embodiments, the information or data includes an indication that a particular allele is present or absent in the sample. In some embodiments, the information or data includes an indication that the patient is more likely to respond to a treatment comprising anti-Aβ.

[0111] "Effector function" refers to the biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors); and B cell activation. It is known in the art that wild-type IgG4 antibodies have lower effector functions than wild-type IgG1 antibodies.

[0112] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of the constant region. This term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering system (also referred to as the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0113] The terms "full-length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody having a heavy chain that has a structure substantially similar to a native antibody structure or that contains an Fc region as defined herein.

[0114] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny, regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell, but may contain mutations. Included herein are mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell.

[0115] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s), including, but not limited to, an additional therapeutic agent.

[0116] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from components of its natural environment. Isolated nucleic acid includes a nucleic acid molecule that is contained in cells that ordinarily contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0117] An "isolated nucleic acid encoding an anti-Aβ antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), wherein such nucleic acid molecules are contained in a single vector or separate vectors, and wherein such nucleic acid molecules are present in one or more locations in a host cell.

[0118] As used herein, the term "early Alzheimer's disease" or "early AD" (e.g., "a patient diagnosed with early AD" or "a person with early AD") includes patients with mild cognitive impairment due to AD, such as memory deficits, and patients with AD biomarkers, e.g., amyloid-positive patients, as well as patients with prodromal AD and mild AD. In some embodiments, patients with early AD have an MMSE score of 22 or greater and a CDR global score of 0.5 or 1.0.

[0119] As used herein, the term "cognitive impairment" refers to difficulty forming new memories, learning new tasks or information, concentrating, or making everyday decisions. Cognitive impairment can range from mild to severe impairment.

[0120] As used herein, the term "cognitive decline" refers to an increase in cognitive impairment over time, often, but not necessarily, due to aging. Cognitive decline can occur at various paces, including gradually, rapidly, and / or intermittently.

[0121] As used herein, the term "delay" refers to a reduction in a particular severity or an increase in the length of time to reach a particular severity, eg, AD symptoms.

[0122] As used herein, the term "onset" refers to the first instance or onset of a pattern, such as, for example, behavior or symptoms, that can generally be used to diagnose an AD patient.

[0123] As used herein, the term "symptom" refers to a physical or cognitive manifestation of a disease, such as AD.

[0124] As used herein, the term "delaying the onset of at least one symptom" refers to a reduction in the severity of one or more symptoms, e.g., AD, or an increase in the length of time before the first onset of one or more symptoms, e.g., AD.

[0125] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., an additional therapeutic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0126] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical disulfide-bonded light chains and two identical heavy chains. From the N-terminus to the C-terminus, each heavy chain contains a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain contains a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. Based on the amino acid sequence of its constant domain, the light chain of an antibody can be assigned to one of two types, called kappa (κ) or lambda (λ).

[0127] The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products that contain information about the indications, uses, dosages, administration, concomitant therapies, contraindications, and / or warnings regarding the use of such therapeutic product. The term "package insert" is also used to refer to instructions typically included in commercial packaging of diagnostic products that contain information regarding the intended use, testing principles, reagent preparation and handling, specimen collection and preparation, calibration of the assay and assay procedure, performance and accuracy data such as assay sensitivity and specificity.

[0128] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence after sequence alignment and, if necessary, the introduction of gaps to achieve the maximum percent sequence identity, without considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithms necessary to achieve maximum alignment across the full length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code, together with user documentation, has been filed with the U.S. Copyright Office, Washington, DC 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from its source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0129] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity between a given amino acid sequence A and a given amino acid sequence B, between a given amino acid sequence A and a given amino acid sequence B, or between a given amino acid sequence A and a given amino acid sequence B (or, alternatively, a given amino acid sequence A having or containing a certain % amino acid sequence identity between a given amino acid sequence B, with a given amino acid sequence B, or with a given amino acid sequence B) is calculated as follows: 100 times fraction (X / Y): where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in its alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless otherwise specified, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0130] The terms "pharmaceutical formulation" and "pharmaceutical composition" are used interchangeably herein and refer to a preparation that is in a form that allows the biological activity of the active ingredient contained therein to be effective, and that does not contain additional components that are unacceptably toxic to the subject to which the formulation is administered.

[0131] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0132] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes not only autonomously replicating nucleic acid structures, but also vectors that are integrated into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0133] An "imaging agent" is a compound that has one or more properties that allow its location to be detected, either directly or indirectly. Examples of such imaging agents include proteins and small molecule compounds that incorporate a label moiety that allows for detection.

[0134] A "label" is a marker attached to a molecule used for detection or imaging. Examples of such labels include radiolabels, fluorophores, chromophores, or affinity tags. In one embodiment, the label is a radiolabel used in medical imaging, such as tritium, technetium-99m, or I-123, or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium-DTPA, manganese-51, manganese-52g, iron oxide, etc.

[0135] As used herein, the terms "prevent" or "prevention," when used in relation to the occurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the disease, disorder, and / or condition and / or delaying the onset or progression of one or more characteristics or symptoms of the disease, disorder, or condition.

[0136] II. Method The present disclosure provides methods for treating autosomal dominant Alzheimer's disease (ADAD).

[0137]

[0010] In one aspect, provided herein is a method of delaying the onset of at least one symptom in a human patient having a genetic mutation that causes familial AD, the method comprising administering to the human patient an effective amount of an anti-Aβ antibody (e.g., crenezumab), wherein administering such treatment to a plurality of human patients results in a delay in the onset of at least one symptom in the plurality of human patients relative to a reference onset of the at least one symptom, where the reference onset of the at least one symptom is that of a plurality of human patients who received a placebo. In some embodiments, the antibody comprises an HVR-H1 amino acid sequence of SEQ ID NO:2, an HVR-H2 amino acid sequence of SEQ ID NO:3, and an HVR-H3 amino acid sequence of SEQ ID NO:4; and an HVR-L1 amino acid sequence of SEQ ID NO:6, an HVR-L2 amino acid sequence of SEQ ID NO:7, and an HVR-L3 amino acid sequence of SEQ ID NO:8.

[0138] In another aspect, provided herein is a method of slowing cognitive decline in a human patient having a genetic mutation that causes familial AD, comprising administering to the human patient an effective amount of an anti-Aβ antibody (e.g., crenezumab), wherein administering such treatment to a plurality of human patients delays cognitive decline in the plurality of human patients relative to a reference cognitive decline, the reference cognitive decline being that of a plurality of human patients who received a placebo. In some embodiments, the antibody comprises an HVR-H1 amino acid sequence of SEQ ID NO:2, an HVR-H2 amino acid sequence of SEQ ID NO:3, and an HVR-H3 amino acid sequence of SEQ ID NO:4; and an HVR-L1 amino acid sequence of SEQ ID NO:6, an HVR-L2 amino acid sequence of SEQ ID NO:7, and an HVR-L3 amino acid sequence of SEQ ID NO:8.

[0139] In another aspect, provided herein is a method for preventing cognitive impairment in a human patient having a genetic mutation that causes familial AD, comprising administering to the human patient an effective amount of an anti-Aβ antibody (e.g., crenezumab), wherein administering such treatment to a plurality of human patients reduces cognitive impairment in the plurality of human patients relative to a reference cognitive impairment, the reference cognitive impairment being that of a plurality of human patients who received a placebo. In some embodiments, the antibody comprises an HVR-H1 amino acid sequence of SEQ ID NO:2, an HVR-H2 amino acid sequence of SEQ ID NO:3, and an HVR-H3 amino acid sequence of SEQ ID NO:4; and an HVR-L1 amino acid sequence of SEQ ID NO:6, an HVR-L2 amino acid sequence of SEQ ID NO:7, and an HVR-L3 amino acid sequence of SEQ ID NO:8.

[0140] antibody In one aspect, the methods of the present invention involve administering an antibody that binds to Aβ. In some embodiments, the methods involve administering an anti-Aβ antibody that can bind with good affinity to monomeric, oligomeric, and fibrillar forms of human Aβ. In some embodiments, the anti-Aβ antibody is an antibody that binds to an epitope of Aβ within residues 13-24 of Aβ. In some embodiments, the anti-Aβ antibody specifically binds to residues 13-24 of Aβ in an extended conformation. While not intending to be bound by any theory of operation, binding to Aβ in an extended conformation is believed to explain the ability of exemplary antibodies to bind to various forms of human Aβ, including monomeric, oligomeric, and fibrillar forms. See Ultsch et al., 2016. In some embodiments, the antibody is crenezumab. In some embodiments, crenezumab binds to both Aβ1-40 and Aβ1-42. In some embodiments, crenezumab inhibits Aβ aggregation. In some embodiments, crenezumab promotes Aβ disaggregation.

[0141] In one embodiment, the antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:5 and a light chain amino acid sequence set forth in SEQ ID NO:9. In another embodiment, the antibody comprises a heavy chain variable region consisting of amino acids 1-112 of the amino acid sequence set forth in SEQ ID NO:5 and a light chain variable region consisting of amino acids 1-112 of the amino acid sequence set forth in SEQ ID NO:9. In some embodiments, the antibody comprises a heavy chain variable region sequence set forth in SEQ ID NO:10 and a light chain variable region sequence set forth in SEQ ID NO:11. In another embodiment, the antibody comprises an HVR-H1 amino acid sequence set forth in SEQ ID NO:2, an HVR-H2 amino acid sequence set forth in SEQ ID NO:3, and an HVR-H3 amino acid sequence set forth in SEQ ID NO:4; and an HVR-L1 amino acid sequence set forth in SEQ ID NO:6, an HVR-L2 amino acid sequence set forth in SEQ ID NO:7, and an HVR-L3 amino acid sequence set forth in SEQ ID NO:8. In another embodiment, the antibody comprises a heavy chain variable region comprising a sequence that is 95%, 96%, 97%, 98%, or 99% or more identical to the amino acid sequence of SEQ ID NO:5. In another embodiment, the antibody comprises a light chain variable region comprising a sequence that is 95%, 96%, 97%, 98%, or 99% or more identical to the amino acid sequence of SEQ ID NO:9.

[0142] In any of the above embodiments, the anti-Aβ antibody is humanized. In one embodiment, the anti-Aβ antibody comprises an HVR as in any of the above embodiments and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework.

[0143] In another aspect, the anti-Aβ antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 5. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but the anti-Aβ antibody comprising that sequence retains the ability to bind to Aβ. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 10. In certain embodiments, the substitutions, insertions, or deletions occur within regions outside the HVRs (i.e., within the FRs). Optionally, the anti-Aβ antibody comprises the VH sequence of SEQ ID NO: 10, including post-translational modifications of that sequence. In another aspect, an anti-Aβ antibody is provided that comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 11. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-Aβ antibody comprising such a sequence retains the ability to bind to Aβ. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in SEQ ID NO: 11. In certain embodiments, the substitutions, insertions, or deletions occur in a region outside the HVR (i.e., within the FR). Optionally, the anti-Aβ antibody comprises the VL sequence of SEQ ID NO: 11, including post-translational modifications of that sequence.

[0144] In another aspect, an anti-Aβ antibody is provided that comprises a VH of any of the embodiments provided above, and a VL of any of the embodiments provided above.

[0145] In a further aspect of the present invention, the anti-Aβ antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-Aβ antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG4 antibody or other antibody class or isotype as defined herein. In another embodiment, the antibody is a bispecific antibody.

[0146] In one embodiment, the anti-Aβ antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 6; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 7; HVR-L3 comprising the amino acid sequence of SEQ ID NO: 8; HVR-H1 comprising the amino acid sequence of SEQ ID NO: 2; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 3; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 4. In some embodiments, the antibody is humanized. In some embodiments, the antibody is of the IgG4 isotype.

[0147] In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 10 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 5 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 9.

[0148] In any of the above embodiments, the anti-Aβ antibody can be humanized. In one embodiment, the anti-Aβ antibody comprises an HVR as in any of the above embodiments and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework.

[0149] In certain embodiments, the anti-Aβ antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which the HVRs, e.g., CDRs (or portions thereof), are derived from a non-human antibody and the FRs (or portions thereof) are derived from a human antibody sequence. Optionally, the humanized antibody also comprises at least a portion of a human constant region. In some embodiments, some FR residues of the humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), for example, to restore or improve the specificity or affinity of the antibody.

[0150] Humanized antibodies and methods for their production are reviewed, e.g., by Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, e.g., by Riechmann et al., Nature, 1988; 332:323-329; Queen et al., Proc. Nat'l Acad. Sci. USA, 1989; 86:10029-10033; U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al. al., Methods, 2005;36:25-34 (describing SDR (a-CDR) grafting); Padlan, Mol. Immunol., 1991;28:489-498 (describing "resurfacing"); Dall'Acqua et al., Methods, 2005;36:43-60 (describing "FR shuffling"); and Osbourn et al., Methods, 2005;36:61-68 and Klimka et al., Br. J. Cancer, 2000;83:252-260 (describing a "guided selection" approach to FR shuffling).

[0151] Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol., 1993;151:2296); framework regions derived from consensus sequences of human antibodies of particular subgroups of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 1992;89:4285; and Presta et al. J. Immunol., 1993;151:2623); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci., 2008;13:1619-1633); and framework regions derived from screening of FR libraries (see, e.g., Baca et al. al., J. Biol. Chem., 1997;272:10678-10684 and Rosok et al., J. Biol. Chem., 1996;271:22611-22618).

[0152] B. Medication and Administration The anti-amyloid beta (Aβ) antibody used in the methods described herein is formulated, dosed and administered in a manner consistent with good medical practice.Consideration factors include the specific subject (for example, gender, age, weight, etc.) to be treated, the clinical condition of the subject (for example, disease severity), the specific form of autosomal dominant Alzheimer's disease, the delivery site of the antibody, the method of administration, the administration schedule and other factors known to medical professionals.

[0153] Pharmaceutical preparations Pharmaceutical formulations of anti-Aβ antibodies for use in the methods described herein are prepared in the form of lyophilized formulations or aqueous solutions by mixing such antibodies or immune molecules having the desired purity with one or more pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Pharmaceutically acceptable carriers are typically non-toxic to recipients at the dosages and concentrations used and include, but are not limited to, buffers such as phosphate, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (approximately Examples of suitable pharmaceutically acceptable carriers include polypeptides of less than 10 residues; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersing agents, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), e.g., human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Application Publication Nos. 2005 / 0260186 and 2006 / 0104968.In one embodiment, the sHASEGP is combined with one or more additional glycosaminoglycanases (eg, chondroitinases).

[0154] In some embodiments, the antibodies of the methods herein may be formulated in an arginine buffer. In one aspect, the arginine buffer may be an arginine succinate buffer. In one such aspect, the concentration of the arginine succinate buffer may be 50 mM or greater. In another such aspect, the concentration of the arginine succinate buffer may be 100 mM or greater. In another such aspect, the concentration of the arginine succinate buffer may be 150 mM or greater. In another such aspect, the concentration of the arginine succinate buffer may be 200 mM or greater. In another aspect, the arginine buffer formulation may further contain a surfactant. In another such aspect, the surfactant is a polysorbate. In another such aspect, the polysorbate is polysorbate 20. In another such aspect, the concentration of polysorbate 20 in the formulation is 0.1% or less. In another such aspect, the concentration of polysorbate 20 in the formulation is 0.05% or less. In another aspect, the pH of the arginine buffer formulation is 4.5 to 7.0. In another aspect, the pH of the arginine buffer formulation is 5.0 to 6.5. In another aspect, the pH of the arginine buffer formulation is 5.0 to 6.0. In another aspect, the pH of the arginine buffer formulation is 5.5. In any of the above embodiments and aspects, the antibody of the present invention may be crenezumab.

[0155] In some embodiments, the formulation contains about 100 mg / mL to about 300 mg / mL of crenezumab, hi some embodiments, the formulation contains about 100 mg / mL, about 120 mg / mL, about 140 mg / mL, about 160 mg / mL, about 180 mg / mL, about 200 mg / mL, about 220 mg / mL, about 240 mg / mL, about 260 mg / mL, about 280 mg / mL, or about 300 mg / mL of crenezumab.

[0156] In some embodiments, the formulation comprises 180 mg / mL crenezumab, 200 mM arginine succinate, 0.05% (w / v) polysorbate 20, and the formulation has a pH of 5.5.

[0157] In some embodiments, the methods herein include administering a placebo. In some embodiments, the placebo comprises the same formulation as the anti-Aβ antibody, except for the antibody. For example, in an embodiment where the formulation comprises 180 mg / mL crenezumab, 200 mM arginine succinate, 0.05% (w / v) polysorbate 20, and the formulation has a pH of 5.5, the placebo comprises a formulation comprising 200 mM arginine succinate, 0.05% (w / v) polysorbate 20, and the formulation has a pH of 5.5.

[0158] In some embodiments, the anti-Aβ antibody is formulated as a liquid for subcutaneous (SC) or intravenous (IV) administration.

[0159] Administration route Dosing can be by any suitable route, e.g., injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is brief or chronic. In one embodiment, the antibody is injected subcutaneously. In another embodiment, the antibody is injected intravenously. In another embodiment, the antibody is administered using a syringe (e.g., pre-filled or not) or an autoinjector.

[0160] In some embodiments, the anti-Aβ antibody is formulated for subcutaneous injection. In some embodiments, the anti-Aβ antibody formulated for subcutaneous injection does not require dilution of the drug product prior to administration.

[0161] In some embodiments, the anti-Aβ antibody is administered by subcutaneous injection into the back of the arm. In some embodiments, the anti-Aβ antibody is administered by SC injection into the thigh. In some embodiments, the anti-Aβ antibody is administered by subcutaneous injection into the abdomen.

[0162] In some embodiments, the anti-Aβ antibody is administered subcutaneously in two injections (eg, two injections of 360 mg for a total dose of 720 mg).

[0163] In some embodiments, the anti-Aβ antibody is administered by intravenous infusion.

[0164] dosage For subcutaneous administration, about 360 mg to about 1000 mg of antibody may be an initial candidate dosage for administration to a patient, whether by one or more separate administrations or by continuous infusion, for example. Typical daily, weekly, biweekly, monthly, or quarterly dosages may range from about 50 mg to about 4560 mg or more, depending on factors such as the patient's medical history and response to the antibody, as well as the attending physician's discretion. Dosages may be administered as a single dose or in divided doses (e.g., two doses of 360 mg for a total dose of 720 mg). For repeated administration over several weeks or longer, depending on symptoms, treatment is generally continued until a desired suppression of disease symptoms occurs. An exemplary dosage of an antibody would be in the range of about 540 mg to about 900 mg. In some embodiments, the total dose administered is in the range of 180 mg to 1440 mg. Exemplary doses of about 180 mg, about 200 mg, about 300 mg, about 360 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1440 mg (or any combination thereof) can be administered to patients. Such doses can be administered intermittently, for example, every week, every two weeks, every three weeks, every four weeks, every month, every two months, every three months, or every six months. However, other dosage regimens can also be useful. The progress of this treatment can be monitored by conventional techniques and assays.

[0165] In certain embodiments, the antibody is administered subcutaneously at a dose of about 360 mg, about 400 mg, about 500 mg, about 540 mg, about 600 mg, about 700 mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg, about 1080 mg, or more. In some embodiments, the antibody is administered subcutaneously at a dose of about 360 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 720 mg, about 720 mg to about 800 mg, about 800 mg to about 900 mg, about 900 mg to about 1000 mg, about 1000 mg to about 1080 mg, about 360 mg to about 600 mg, about 500 mg to about 720 mg, about 700 mg to about 1000 mg, or about 720 mg to about 1080 mg. In some embodiments, the antibody is administered subcutaneously at a dose of about 720 mg or greater. In some embodiments, the antibody is delivered at a dose of about 300 mg. In some embodiments, the dose is administered subcutaneously every two weeks or every four weeks over a period of time. In certain embodiments, the period is 6 months, 1 year, 18 months, 2 years, 5 years, 10 years, 15 years, 20 years, or the patient's lifetime.

[0166] In some embodiments, the antibody is administered every two weeks in a total volume of 4.0 mL (2 x 2.0 mL) for two subcutaneous injections of 360 mg each (720 mg total). In some embodiments, the antibody is administered every two weeks for a period of at least 260 weeks. In some embodiments, the antibody is administered every two weeks for a period of at least 284 weeks. In some embodiments, the antibody is administered every two weeks for at least 10 years. In some embodiments, the antibody is administered every two weeks for at least 15 years. In some embodiments, the antibody is administered every two weeks for at least 20 years. In some embodiments, the antibody is administered every two weeks for the patient's lifetime.

[0167] In some embodiments, the placebo is administered subcutaneously. In some embodiments, the placebo is administered in two subcutaneous injections (2 x 2.0 mL) with a total volume of 4.0 mL every two weeks. In some embodiments, the placebo is administered every two weeks for a period of at least 260 weeks.

[0168] For IV administration, an initial candidate dosage for administration to a patient may be about 15 mg / kg to about 200 mg / kg (e.g., 50 mg / kg to 120 mg / kg, or any dosage within that range), whether by one or more separate administrations or by continuous infusion. A typical daily, weekly, biweekly, monthly, or quarterly dosage may range from about 15 mg / kg to 200 mg / kg or more, depending on factors such as the patient's medical history and response to the antibody, as well as the attending physician's discretion. Dosages may be administered as a single dose or in divided doses (e.g., two doses of 30 mg / kg for a total dose of 60 mg / kg). For repeated administration over several weeks or longer, depending on symptoms, treatment is generally continued until a desired suppression of disease symptoms occurs. One exemplary dosage of an antibody would be in the range of about 50 mg / kg to about 150 mg / kg. Thus, one or more doses of about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, or about 130 mg / kg (or any combination thereof) may be administered to the patient. In some embodiments, one or more doses of about 60 mg / kg or greater may be administered to the patient. In some embodiments, the total dose administered is in the range of 1500 mg to 24000 mg. An exemplary dose of about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 7200 mg, about 10000 mg, about 10500 mg, about 11000 mg, about 12000 mg, about 13000 mg, about 14000 mg, about 15000 mg, about 16000 mg, about 17000 mg, about 18000 mg, about 19000 mg, about 20000 mg, about 20500 mg, about 21000 mg, about 22000 mg, about 23000 mg, or about 24000 mg (or any combination thereof) may be administered to a patient.In some embodiments, the antibody is administered by IV at a dose of about 60 mg / kg or more; or b) a fixed dose of 4200 mg or more; or c) a fixed dose of about 4200 mg. Such doses can be administered intermittently, for example, every week, every two weeks, every three weeks, every four weeks, every month, every two months, every three months, or every six months. However, other dosage regimens may also be useful. The progress of this treatment can be monitored by conventional techniques and assays.

[0169] In certain embodiments, the antibody is administered IV at a dose of about 15 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, or a flat dose, e.g., about 1500 mg, about 1800 mg, about 2000 mg, about 2400 mg, about 3000 mg, about 3200 mg, about 4000 mg, about 5000 mg, about 5400 mg, about 6000 mg, about 7000 mg, about 7200 mg, about 8000 mg, or more. In some embodiments, the antibody is administered at a dose of about 15 mg / kg to about 20 mg / kg, about 20 mg / kg to about 30 mg / kg, about 30 mg / kg to about 40 mg / kg, about 40 mg / kg to about 45 mg / kg, about 45 mg / kg to about 50 mg / kg, about 50 mg / kg to about 60 mg / kg, about 60 mg / kg to about 70 mg / kg, about 70 mg / kg to about 80 mg / kg, about 80 mg / kg to about 90 mg / kg, about 90 mg / kg to about 100 mg / kg, or about 100 mg / kg. Doses of about 110 mg / kg, about 110 mg / kg to about 120 mg / kg, about 120 mg / kg to about 130 mg / kg, about 130 mg / kg to about 140 mg / kg, about 140 mg / kg to about 150 mg / kg, or a flat dose, for example, about 1500 mg to about 1800 mg, about 1800 mg to about 2000 mg, or about 2000 mg to about 2400 mg , about 2400 mg to about 3000 mg, about 3000 mg to about 3200 mg, about 3200 mg to about 4000 mg, about 4000 mg to about 5000 mg, about 5000 mg to about 5400 mg, about 5400 mg to about 6000 mg, about 6000 mg to about 7000 mg, about 7000 mg to about 7200 mg, or about 7200 mg to about 8000 mg. In some embodiments, the dose is administered IV every two weeks or every four weeks for a period of time. In certain embodiments, the period is 6 months, 1 year, 18 months, 2 years, 5 years, 10 years, 15 years, 20 years, or the patient's lifetime.

[0170] In some embodiments, the antibody is administered intravenously at a dose of 60 mg / kg every 4 weeks. In some embodiments, the antibody is administered every 4 weeks for at least 260 weeks. In some embodiments, the antibody is administered every 4 weeks for at least 5 years. In some embodiments, the antibody is administered every 4 weeks for at least 6 years. In some embodiments, the antibody is administered every 4 weeks for at least 7 years. In some embodiments, the antibody is administered every 4 weeks for at least 8 years. In some embodiments, the antibody is administered every 4 weeks for at least 9 years. In some embodiments, the antibody is administered every 4 weeks for at least 10 years. In some embodiments, the antibody is administered every 4 weeks for at least 11 years. In some embodiments, the antibody is administered every 4 weeks for at least 12 years. In some embodiments, the antibody is administered every 4 weeks for at least 13 years. In some embodiments, the antibody is administered every 4 weeks for at least 14 years. In some embodiments, the antibody is administered every 4 weeks for at least 15 years. In some embodiments, the antibody is administered every 4 weeks for at least 16 years. In some embodiments, the antibody is administered every 4 weeks for at least 17 years. In some embodiments, the antibody is administered every 4 weeks for at least 18 years. In some embodiments, the antibody is administered every 4 weeks for at least 19 years. In some embodiments, the antibody is administered every 4 weeks for at least 20 years. In some embodiments, the antibody is administered every 4 weeks for the patient's lifetime.

[0171] In some embodiments, the placebo is administered intravenously. In some embodiments, the placebo is administered every four weeks for at least 260 weeks.

[0172] Patient weight is used to calculate IV doses. If the patient's weight changes by more than 10% from the previous reference weight, the current weight becomes the new reference weight for subsequent dosing. If the patient's weight again changes by more than 10%, an additional recalculation occurs.

[0173] In some embodiments, patients who have adverse effects to treatment may receive reduced or modified doses of the drug.

[0174] C. Treatment Response and Assessment In some embodiments, the methods provided herein provide one or more benefits to a human patient with a genetic mutation that causes familial AD. In some embodiments, the benefit (such as a delay in the onset of symptoms or a slowing of cognitive decline) is measured relative to a "reference" value. In some embodiments, the reference value is a measurement obtained from one or more individuals with the same genetic mutation who have not received an anti-Aβ antibody. In some embodiments, the individuals who have not received an anti-Aβ antibody receive a placebo. In some embodiments, the reference value is a measurement obtained from one or more individuals who do not have a genetic mutation associated with familial AD who have not received an anti-Aβ antibody. In some embodiments, the individuals who have not received an anti-Aβ antibody receive a placebo. In some embodiments, the reference is a measurement obtained from a plurality of individuals, including one or more individuals with the same genetic mutation as the patient receiving an anti-Aβ antibody and one or more individuals who do not have a genetic mutation associated with familial AD. In some embodiments, a population of human patients who receive an anti-Aβ antibody experience AD progression, but to a lesser extent than a reference measure of progression obtained from individuals who have not received an anti-Aβ antibody. In some embodiments, the human patient, or a plurality of human patients who receive an anti-Aβ antibody, have the same genetic mutation as the individuals in the reference group.

[0175] In certain aspects, provided herein are methods for delaying the onset of at least one symptom or slowing cognitive decline in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering an effective amount of a humanized monoclonal anti-amyloid beta to the human patient, wherein when such treatment is administered to a plurality of human patients, relative to a reference onset of at least one symptom or cognitive decline, the reference onset of at least one symptom or cognitive decline is that of a plurality of human patients who received a placebo.

[0176] In some embodiments, administering such a treatment delays the onset of at least one symptom in a plurality of human patients relative to a reference onset of the at least one symptom. In some embodiments, administering such a treatment delays the onset of at least one symptom relative to a reference onset of the at least one symptom from about 5 to about 8 years after treatment. In some embodiments, the delay in onset of at least one symptom is statistically significant relative to or compared to the reference onset of the symptom. In some embodiments, administering such a treatment slows cognitive decline in a plurality of human patients relative to a reference cognitive decline. In some embodiments, administering such a treatment slows cognitive decline in a plurality of human patients statistically significant relative to or compared to the reference cognitive decline from about 5 to about 8 years after treatment. In some embodiments, administering such a treatment reduces cognitive impairment in a plurality of human patients relative to a reference cognitive impairment. In some embodiments, administering such a treatment reduces cognitive impairment in a plurality of human patients relative to or compared to a reference cognitive impairment from about 5 to about 8 years after initiation of treatment. In some embodiments, the reduction in cognitive impairment is statistically significant relative to or compared to the reference, hi some embodiments, administering such treatment delays the onset of cognitive impairment relative to or compared to the reference cognitive impairment.

[0177] In some embodiments, administering such a treatment delays the onset of at least one symptom in a plurality of human patients relative to a reference onset of the at least one symptom. In some embodiments, administering such a treatment delays the onset of at least one symptom relative to a reference onset of the at least one symptom from about 5 to about 8 years after treatment. In some embodiments, the delay in onset of at least one symptom is statistically significant relative to or compared to the reference onset of the at least one symptom. In some embodiments, administering such a treatment slows cognitive decline in a plurality of human patients relative to a reference cognitive decline. In some embodiments, administering such a treatment slows cognitive decline in a plurality of human patients statistically significant relative to or compared to the reference cognitive decline from about 5 to about 8 years after treatment. In some embodiments, administering such a treatment reduces cognitive impairment in a plurality of human patients relative to a reference cognitive impairment. In some embodiments, administering such a treatment reduces cognitive impairment in a plurality of human patients relative to or compared to the reference cognitive impairment from about 5 to about 8 years after initiation of treatment. In some embodiments, the reduction in cognitive impairment is statistically significant relative to or compared to the reference.

[0178] In some embodiments, one or more cognitive, functional, and / or behavioral assessments are conducted to measure at least one symptom, e.g., delay of AD or reduction of cognitive impairment. In some embodiments, one or more assessments are conducted only on the patient. In some embodiments, one or more assessments are conducted on a study partner. In some embodiments, one or more assessments are conducted on both the patient and the study partner. In some embodiments, the assessments are conducted by one or more independent, blinded raters. In some embodiments, the independent, blinded rater has the role of psychometrist. In some embodiments, the independent, blinded rater has the role of global rater. In some embodiments, the assessments are conducted by two or more independent, blinded raters, including at least one rater having the role of psychometrist and at least one rater having the role of global rater.

[0179] In some embodiments, the one or more assessments are not performed immediately after the patient is dosed with an antibody according to the methods herein. In some embodiments, the one or more assessments are not performed immediately after the patient has undergone a potentially stressful procedure (e.g., a blood draw or a procedure involving sedation). In some embodiments, the patient does not undergo one or more assessments while fasting.

[0180] In some embodiments, one or more assessments are performed throughout the course of treatment. For example, assessments can be performed every 1, 2, 4, 6, 8, 10, or 12 weeks. In some embodiments, assessments are not performed on a regular schedule, for example, assessments can be performed at the discretion of the treating physician. In some embodiments, one or more assessments are performed on the first day of treatment. In some embodiments, the assessment performed on the first day of treatment is used as a baseline assessment to which subsequent assessments are compared.

[0181] In some embodiments, one or more assessments given to the patient and / or research partner are performed by the same psychometrician and / or the same global assessor at each visit. In some embodiments, one or more assessments are given by the research partner. The research partner is an individual who can report the patient's cognitive changes and otherwise assist the patient in complying with the treatment regimen. In some embodiments, the Study Partner Characterization Questionnaire (SPCQ) is completed before the study partner assessment is conducted at each time point. The SPCQ is a simple set of questions designed to identify the study partner, evaluate the patient's living environment (e.g., whether living alone or with others), and evaluate the relationship between the study partner and the participant.

[0182] In some embodiments, the delay of at least one symptom, reduction of cognitive decline, or prevention of cognitive impairment is measured according to the API ADAD cognitive composite test battery. The API ADAD cognitive composite test battery provides a composite cognitive test score designed to be highly sensitive for detecting and tracking preclinical cognitive decline, corresponding to the analysis of change from baseline, rather than optimizing the discrimination between those who progress to clinical AD and those who remain cognitively unimpaired (see, e.g., Ayutyanont et al., J. Clin. Psychiatry, 2014; 75(6):652-660, and Tariot et al., Alzheimers Dement., 2018; 4:150-160; the entire contents of which are incorporated herein by reference). The API ADAD cognitive composite test battery consists of the Mini-Mental State Examination (MMSE), word lists, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) construct exercises, the Multilingual Naming Test, and Raven's Progressive Matrices. The MMSE assesses orientation, attention, concentration, naming, repetition, comprehension, sentence construction, and picture copying (see, e.g., Folstein et al., J. Psychiatr. Res., 1975; 12:189-198, which is incorporated herein by reference in its entirety); for calculations in the API ADAD Composite Test Battery, only the orientation score over time from the MMSE is used. The word list is a measure of delayed verbal memory administered according to the CERAD test protocol, consisting of four parallel word lists derived from the ADAS-Cog word pool (see, e.g., Morris et al., Neurology, 1989; 39:1159-1165, which is incorporated herein by reference in its entirety); for calculations in the API ADAD Composite Test Battery, only the recall score is used.The CERAD Constructive Practice Test is widely used to assess cognitive deficits associated with Alzheimer's disease and consists of four line drawings of increasing complexity (see, e.g., Morris et al., Neurology, 1989;39:1159-1165, incorporated herein by reference in its entirety); for the purposes of the API ADAD Composite Test Battery, subjects are shown a diagram and then asked to immediately recall the diagram. The Multilingual Naming Test is a visual face-to-face naming measure that requires participants to name objects depicted on a schematic diagram, graded by difficulty based on frequency of occurrence (see, e.g., Gollan et al., Biling, 2012;15:189-198, incorporated herein by reference in its entirety). Raven's Progressive Matrices are a non-verbal multiple-choice measure of general ability and reasoning in the visual modality that requires a special design and conceptualization of numerical relationships in which each participant is asked to identify missing components to complete the pattern (see, e.g., Raven, Raven Progressive Matrices and Vocabulary Scale, 1976, incorporated herein by reference in its entirety).

[0183] In some embodiments, the API ADAD cognitive composite test battery is administered in the following order: MMSE, Multilingual Naming Test, Word List: Memory, CERAD Constructive Exercises, Word List: Recall, Word List: Recognition, Raven's Progressive Matrices (Set A).

[0184] In some embodiments, the API ADAD cognitive composite test battery is administered every 12 to 28 weeks during the course of treatment. In some embodiments, for patients receiving antibodies by subcutaneous injection, the API ADAD cognitive composite test battery is administered at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260. In some embodiments, for patients receiving antibodies intravenously, the API ADAD cognitive composite test battery is administered at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260. In some embodiments, administration of the API ADAD cognitive composite test battery may continue every 24 to 28 weeks thereafter until treatment is stopped.

[0185] In some embodiments, administering such a treatment reduces decline on the API ADAD Composite Test Battery in a plurality of human patients relative to or compared to a reference API ADAD Cognitive Composite Test Battery from about 5 to about 8 years after initiation of treatment. In some embodiments, the reduction in decline is statistically significant relative to or compared to the reference. In some embodiments, administering such a treatment results in an annualized rate of change on the API ADAD Composite Cognitive Test Battery. In some embodiments, administering such a treatment reduces the annualized rate of change on the API ADAD Composite Cognitive Test Battery relative to or compared to a reference annualized rate of change on the API ADAD Cognitive Composite Test Battery.

[0186] In some embodiments, administering such a treatment to a plurality of human patients reduces the annual rate of change in the API ADAD composite score for the plurality of human patients relative to a reference annual rate of change in the API ADAD composite score, where the reference annual rate of change in the API ADAD composite score is the annual rate of change in the API ADAD composite score for the plurality of human patients receiving a placebo. In some embodiments, the API ADAD composite cognitive test battery includes Word List Recall, Multilingual Naming Test, Mini-Mental State Examination (MMSE), CERAD Construct Exercises, and Raven's Progressive Matrices. In some embodiments, administering such a treatment reduces the annual rate of change in the API ADAD composite score after about 5 or more years of treatment. In some embodiments, administering such a treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by at least 20%, at least 30%, at least 40%, at least 50%, about 20% to about 40%, or about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% relative to a reference annual rate of change in API ADAD composite score. In some embodiments, administering such a treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by at least about 20% relative to a reference annual rate of change in API ADAD composite score. In some embodiments, administering such a treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by at least about 30% relative to a reference annual rate of change in API ADAD composite score. In some embodiments, administering such a treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by 20% to 40% relative to a reference annual rate of change in API ADAD composite score. In some embodiments, administration of such a treatment reduces the annual rate of change in API ADAD composite scores of a plurality of human patients by about 22% relative to a reference annual rate of change in API ADAD composite scores. In some embodiments, administration of such a treatment to a plurality of human patients reduces decline in the cueing index of the Free and Cued Selective Association Task (FCSRT).The FCSRT provides an assessment of immediate and delayed verbal episodic memory using controlled learning to optimize encoding specificity for more effective recall (see, e.g., Grober et al., Dev. Neuropsychol., 1987;3:13-36 and Buschke, J. Clin. Neuropsychol., 1984;6:433-440, which are incorporated herein by reference in their entireties). In this test, participants are presented with items on cards, study the items, attempt free recall of the items, and then perform semantic cued recall of items not generated by the participant during free recall. The FCSRT is believed to be sensitive to conditions such as AD that impair the function of the hippocampus and its connected networks.

[0187] In some embodiments, administering such a treatment reduces the decline in the FCSRT Cue Index of a plurality of human patients relative to or compared to a reference decline in the FCSRT Cue Index from about 5 to about 8 years after initiation of treatment. In some embodiments, the reduced decline is statistically significant relative to or compared to the reference decline. In some embodiments, administering such a treatment reduces the annual rate of change in the FCSRT Cue Index of a plurality of human patients relative to or compared to a reference annual rate of change in the FCSRT Cue Index. In some embodiments, administering such a treatment results in a statistically significant reduction in the annual rate of change in the FCSRT Cue Index of a plurality of human patients relative to or compared to a reference annual rate of change in the FCSRT Cue Index from about 5 to about 8 years after initiation of treatment.

[0188] In some embodiments, administration of such treatment reduces the annual rate of change in FCSRT cue index of a plurality of human patients by at least 10%, at least 20%, at least 30%, at least 40%, about 10% to about 30%, or about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, about 26%, about 27%, about 28%, or about 30% relative to a reference annual rate of change in FCSRT cue index.

[0189] In some embodiments, administration of such treatment reduces the annual rate of change in the FCSRT cue index for a plurality of human patients by at least about 10%. In some embodiments, administration of such treatment reduces the annual rate of change in the FCSRT cue index for a plurality of human patients by at least about 20%. In some embodiments, administration of such treatment reduces the annual rate of change in the FCSRT cue index for a plurality of human patients by about 10% to about 30%. In some embodiments, administration of such treatment reduces the annual rate of change in the FCSRT cue index for a plurality of human patients by about 20% to about 30%.

[0190] In some embodiments, the FCSRT cueing index is assessed using controlled learning.

[0191] In some embodiments, the FCSRT Cue Index is administered every 12 to 28 weeks during the course of treatment. In some embodiments, administration of the FCSRT Cue Index may continue every 24 to 28 weeks thereafter until treatment is stopped.

[0192] In some embodiments, administration of such treatment results in a statistically significant reduction in change above baseline in a cognitive measure of a plurality of human patients relative to or compared to a reference cognitive measure, where the reference cognitive measure is a cognitive measure of a plurality of human patients who received a placebo, and the cognitive measure is selected from the group consisting of: i) the Trail Making Test; ii) the Mini-Mental State Examination (MMSE); iii) the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) index score; iv) scores on each component of the API ADAD Composite Cognitive Test Battery; v) the Preclinical Alzheimer's Disease Cognitive Composite (PACC); and vi) other clinical endpoints.

[0193] The Trail-Making Test includes two parts and is described in Armitage, Psychological Monographs, 1946, 60:1-48, which is incorporated herein by reference in its entirety. During Part A, participants are instructed to connect numbered circles in ascending order as quickly as possible. Part B uses a mixture of numbered or letter-containing circles, and participants must connect the circles alternating numbers and letters in ascending order. Performance is judged in terms of time to completion, number of correctly connected circles, and number of errors.

[0194] The RBANS is a standardized, brief, individually administered neurocognitive battery that measures attention, language, visuospatial / constructive abilities, and immediate and delayed memory (see, e.g., Randolf, Repeatable Battery for the Assessment of Neuropsychological Status, 1998, incorporated herein by reference in its entirety).

[0195] The Preclinical Alzheimer's Disease Cognitive Composite (PACC) is a composite composed of various well-established measures that assess cognitive function (see, e.g., Donohue et al., JAMA Neurology, 2014, 71:961-970, which is incorporated herein by reference in its entirety). As used herein, the PACC includes the FCSRT free and cued recall, MMSE, RBAN story recall, and RBAN coding scores.

[0196] In some embodiments, administration of such treatment reduces the change above baseline in i) the Trial Creation Test, ii) the Mini-Mental State Examination (MMSE), iii) the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) index score, iv) the scores on each component of the API ADAD Composite Cognitive Test Battery, v) the Preclinical Alzheimer's Disease Cognitive Composite (PACC), and vi) other clinical endpoints.

[0197] In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in a neuropsychiatric inventory (NPI) of a plurality of human patients relative to or compared to a reference NPI, where the reference NPI is an NPI of a plurality of human patients who received a placebo. In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in the NPI at about 5 to about 8 years after initiation of treatment.

[0198] The NPI is a well-validated and reliable multi-item instrument for assessing the psychopathology of AD and the level of distress experienced by an informant in response to the presence of a given feature (see, e.g., Kaufer et al., J. Neuropsychiatry Clin. Neurosci., 2000;12:233-239, Cummings et al., Neurology, 1994;44:2308-2314, which are incorporated herein by reference in their entireties). In some embodiments, the assessment is based on an interview with the informant and assesses both the presence and severity of neuropsychiatric features, including, but not limited to, delusions, hallucinations, dysphoria, anxiety, agitation / aggression, euphoria, incontrollability, irritability, lability, apathy, and abnormal motor behavior, and informant distress.

[0199] In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in Functional Assessment of Alzheimer's Disease Staging (FAST) total scores for a plurality of human patients compared to or compared to a reference FAST total score, where the reference FAST total score is a FAST total score for a plurality of human patients who received a placebo. In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in FAST total score from about 5 to about 8 years after initiation of treatment.

[0200] The FAST was developed for use with Alzheimer's disease (AD) patients to grade their level of impairment for AD (Reisberg, Psychopharmacol. Bull., 1988;24:653-659, incorporated herein by reference in its entirety). The FAST is composed of seven major levels of functioning (from normal adult to severe AD) and is derived from axis V of the Brief Cognitive Rating Scale (BCRS) (Reisberg et al., Psychopharmacol. Bull., 1983;47:47-50, incorporated herein by reference in its entirety), which itself is derived from the Global Deterioration Scale (Reisberg et al., Am. J. Psychiatry, 1982;139:1136-1139, incorporated herein by reference in its entirety). Thus, the stages and substages are designed to correlate with the overall level of deterioration of the Composite Deterioration Scale of Cognitive and Functional Abilities Measure (Sclan and Reisberg, Int. Psychogeriatr., 1992;4:55-69, which is incorporated herein by reference in its entirety).

[0201] In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in a Subject Memory Checklist (SMC) of a plurality of human patients relative to or compared to a reference SMC, where the reference SMC is the SMC of a plurality of human patients who received a placebo. In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in SMC scores from about 5 to about 8 years after initiation of treatment.

[0202] The Subjective Memory Checklist (SMC) is an assessment developed to collect subjective assessments of memory status from both participants and informants. Participants and informants are asked to rate the frequency with which a given participant has difficulty with memory and thinking in various areas. The SMC has a research partner portion and a participant portion. In some embodiments, the average subjective memory checklist score is greater than 22 and is based on the average of the component scores of the participant and research partner.

[0203] In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in the Geriatric Depression Scale (GDS) of a plurality of human patients relative to or compared to a reference GDS, where the reference GDS is the GDS of a plurality of human patients who received a placebo. In some embodiments, administration of such treatment results in a statistically significant reduction in the change above baseline in GDS scores from about 5 to about 8 years after initiation of treatment.

[0204] The Geriatric Depression Scale (GDS) is a scale designed to identify depressive symptoms in elderly people (Sheikh and Yesavage, Clinical Gerontologist, 1986, 5:165-173, the entire contents of which are incorporated herein by reference). This scale consists of 15 questions that participants are asked to answer based on how they felt over the past week, and each answer is given a score of 1, indicating depressive symptoms. A total score of 0 to 4 is considered normal, a score of 5 to 8 indicates mild depression, a score of 9 to 11 indicates moderate depression, and a score of 12 to 15 indicates severe depression.

[0205] In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients relative to a reference SUVR for amyloid PET, where the reference SUVR for amyloid PET is the SUVR for amyloid PET in a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by at least 3% relative to the reference SUVR for amyloid PET. In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by at least 10% relative to the reference SUVR for amyloid PET. In some embodiments, administration of such a treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by about 3% to about 10% relative to the reference SUVR for amyloid PET. In some embodiments, administration of such treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% compared to the reference SUVR for amyloid PET. In some embodiments, administration of such treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in a plurality of human patients by about 3% compared to the reference SUVR for amyloid PET.

[0206] In some embodiments, administering such a treatment to a plurality of human patients increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in the plurality of human patients relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD, where the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD is the time to progression in the plurality of human patients who received a placebo. In some embodiments, administering such a treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in the plurality of human patients relative to the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD, from about 5 to about 8 years after initiation of treatment. In some embodiments, the increase in time to progression is statistically significant relative to or compared to the reference.

[0207] In some embodiments, administration of such a treatment to a plurality of human patients increases the time from preclinical AD to AD dementia in the plurality of human patients by about 10% to about 30% relative to a reference time from preclinical AD to AD dementia. In some embodiments, administration of such a treatment to a plurality of human patients increases the time from preclinical AD to AD dementia in the plurality of human patients by at least about 10% relative to a reference time from preclinical AD to AD dementia. In some embodiments, administration of such a treatment to a plurality of human patients increases the time from preclinical AD to AD dementia in the plurality of human patients by at least about 20% relative to a reference time from preclinical AD to AD dementia.

[0208] In some embodiments, administration of such a treatment to a plurality of human patients increases the time from preclinical AD to mild cognitive impairment due to AD in the plurality of human patients by about 10% to about 30% relative to a reference time from preclinical AD to mild cognitive impairment due to AD. In some embodiments, administration of such a treatment to a plurality of human patients increases the time from preclinical AD to mild cognitive impairment due to AD in the plurality of human patients by at least about 10% relative to a reference time from preclinical AD to mild cognitive impairment due to AD. In some embodiments, administration of such a treatment to a plurality of human patients increases the time from preclinical AD to mild cognitive impairment due to AD in the plurality of human patients by at least about 20% relative to a reference time from preclinical AD to mild cognitive impairment due to AD.

[0209] In some embodiments, administration of such a treatment to a plurality of human patients increases the time to progression from preclinical AD to AD dementia in the plurality of human patients by about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, relative to a reference time to progression from preclinical AD to AD dementia. In some embodiments, administration of such a treatment to a plurality of human patients increases the time to progression from preclinical AD to AD dementia in the plurality of human patients by about 21%, relative to a reference time to progression from preclinical AD to AD dementia.

[0210] In some embodiments, administration of such a treatment to a plurality of human patients increases the time to progression from preclinical AD to mild cognitive impairment due to AD in the plurality of human patients by about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, relative to the reference time to progression from preclinical AD to mild cognitive impairment due to AD. In some embodiments, administration of such a treatment to a plurality of human patients increases the time to progression from preclinical AD to mild cognitive impairment due to AD in the plurality of human patients by about 21%, relative to the reference time to progression from preclinical AD to mild cognitive impairment due to AD.

[0211] In some embodiments, progression to mild cognitive impairment (MCI) is assessed every 12 to 28 weeks during the course of treatment. In some embodiments, progression to MCI is assessed every 12 to 28 weeks during the course of treatment. In some embodiments, progression to MCI is assessed at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody by subcutaneous injection. In some embodiments, progression to MCI is assessed at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody intravenously. In some embodiments, progression to MCI is assessed every 24 to 28 weeks thereafter until treatment is stopped.

[0212] In some embodiments, progression to AD dementia is assessed every 12-28 weeks during the course of treatment. In some embodiments, progression to AD dementia is assessed every 12-28 weeks during the course of treatment. In some embodiments, progression to AD dementia is assessed at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody by subcutaneous injection. In some embodiments, progression to AD dementia is assessed at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody intravenously. In some embodiments, progression to AD dementia is assessed every 24-28 weeks thereafter until treatment is stopped.

[0213] In some embodiments, progression to mild cognitive impairment (MCI) is determined based in part on the mean subjective memory checklist (SMC) score and based on cognitive concerns in the physician's judgment. In some embodiments, SMC assessments are performed every 12-28 weeks during the course of treatment. In some embodiments, SMC assessments are performed every 12-28 weeks during the course of treatment. In some embodiments, SMC assessments are performed at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody by subcutaneous injection. In some embodiments, SMC assessments are performed at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody intravenously. In some embodiments, SMC assessments may continue to be performed every 24-28 weeks thereafter until treatment is stopped.

[0214] In some embodiments, MCI is a less severe stage of dementia than dementia. In some embodiments, MCI involves a decline in cognitive abilities such as language, memory, reasoning, judgment, or perception that is not due to normal aging. Individuals in the severe MCI stage can independently drive, shop, cook, pay bills, manage finances, do household chores, and perform other well-learned skills that do not pose a significant demand when learning new information. The MCI stage is not seen in normal aging individuals and is due to one or more cognitive impairments. In Alzheimer's disease, the MCI stage lasts an average of 7 years.

[0215] In some embodiments, progression to MCI is determined based on objective evidence of impairment in the physician's judgment in one or more cognitive domains, based on review of the Clinical Dementia Rating (CDR), Word List (Recall), MMSE, and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The physician may further choose to review other clinical and cognitive test results, except for the API ADAD Composite Cognitive Test total score or CERAD total score, when rendering this opinion.

[0216] The CDR describes the degree of impairment in five performance categories of cognitive function, including memory, orientation, judgment and problem-solving, social problems, household and hobbies, and personal care (see, e.g., Morris, Neurology, 1993; 43:2412-2413, the entire contents of which are incorporated herein by reference). The impairment ratings obtained in each of the six functional categories are combined into a global dementia assessment, with a score of 0 indicating no dementia, a score of 0.5 indicating MCI, and scores of 1, 2, or 3 indicating progressively more severe dementia (see, e.g., Morris 1993 and Morris et al., Arch. Neurol., 58(3):397-405, 2001). The use of the CDR box sum provides a more refined measure of change (Berg et al., Ann. Neurol., 1992; 31:242-249, the entire contents of which are incorporated herein by reference).

[0217] In some embodiments, CDR assessments are performed every 12 to 28 weeks during the course of treatment. In some embodiments, CDR assessments are performed every 12 to 28 weeks during the course of treatment. In some embodiments, CDR assessments are performed at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody by subcutaneous injection. In some embodiments, CDR assessments are performed at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody intravenously. In some embodiments, CDR assessments may continue every 24 to 28 weeks thereafter until treatment is stopped. In some embodiments, progression to MCI is determined based in part on review of the Functional Assessment Staging Test (FAST) and, in the physician's judgment, on maintenance of functional ability. In some embodiments, FAST assessments are performed every 12-28 weeks during the course of treatment. In some embodiments, FAST assessments are performed every 12-28 weeks during the course of treatment. In some embodiments, FAST assessments are performed at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody by subcutaneous injection. In some embodiments, FAST assessments are performed at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody intravenously. In some embodiments, FAST assessments may continue to be performed every 24-28 weeks thereafter until treatment is stopped.

[0218] In some embodiments, progression to MCI requires cognitive concern in the physician's judgment based in part on a mean subjective Memory Checklist (SMC) score; objective evidence of impairment in one or more cognitive domains in the physician's judgment based in part on a review of the CDR, word list (recall), MMSE, and RBANS; maintenance of functional ability in the physician's judgment based in part on a review of the FAST; documentation that MCI criteria have been met; and agreement by an external adjudication committee that progression to MCI criteria has been met.

[0219] In some embodiments, progression to AD dementia is determined by a physician review of the medical history, participant and researcher interviews to establish a significant deterioration in the participant's cognitive and functional status since baseline, and a review of the CDR, word list (recall), MMSE total, RBAN, and Neuropsychiatric Inventory (NPI). The physician may also choose to review other clinical and cognitive test results when rendering this opinion, except for the API ADAD Composite Cognitive Test total score or CERAD total score. A determination of progression to AD dementia further requires agreement by an external adjudication committee that dementia criteria are met and that progression to AD dementia is met.

[0220] In some embodiments, NPI assessments are performed every 12-28 weeks during the course of treatment. In some embodiments, NPI assessments are performed every 12-28 weeks during the course of treatment. In some embodiments, NPI assessments are performed at weeks 1, 12, 24, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody by subcutaneous injection. In some embodiments, NPI assessments are performed at weeks 1, 24, 36, 52, 76, 104, 128, 156, 180, 208, 232, and 260 for patients receiving the antibody intravenously. In some embodiments, NPI assessments may continue to be performed every 24-28 weeks thereafter until treatment is stopped.

[0221] In some embodiments, administering the treatment to a plurality of human patients increases the time to progression to a non-zero score on the Clinical Dementia Rating (CDR) scale global score for the plurality of human patients. In some embodiments, administering the treatment increases the time to progression to a non-zero score on the CDR scale global score for the plurality of human patients at about 5 to about 8 years after initiation of treatment relative to or compared to a reference CDR scale global score, where the reference CDR scale global score is the CDR scale global score for the plurality of human patients who received a placebo. In some embodiments, the increase in time to progression to a non-zero score relative to or compared to the reference is statistically significant. In some embodiments, the CDR scale global score represents impairments in memory, orientation, judgment and problem-solving, social problems, household and hobbies, and personal care.

[0222] In some embodiments, administration of such treatment increases the time to progression of the CDR scale global score to non-zero in a plurality of human patients by about 5% to about 20% relative to a reference time to progression of the CDR scale global score to non-zero. In some embodiments, administration of such treatment increases the time to progression of the CDR scale global score to non-zero in a plurality of human patients by at least about 5% relative to a reference time to progression of the CDR scale global score to non-zero. In some embodiments, administration of such treatment increases the time to progression of the CDR scale global score to non-zero in a plurality of human patients by at least about 10% relative to a reference time to progression of the CDR scale global score to non-zero. In some embodiments, administering such treatment increases the time to progression of the CDR scale global score to non-zero in a plurality of human patients by about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% relative to a reference time to progression of the CDR scale global score to non-zero. In some embodiments, administering such treatment increases the time to progression of the CDR scale global score to non-zero in a plurality of human patients by 8% relative to a reference time to progression of the CDR scale global score to non-zero. In some embodiments, administering the treatment to a plurality of human patients reduces the decline in the Clinical Dementia Rating (CDR) scale global score in the plurality of human patients. In some embodiments, administration of the treatment results in a reduction in decline in the CDR scale global scores of a plurality of human patients from about 5 to about 8 years after initiation of treatment relative to or compared to a reference CDR scale global score, where the reference CDR scale global score is the CDR scale global score of a plurality of human patients who received a placebo. In some embodiments, the reduction in decline is statistically significant relative to or compared to the reference. In some embodiments, the CDR scale global score represents impairments in memory, orientation, judgment and problem-solving, social problems, household and hobbies, and personal care.

[0223] In some embodiments, administration of such treatment to a plurality of human patients reduces the decline in the Sum of Boxes on the Clinical Dementia Rating (CDR) scale for the plurality of human patients relative to a reference decline in the Sum of Boxes on the CDR scale, where the reference decline in the Sum of Boxes on the CDR scale is the decline in the Sum of Boxes on the CDR scale for the plurality of human patients who received a placebo. In some embodiments, administration of such treatment results in a statistically significant reduced decline in the Sum of Boxes on the CDR scale for the plurality of human subjects relative to or compared to the reference decline in the Sum of Boxes on the CDR scale at about 5 to about 8 years after initiation of treatment.

[0224] In some embodiments, administration of such treatment to a plurality of human patients reduces the decline in the Clinical Dementia Rating (CDR) scale Global Sum of Boxes scores for the plurality of human patients relative to a reference decline in the Global Sum of Boxes score for the CDR scale, where the reference decline in the Global Sum of Boxes score for the CDR scale is the decline in the Global Sum of Boxes score for the plurality of human patients who received a placebo.

[0225] In some embodiments, administration of such treatment to a plurality of human patients reduces the annualized rate of change in the Sum of Boxes on the Clinical Dementia Rating (CDR) scale for the plurality of human patients relative to a reference annualized rate of change in the Sum of Boxes on the CDR scale, where the reference annualized rate of change in the Sum of Boxes on the CDR scale is the annualized rate of change in the Sum of Boxes on the CDR scale for the plurality of human patients who received a placebo. In some embodiments, administration of such treatment results in a statistically significant attenuation in the annualized rate of change in the Sum of Boxes on the CDR scale for the plurality of human subjects relative to or compared to the reference annualized rate of change in the Sum of Boxes on the CDR scale at about 5 to about 8 years after initiation of treatment. In some embodiments, administration of such treatment reduces the annualized rate of change in the Sum of Boxes global score on the CDR scale for the plurality of human patients by at least 5% relative to the reference Sum of Boxes global score on the CDR scale. In some embodiments, administration of such treatment reduces the annualized rate of change in the Sum of Boxes global score on the CDR scale for the plurality of human patients by at least 10% relative to the reference Sum of Boxes global score on the CDR scale. In some embodiments, administration of such treatment reduces the annual rate of change in the Sum of Boxes global score of the CDR measure in a plurality of human patients by about 5% to about 20% relative to the Sum of Boxes global score of the reference CDR measure. In some embodiments, administration of such treatment reduces the annual rate of change in the Sum of Boxes global score of the CDR measure in a plurality of human patients by about 3%, about 5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20% relative to the Sum of Boxes global score of the reference CDR measure. In some embodiments, administration of such treatment reduces the annual rate of change in the Sum of Boxes global score of the CDR measure in a plurality of human patients by about 9% relative to the Sum of Boxes global score of the reference CDR measure.

[0226] In some embodiments, administering such a treatment to a plurality of human patients reduces the annualized rate of change in a measure of global neurocognitive function for the plurality of human patients relative to a reference annualized rate of change in a measure of global neurocognitive function, where the reference annualized rate of change in a measure of global neurocognitive function is the annualized rate of change in a measure of global neurocognitive function for the plurality of human patients who received a placebo. In some embodiments, the annualized rate of change in a measure of global neurocognitive function is determined using a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score. In some embodiments, administering such a treatment results in a statistically significant reduction in the annualized rate of change in RBANS score relative to or compared to the reference annualized rate of change in RBANS score at about 5 to about 8 years after initiation of treatment.

[0227] In some embodiments, the annual rate of change in a measure of global neurocognitive function is determined using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score. In some embodiments, administration of such a treatment results in a numerically advantageous reduction in the annual rate of change in the RBANS score relative to or compared to a reference annual rate of change in the RBANS score. In some embodiments, administration of such a treatment results in a reduction in the RBANS score by at least 40% relative to a reference RBANS score. In some embodiments, administration of such a treatment results in a reduction in the RBANS score by at least 50% relative to a reference RBANS score. In some embodiments, administration of such a treatment results in a reduction in the RBANS score by about 30% to about 60% relative to a reference RBANS score. In some embodiments, administration of such a treatment results in a reduction in the RBANS score by about 40% to about 50% relative to a reference RBANS score. In some embodiments, administration of such treatment results in a reduction in the RBANS score of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 50%, about 55%, or about 60% relative to the reference RBANS score. In some embodiments, administration of such treatment results in a reduction in the RBANS score of about 43% relative to the reference RBANS score.

[0228] Biomarkers In some embodiments, the methods herein further provide an effect on a biomarker associated with MCI and / or AD. In some embodiments, the effect on the biomarker is compared to a reference level of the biomarker. In some embodiments, biomarkers associated with MCI and / or AD include: CDR, word list:recall, MMSE total, RBANS, FAST, and / or NPI. In some embodiments, the effect on the biomarker is compared to a baseline level of the biomarker established at the start of treatment. In some embodiments, the effect on the biomarker is compared to a baseline level of the biomarker. In some embodiments, the effect on the biomarker is observed about 12 weeks after the start of treatment. In some embodiments, the effect on the biomarker is observed about 5 years after the start of treatment. In some embodiments, the effect on the biomarker is observed more than 5 years after the start of treatment, for example, about 6, about 7, about 8, about 9, about 10, about 15, or about 20 years or more after the start of treatment.

[0229] In some embodiments, the reference level is based on the level of the biomarker in a patient population receiving a placebo.

[0230] In some embodiments, the biomarker is an imaging biomarker (e.g., a biomarker assessed using positron emission tomography (PET) or magnetic resonance imaging (MRI)). In some embodiments, the biomarker is assessed using an immunoassay. In some embodiments, the biomarker is assessed using an ELISA (enzyme-linked immunosorbent assay).

[0231] Brain amyloid burden or burden, neurofibrillary tangles, and / or regional cerebral metabolic rate of glucose (CMRgI) can be assessed using neurological imaging techniques and tools, for example, using PET (positron emission tomography) scans. Serial PET scans of patients over time, for example, before and after administration of treatment (or at one or more intervals throughout the course of a treatment regimen), can allow for the detection of increased, decreased, or unchanged amyloid burden, neurofibrillary tangles, and / or glucose metabolism in the brain. This technology can further be used to determine whether these biomarkers are increasing or decreasing.

[0232] Tau levels or tau burden in a patient can be assessed using neurological imaging techniques and tools, for example, using positron emission tomography (PET) scans. In such methods, a tracer molecule known to bind to tau is radiolabeled with a PET-sensitive radioisotope and introduced into the patient. In conjunction with scans of the patient's brain, the location and amount (i.e., distribution) of tau can be imaged based on the assumption that the tracer binds to tau molecules. Serial PET scans of the patient over time, for example, before and after administration of treatment (or at one or more intervals throughout the course of a treatment regimen), can allow for the detection of increased, decreased, or unchanged tau burden in the patient's brain. Patient tau levels can also be assessed by measuring tau in blood, serum, plasma, or CSF samples from the patient. One or more of these techniques can be used to determine whether total tau is increasing or decreasing, or whether a given isoform of tau (e.g., aggregated tau) is increasing or decreasing at various time points throughout the course of treatment.

[0233] In some embodiments, the tau tracer is [18F]Genentech tau probe 1 ([ 18[F]GTP1). In other embodiments, other tau probes can be used. Examples of such tracer molecules include, but are not limited to: RO-948 (F. Hoffmann-La Roche AG); AV-1451 ("Flortaucepir", Avid, Inc.); PI-2014 and PI-2620 (AC Immune); MK-6240 (Merck Sharp & Dohme); and T-808 (Eli Lilly & Co.).

[0234] Methods for quantifying tau distribution in a patient's brain based on imaging of radiolabeled tracers include the "standardized uptake value ratio" (SUVR) (see, e.g., J. Nucl. Med., S. Sanabria Bohorquez et al., 58(1), (2017), incorporated herein by reference).

[0235] [ 18 Tau imaging using radioligands such as [F]GTP1 offers advantages over traditional CSF biomarker assessments in that it allows for the assessment of the relationship between the distribution of tau pathology and response to anti-tau therapy. For example, long-term [F]GTP1 18 [F]GTP1 PET imaging data may inform on the relationship between the spatial distribution of tau pathology, cognitive function, and disease progression, and therefore may be collected to assess the response of this biomarker, as is done with semolinemab, for example.

[0236] In some embodiments, administering such treatment according to the methods herein produces an effect on a tau-based cerebrospinal fluid (CSF) biomarker relative to or compared to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a tau-based CSF biomarker in a plurality of human patients who received a placebo. Tau is a microtubule-associated protein that forms insoluble filaments that accumulate as neurofibrillary tangles in AD patients. In some embodiments, the tau-based CSF biomarker is detected using an elecsys assay by Roche Diagnostics. In some embodiments, the tau-based CSF biomarker is detected using a fluorine-labeled probe. In some embodiments, the fluorine label is fluorine-18 ( 18 F). In some embodiments, the probe comprises: 18 FGTP1 (e.g., Bohorquez et al., Eur. J. Nucl. Med. Mol. Imaging, 2019;46(10):2077-2089). In some embodiments, the tau-based CSF biomarker is measured using positron emission tomography (PET). In some embodiments, administering such a treatment results in a statistically significant change in the tau-based CSF biomarker in a plurality of human patients relative to or compared to a reference tau-based CSF biomarker about 12 weeks after initiation of treatment. In some embodiments, administering such a treatment results in a statistically significant change in the tau-based CSF biomarker in a plurality of human patients relative to or compared to a reference tau-based CSF biomarker about 5 to about 8 years after initiation of treatment. In some embodiments, administering a treatment according to the methods herein results in a decrease in the tau-based CSF biomarker relative to or compared to the reference tau-based CSF biomarker.

[0237] In some embodiments, administering such treatment reduces the annualized rate of change of the tau-based CSF biomarker in a plurality of human patients compared to a reference annualized rate of change of the tau-based CSF biomarker, where the reference annualized rate of change of the tau-based CSF biomarker is the annualized rate of change of the tau-based CSF biomarker in a plurality of human patients who received a placebo.

[0238] In some embodiments, administering such treatment results in a reduction in the annual rate of the tau-based CSF biomarker in a plurality of human patients relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker. In some embodiments, administering such treatment results in a reduction in the annual rate of the tau-based CSF biomarker in a plurality of human patients by at least 40% relative to the reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker. In some embodiments, administering such treatment results in a reduction in the annual rate of the tau-based CSF biomarker in a plurality of human patients by at least 30% relative to the reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker. In some embodiments, administration of such treatment results in a 30% to 50% reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker. In some embodiments, administration of such treatment results in a reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients by about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 45%, or about 50% relative to the reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker. In some embodiments, administration of such treatment reduces the annual rate of tau-based CSF biomarker in a plurality of human patients by about 37% relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker.

[0239] In some embodiments, administering such treatment results in a reduction in the annual rate of the tau-based CSF biomarker in a plurality of human patients relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau[ttau]-based CSF biomarker. In some embodiments, administering such treatment results in a reduction in the annual rate of the tau-based CSF biomarker in a plurality of human patients by at least about 20% relative to the reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau[ttau]-based CSF biomarker. In some embodiments, administering such treatment results in a reduction in the annual rate of the tau-based CSF biomarker in a plurality of human patients by at least about 30% relative to the reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau[ttau]-based CSF biomarker. In some embodiments, administration of such treatment results in a reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients by about 20% to about 40% relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau[ttau]-based CSF biomarker. In some embodiments, administration of such treatment results in a reduction in the annual rate of tau-based CSF biomarker in a plurality of human patients by about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau[ttau]-based CSF biomarker. In some embodiments, administration of such treatment reduces the annual rate of a tau-based CSF biomarker in a plurality of human patients by about 28% relative to a reference tau-based CSF biomarker, wherein the tau-based CSF biomarker is a total tau [ttau]-based CSF biomarker.

[0240] In some embodiments, administering such treatment to a plurality of human patients results in an effect on brain tau load compared to a reference brain tau load, where the reference brain tau load is the brain tau load of a plurality of human patients who received a placebo. In some embodiments, the brain tau load is measured using positron emission tomography (tau PET). In some embodiments, administering such treatment reduces the annual rate of change in tau PET measurements in a plurality of human patients relative to a reference tau PET, where the reference tau PET measurements are the tau PET measurements of a plurality of human patients who received a placebo. In some embodiments, the brain tau load is detected using a fluorine-labeled probe. In some embodiments, the fluorine label is fluorine-18 ( 18 F). In some embodiments, the probe comprises: 18 F GTP1 (e.g., Bohorquez et al., Eur. J. Nucl. Med. Mol. Imaging, 2019;46(10):2077-2089).

[0241] In some embodiments, administration of such treatment to a plurality of human patients results in a numerically favorable effect on Tau PET compared to a reference brain Tau PET, where the reference brain Tau PET is a brain Tau PET of a plurality of human patients who received a placebo. In some embodiments, administration of such treatment to a plurality of human patients reduces the annualized incidence of Tau PET in the plurality of human patients by about 40% to about 60% relative to the reference Tau PET. In some embodiments, administration of such treatment to a plurality of human patients reduces the annualized incidence of Tau PET in the plurality of human patients by about 50% to about 60% relative to the reference Tau PET. In some embodiments, administration of such treatment to a plurality of human patients reduces the annualized incidence of Tau PET in the plurality of human patients by at least 40% relative to the reference Tau PET. In some embodiments, administration of such treatment to a plurality of human patients reduces the annualized incidence of Tau PET in the plurality of human patients by at least 50% relative to the reference Tau PET. In some embodiments, administration of such treatment to a plurality of human patients reduces the annual rate of tau PET in the plurality of human patients by about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% relative to a reference tau PET. In some embodiments, administration of such treatment to a plurality of human patients reduces the annual incidence of tau PET in the plurality of human patients by about 51% relative to a reference tau PET.

[0242] In some embodiments, administering such treatment in accordance with the methods herein reduces the brain fibrillary amyloid burden in a predetermined region of interest in a plurality of human patients relative to a reference brain fibrillary amyloid burden in the predetermined region of interest, where the reference brain fibrillary amyloid burden in the predetermined region of interest is the brain fibrillary amyloid burden in the predetermined region of interest in a plurality of human patients who received a placebo. In some embodiments, administering such treatment in accordance with the methods herein reduces the annual rate of change in amyloid burden in a plurality of human patients relative to a reference annual rate of change in amyloid burden, where the reference annual rate of change in amyloid burden is the annual rate of change in amyloid burden (e.g., as measured by PET) in a plurality of patients who received a placebo. In some embodiments, brain fibrillary amyloid burden is measured using a fluorine-labeled probe. In some embodiments, the fluorine label is fluorine-18 ( 18 In some embodiments, the probe is florbetapir (e.g., Wong, J. Nucl. Med., 2010;51(6):913-920). Florbetapir binds to beta amyloid. 18 It is an F-labeled compound that has been shown to accumulate in areas associated with beta-amyloid deposits. In some embodiments, cerebral fibrillary amyloid burden is measured by positron emission tomography (PET). In some embodiments, a florbetapir PET scan is considered positive if it establishes the presence of moderate to frequent neuritic plaques based on a focused visual reading of the scan. In some embodiments, administration of such treatment results in a statistically significant reduction in regional cerebral fibrillary amyloid burden in a plurality of human patients relative to or compared to a reference cerebral fibrillary amyloid burden at about 5 to about 8 years after initiation of treatment.

[0243] In some embodiments, administering such a treatment reduces the brain fibrillary amyloid burden in a predetermined region of interest of a plurality of human patients relative to a reference brain fibrillary amyloid burden in the predetermined region of interest, where the reference brain fibrillary amyloid burden in the predetermined region of interest is the brain fibrillary amyloid burden in the predetermined region of interest of a plurality of human patients who received a placebo. In some embodiments, the brain fibrillary amyloid burden is measured using florbetapir positron emission tomography (PET). In some embodiments, administering such a treatment reduces the annual rate of change of amyloid burden measured by PET in a plurality of human patients by at least 3% relative to the reference amyloid burden measured by PET. In some embodiments, administering such a treatment reduces the annual rate of change of amyloid burden measured by PET in a plurality of human patients by at least 10% relative to the reference amyloid burden measured by PET. In some embodiments, administering such a treatment reduces the annual rate of change of amyloid burden measured by PET in a plurality of human patients by about 3% to about 10% relative to the reference amyloid burden measured by PET. In some embodiments, administration of such treatment reduces the annual rate of change of amyloid burden measured by PET in a plurality of human patients by about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% relative to a reference amyloid burden measured by PET. In some embodiments, administration of such treatment reduces the annual rate of change of amyloid burden measured by PET in a plurality of human patients by about 3% relative to a reference amyloid burden measured by PET.

[0244] In some embodiments, brain fibrillary amyloid burden is measured in a predetermined region of interest in patients receiving an anti-amyloid beta (Aβ) antibody and / or a placebo. In some embodiments, brain fibrillary amyloid burden is measured in the brain. In some embodiments, brain fibrillary amyloid burden is measured in a region of the brain that contains amyloid deposits. In some embodiments, brain fibrillary amyloid burden is repeatedly measured in the same region of the brain to evaluate the effect of anti-amyloid beta (Aβ) antibody treatment on brain fibrillary burden.

[0245] In some embodiments, administering such treatment in accordance with the methods herein reduces regional cerebral metabolic rate of glucose (CMRgI) in a plurality of human patients relative to a reference reduction in CMRgI, the reference reduction in CMRgI being a reduction in CMRgI in a plurality of human patients who received a placebo. In some embodiments, CMRgI is measured using a fluorine-labeled probe. In some embodiments, the fluorine label is fluorine-18 ( 18 F). In some embodiments, the probe is fluorodeoxyglucose (FDG). In some embodiments, CMRgI is measured using FDG-positron emission tomography (PET). In some embodiments, administering such a treatment reduces FDG PET measurements in a plurality of human patients relative to a reference FDG PET measurement, where the reference FDG PET measurement is an FDG PET measurement in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment results in a statistically significant reduced decrease in regional CMRgI in a plurality of human patients relative to or compared to the reference decrease in CMRgI at about 12 weeks after initiation of treatment. In some embodiments, administering such a treatment results in a statistically significant reduced decrease in regional CMRgI in a plurality of human patients relative to or compared to the reference decrease in CMRgI at about 5 to about 8 years after initiation of treatment.

[0246] In some embodiments, administration of such a treatment reduces annualized FDG PET measurements in a plurality of human patients relative to a reference annualized FDG PET measurement. In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients relative to the reference annualized SUVR for FDG PET. In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by at least 10% relative to the reference annualized SUVR for FDG PET. In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by at least 20% relative to the reference annualized SUVR for FDG PET. In some embodiments, administration of such a treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by about 10% to about 30% relative to the reference annualized SUVR for FDG PET. In some embodiments, administration of such treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% compared to a reference annualized SUVR for FDG PET. In some embodiments, administration of such treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in a plurality of human patients by about 18% compared to a reference annualized SUVR for FDG PET.

[0247] In some embodiments, administering such treatment in accordance with the methods herein reduces brain atrophy in a plurality of human patients relative to a reference brain atrophy, where the reference brain atrophy is brain atrophy in a plurality of human patients receiving a placebo. In some embodiments, administering such treatment results in a statistically significant reduction in brain atrophy in a plurality of human patients relative to or compared to the reference brain atrophy about 12 weeks after initiation of treatment. In some embodiments, administering such treatment results in a statistically significant reduction in brain atrophy in a plurality of human patients relative to or compared to the reference brain atrophy about 5 to about 8 years after initiation of treatment. In some embodiments, brain atrophy is measured using volumetric MRI. In some embodiments, the volumetric MRI is measured across the whole brain. In some embodiments, administering such treatment reduces the annual rate of change in brain atrophy in a plurality of human patients by at least 60% relative to a reference brain atrophy, where the reduction is measured by volumetric MRI of the whole brain. In some embodiments, administration of such treatment reduces the annual rate of change in brain atrophy in a plurality of human patients by at least 70% relative to a reference brain atrophy, as measured by whole brain volumetric MRI. In some embodiments, administration of such treatment reduces the annual rate of change in brain atrophy in a plurality of human patients by about 60% to about 70% relative to a reference brain atrophy, as measured by whole brain volumetric MRI. In some embodiments, administration of such treatment reduces the annual rate of change in brain atrophy in a plurality of human patients by about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, or about 70% relative to a reference brain atrophy, as measured by whole brain volumetric MRI.

[0248] In some embodiments, volumetric MRI is measured on both hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by at least 5% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by at least 10% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by about 5% to about 20% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by about 5%, about 6%, about 7%, about 8%, about 9%, or about 10% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi.

[0249] In some embodiments, administering such treatment in accordance with the methods herein reduces the annual rate of change in brain atrophy in a plurality of human patients relative to a reference brain atrophy, where the reference brain atrophy is the annual rate of change in brain atrophy in a plurality of human patients who received a placebo. In some embodiments, administering such treatment results in a statistically significant reduction in brain atrophy in a plurality of human patients relative to or compared to the reference brain atrophy about 12 weeks after initiation of treatment. In some embodiments, administering such treatment results in a statistically significant reduction in brain atrophy in a plurality of human patients relative to or compared to the reference brain atrophy about 5 to about 8 years after initiation of treatment. In some embodiments, brain atrophy is measured using volumetric MRI. In some embodiments, the volumetric MRI is measured across the brain. In some embodiments, whole-brain shrinkage is measured using volumetric MRI. In some embodiments, administering such treatment results in at least a 5% reduction in the annual rate of change in brain atrophy in a plurality of human patients relative to a reference brain atrophy, where the reduction is measured by volumetric MRI of the whole brain. In some embodiments, administration of such treatment results in a reduction in the annual rate of change in brain atrophy of a plurality of human patients by at least 10% relative to a reference brain atrophy, as measured by whole brain volumetric MRI. In some embodiments, administration of such treatment results in a reduction in the annual rate of change in brain atrophy of a plurality of human patients by about 5% to about 20% relative to a reference brain atrophy, as measured by whole brain volumetric MRI. In some embodiments, administration of such treatment results in a reduction in the annual rate of change in brain atrophy of a plurality of human patients by about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 25%, or about 30% relative to a reference brain atrophy, as measured by whole brain volumetric MRI.

[0250] In some embodiments, volumetric MRI is measured on both hippocampi. In some embodiments, hippocampal shrinkage is measured using volumetric MRI. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by at least 1% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by at least 2% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by about 1% to about 10% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi. In some embodiments, administration of such a treatment reduces the annual rate of change in brain atrophy for a plurality of human patients by about 1%, about 2%, about 3%, about 4%, about 5%, or about 10% relative to a reference brain atrophy, as measured by volumetric MRI of the bilateral hippocampi.

[0251] In some embodiments, administering such a treatment according to the methods herein reduces the annualized rate of change in brain atrophy in a plurality of human patients relative to a reference annualized rate of change in brain atrophy, where the reference annualized rate of change in brain atrophy is the annualized rate of change in brain atrophy in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment results in a statistically significant reduction in the annualized rate of change in brain atrophy in a plurality of human patients relative to or compared to the reference annualized rate of change in brain atrophy about 12 weeks after initiation of treatment. In some embodiments, administering such a treatment results in a statistically significant reduction in the annualized rate of change in brain atrophy in a plurality of human patients relative to or compared to the reference annualized rate of change in brain atrophy about 5 to about 8 years after initiation of treatment. In some embodiments, brain atrophy is measured using volumetric MRI.

[0252] In some embodiments, administration of such a treatment reduces cerebrospinal fluid (CSF) neurofilament light (CSF NfL) in a plurality of human patients relative to a reference CSF NfL, the reference CSF NfL being derived from a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment reduces CSF NfL in a plurality of human patients by at least 10% relative to the reference CSF NfL. In some embodiments, administration of such a treatment reduces CSF NfL in a plurality of human patients by at least 20% relative to the reference CSF NfL. In some embodiments, administration of such a treatment reduces CSF NfL in a plurality of human patients by about 10% to about 30% relative to the reference CSF NfL. In some embodiments, administration of such a treatment results in a relative reduction in CSF NfL in a plurality of human patients by about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 35%, or about 30% relative to the reference CSF NfL. In some embodiments, administration of such a treatment results in a relative reduction in CSF NfL in a plurality of human patients by about 18% relative to the reference CSF NfL.

[0253] In some embodiments, administering such treatment according to the present method produces an effect on plasma biomarkers of multiple human patients compared to a reference plasma biomarker, wherein the reference plasma biomarker is the plasma biomarker of multiple human patients receiving a placebo. In some embodiments, the plasma biomarker is measured using an immunoassay. In some embodiments, the plasma biomarker is any one of Aβ42, Aβ40, pTau181, pTau217, NfL, GFAP, YKL-40, or sTREM. In some embodiments, the plasma biomarker is the ratio of Aβ42 to Aβ40.

[0254] In some embodiments, administering such treatment results in an increase in the annualized rate of change of the plasma Aβ42 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma Aβ42 biomarker, wherein the reference plasma Aβ42 biomarker is the annualized rate of change of the plasma Aβ42 biomarker in a plurality of human patients who received a placebo.

[0255] In some embodiments, administering such treatment results in an increase in the annualized rate of change of the plasma Aβ40 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma Aβ40 biomarker, wherein the reference plasma Aβ40 biomarker is the annualized rate of change of the plasma Aβ40 biomarker in a plurality of human patients who received a placebo.

[0256] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma pTau181 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma pTau181 biomarker, where the reference plasma pTau181 biomarker is the annualized rate of change of the plasma pTau181 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces pTau181 in a plurality of human patients by at least about 2% relative to the reference pTau181. In some embodiments, administering such a treatment reduces pTau181 in a plurality of human patients by at least about 5% relative to the reference pTau181. In some embodiments, administering such a treatment reduces pTau181 in a plurality of human patients by about 2% to about 10% relative to the reference pTau181. In some embodiments, administration of such treatment results in a reduction in pTau181 in a plurality of human patients by about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% relative to the reference pTau181. In some embodiments, administration of such treatment results in a reduction in pTau181 in a plurality of human patients by about 6% or about 6.2% relative to the reference pTau181.

[0257] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma pTau217 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma pTau217 biomarker, where the reference plasma pTau217 biomarker is the annualized rate of change of the plasma pTau217 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces pTau217 in a plurality of human patients by at least about 5% relative to the reference pTau217. In some embodiments, administering such a treatment reduces pTau217 in a plurality of human patients by at least about 10% relative to the reference pTau217. In some embodiments, administering such a treatment reduces pTau217 in a plurality of human patients by about 5% to about 15% relative to the reference pTau217. In some embodiments, administration of such treatment results in a reduction in pTau217 in a plurality of human patients by about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% relative to a reference pTau217. In some embodiments, administration of such treatment results in a reduction in pTau217 in a plurality of human patients by about 9% relative to a reference pTau217.

[0258] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of a plasma NfL biomarker in a plurality of human patients compared to a reference annualized rate of change of a plasma NfL biomarker, where the reference plasma NfL biomarker is the annualized rate of change of a plasma NfL biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces NfL in a plurality of human patients by at least about 5% relative to the reference NfL. In some embodiments, administering such a treatment reduces NfL in a plurality of human patients by at least about 10% relative to the reference NfL. In some embodiments, administering such a treatment reduces NfL in a plurality of human patients by about 5% to about 15% relative to the reference NfL. In some embodiments, administering such a treatment reduces NfL in a plurality of human patients by about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% relative to the reference NfL. In some embodiments, administration of such a treatment results in a relative reduction in NfL in a plurality of human patients of about 10%, or about 10.5%, relative to a reference NfL.

[0259] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma GFAP biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma GFAP biomarker, where the reference plasma GFAP biomarker is the annualized rate of change of the plasma GFAP biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces GFAP in a plurality of human patients by at least about 10% relative to the reference GFAP. In some embodiments, administering such a treatment reduces GFAP in a plurality of human patients by at least about 15% relative to the reference GFAP. In some embodiments, administering such a treatment reduces GFAP in a plurality of human patients by about 10% to about 20% relative to the reference GFAP. In some embodiments, administering such a treatment reduces GFAP in a plurality of human patients by about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% relative to the reference GFAP. In some embodiments, administration of such treatment results in a relative reduction in GFAP in a plurality of human patients of about 17% or about 17.7% relative to the reference GFAP.

[0260] In some embodiments, administration of such a treatment results in a reduction in the annualized rate of change of the plasma YKL-40 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma YKL-40 biomarker, where the reference plasma YKL-40 biomarker is the annualized rate of change of the plasma YKL-40 biomarker in a plurality of human patients who received a placebo. In some embodiments, administration of such a treatment results in a reduction in YKL-40 in a plurality of human patients by at least about 8% relative to the reference YKL-40. In some embodiments, administration of such a treatment results in a reduction in YKL-40 in a plurality of human patients by at least about 15% relative to the reference YKL-40. In some embodiments, administration of such a treatment results in a reduction in YKL-40 in a plurality of human patients by about 8% to about 20% relative to the reference YKL-40. In some embodiments, administration of such treatment results in a relative reduction in YKL-40 in a plurality of human patients of about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% relative to the reference YKL-40, hi some embodiments, administration of such treatment results in a relative reduction in YKL-40 in a plurality of human patients of about 12% or about 12.4% relative to the reference YKL-40.

[0261] In some embodiments, administering such a treatment results in a reduction in the annualized rate of change of the plasma sTREM2 biomarker in a plurality of human patients compared to a reference annualized rate of change of the plasma sTREM2 biomarker, where the reference plasma sTREM2 biomarker is the annualized rate of change of the plasma sTREM2 biomarker in a plurality of human patients who received a placebo. In some embodiments, administering such a treatment reduces sTREM2 in a plurality of human patients by at least about 15% relative to the reference sTREM2. In some embodiments, administering such a treatment reduces sTREM2 in a plurality of human patients by at least about 25% relative to the reference sTREM2. In some embodiments, administering such a treatment reduces sTREM2 in a plurality of human patients by about 15% to about 30% relative to the reference sTREM2. In some embodiments, administration of such a treatment reduces sTREM2 in a plurality of human patients by about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% relative to a reference sTREM2. In some embodiments, administration of such a treatment reduces sTREM2 in a plurality of human patients by about 23% or about 23.1% relative to a reference sTREM2.

[0262] III. Patient Population The present invention provides a method for delaying the onset of at least one symptom or slowing cognitive decline in a human patient with a genetic mutation that causes familial Alzheimer's disease (AD). In some embodiments, the mutation is an autosomal mutation. In some embodiments, the mutation is an autosomal dominant mutation.

[0263] In some embodiments, the genetic mutation that causes familial AD is a mutation in one or more of presenilin 1 (PSEN1), presenilin 2 (PSEN2), and / or amyloid precursor protein (APP). In some embodiments, the mutation is an autosomal dominant mutation. Autosomal dominant mutations in PSEN1, PSEN2, and APP are known in the art (see, for example, the mutation database maintained on the World Wide Web by ALZFORUM, which is incorporated herein by reference in its entirety).

[0264] In some embodiments, the mutation that causes familial AD is a mutation in PSEN1. In some embodiments, the mutation includes one or more of E280A, P117L, M139T, M146L, M146V, H163R, L166P, M233T, L235P, A246E, P264L, R278I, L286V, and L435F. In some embodiments, the genetic mutation is an E280A mutation in PSEN1.

[0265] In some embodiments, the familial AD-causing mutation is a mutation in PSEN2. In some embodiments, the mutation comprises one or more of N141I, T122P, M239V, M239I, and M298T.

[0266] In some embodiments, the familial AD-causing mutation is a mutation in APP, hi some embodiments, the mutation includes one or more of KM670 / 671NL, A673T, E693Q, E693G, E693del, D694N, T714I, I716F, I716V, V717F, and V717I.

[0267] In some embodiments, the human patient is 100 years of age or younger. In some embodiments, the human patient is 60 years of age or younger. In some embodiments, the human patient is 20 years of age or older. In some embodiments, the human patient is 30 years of age or older. In some embodiments, the human patient is 20 to 100 years of age. In some embodiments, the human patient is 20 to 30 years of age. In some embodiments, the human patient is 20 to 40 years of age. In some embodiments, the human patient is 20 to 50 years of age. In some embodiments, the human patient is 20 to 60 years of age. In some embodiments, the human patient is 20 to 70 years of age. In some embodiments, the human patient is 20 to 80 years of age. In some embodiments, the human patient is 20 to 90 years of age. In some embodiments, the human patient is 30 to 40 years of age. In some embodiments, the human patient is 30 to 50 years of age. In some embodiments, the human patient is 30 to 60 years of age. In some embodiments, the human patient is 30 to 70 years of age. In some embodiments, the human patient is 30 to 80 years of age. In some embodiments, the human patient is between 30 and 90 years old. In some embodiments, the human patient is between 30 and 100 years old. In some embodiments, the human patient is between 40 and 50 years old. In some embodiments, the human patient is between 40 and 60 years old. In some embodiments, the human patient is between 40 and 70 years old. In some embodiments, the human patient is between 40 and 80 years old. In some embodiments, the human patient is between 40 and 90 years old. In some embodiments, the human patient is between 40 and 100 years old. In some embodiments, the human patient is between 50 and 60 years old. In some embodiments, the human patient is between 50 and 70 years old. In some embodiments, the human patient is between 50 and 80 years old. In some embodiments, the human patient is between 50 and 90 years old. In some embodiments, the human patient is between 50 and 100 years old. In some embodiments, the human patient is between 60 and 70 years old. In some embodiments, the human patient is between 60 and 80 years old. In some embodiments, the human patient is between 60 and 90 years old. In some embodiments, the human patient is between 60 and 100 years old.In some embodiments, the human patient is between 70 and 80 years old. In some embodiments, the human patient is between 70 and 90 years old. In some embodiments, the human patient is between 70 and 100 years old. In some embodiments, the human patient is between 80 and 90 years old. In some embodiments, the human patient is between 80 and 100 years old. In some embodiments, the human patient is between 90 and 100 years old. In some embodiments, the human patient is between 30 and 60 years old.

[0268] In some embodiments, a human patient is characterized as having preclinical AD, e.g., the patient is at particular risk for developing AD dementia, but is not yet hypersymptomatic and does not meet the criteria for MCI or dementia (see, e.g., Reiman et al., Biomark. Med., 2010, 4:3-14; Sperling et al., Alzheimers Dement, 2011, 7:280-292).

[0269] In some embodiments, the human patient does not meet the criteria for dementia due to AD as defined by McKhann et al., Alzheimers Dement., 2011;7:263-269.

[0270] In some embodiments, the patient has an MMSE of 24 or greater for patients with less than 9 years of education, or 26 or greater for patients with 9 or more years of education.

[0271] In some embodiments, the human patient does not meet criteria for mild cognitive impairment (MCI) due to AD (see, e.g., Albert et al., Alzheimers Dement., 2011;7:270-279). In some embodiments, the criteria for MCI due to AD include: cognitive concern in the physician's judgment, based in part on a mean subjective memory checklist score of >22 (average of participant and study partner component scores); word list: recall <3 for participants with less than 9 years of education, or word list: recall <5 for participants with 9 or more years of education; and maintenance of independence of functional activities in the physician's judgment, based in part on a review of the Functional Assessment Staging Score (FAST) (see, e.g., Sclan and Reisberg, Int. Psychogeriatr, 1992;4:55-69).

[0272] In some embodiments, the human patient has adequate vision and hearing, at the discretion of the physician, to be able to complete one or more cognitive, functional, and / or behavioral assessments.

[0273] In some embodiments, human patients are paired with a research partner who will participate in the treatment but will not receive it. In some embodiments, the research partner accompanies the patient to all required clinical visits and / or treatment-related events. In some embodiments, the research partner provides telephone assessments of the patient. In some embodiments, the research partner spends sufficient time with the patient to become familiar with the patient's overall functioning and behavior and can provide pertinent information about the patient, including the patient's home activities, hobbies, daily living, social skills, basic activities of daily living, work and education history; the patient's cognitive abilities, including memory, language, temporal and spatial orientation, judgment, and problem-solving; the patient's emotional and psychological state; and information about the patient's overall health. In some embodiments, the patient and research partner provide evidence of sufficient premorbid function (e.g., intellectual, visual, and auditory). In some embodiments, the patient and research partner have evidence of fluency and language reading ability in the language in which the study assessment will be conducted.

[0274] In some embodiments, the human patient is willing and able to undergo neuroimaging. In some embodiments, the neuroimaging may include, but is not limited to, positron emission tomography (PET). In some embodiments, the neuroimaging may include, but is not limited to, magnetic resonance imaging (MRI).

[0275] In some embodiments, the human patient is in good general health, hi some embodiments, the human patient has no known comorbidities that would be expected to interfere with the methods described herein.

[0276] In some embodiments, the human patient weighs no less than 45 kg. In some embodiments, the patient weighs no more than 120 kg.

[0277] In some embodiments, the human patient does not have brain MRI imaging results at baseline showing evidence of any of the following: (a) ARIA-E (cerebral VE, sulcal effusion), infection, significant cerebrovascular pathology, clinically significant lacunar infarction or multiple lacunae in cognitively important areas, or cortical infarction or clinically significant focal lesions; (b) more than four cerebral microbleeds (lesions ≦10 mm in diameter) regardless of anatomical location or diagnostic characterization as "probable" or "definite"; or (c) a single area of superficial siderosis of the CNS or a previous cerebral large hemorrhage (lesions >0 mm in diameter).

[0278] In some embodiments, the human patient does not use other medications that may significantly affect cognition. In some embodiments, other medications include, but are not limited to, sedatives, narcotics (e.g., opiates / opioids), hypnotics, over-the-counter (OTC) sleep aids, or sedative antiallergic drugs. In some embodiments, the patient may use these medications on a short-term or intermittent basis as deemed medically necessary for the treatment of non-excluded medical conditions. In some embodiments, the patient may use a stable low-dose tricyclic antidepressant or benzodiazepine for the treatment of non-excluded medical conditions.

[0279] In some embodiments, the human patient does not use typical antipsychotics or barbiturates. In some embodiments, the patient does not use non-anticholinergic antidepressants or atypical antipsychotics unless maintained on a stable dose regimen for at least 6 weeks prior to treatment. In some embodiments, the patient does not use FDA / INVIMA-approved drugs for the treatment of late-onset AD at baseline. In some embodiments, the patient does not use anticoagulants. In some embodiments, the patient does not exhibit a known coagulopathy or a platelet count below 100,000 cells / μL within 4 weeks of the treatment visit. In some embodiments, the patient does not use any biologic therapy within 5 half-lives or 3 months prior to treatment, whichever is longer. In some embodiments, the patient may use routinely recommended vaccinations. In some embodiments, the patient does not use antiseizure drugs, anti-Parkinson's drugs, or stimulants (e.g., methylphenidate). In some embodiments, the patient does not use any investigational drug, device, or experimental drug within 60 days (or 5 half-lives, whichever is longer) of the treatment visit. In some embodiments, the patient has no prior treatment with crenezumab (MABT5102A) or any other therapeutic agent targeting Aβ. In some embodiments, the patient has no history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins.

[0280] In some embodiments, the method includes a comparison with a reference, for example, a reference occurrence of at least one symptom or a reference level of a biomarker. In some embodiments, the reference is established by a plurality of human patients receiving a placebo. In some embodiments, the plurality of human patients receiving the placebo includes carriers of familial AD gene mutations. In some embodiments, the plurality of human patients receiving the placebo includes non-carriers of familial AD gene mutations. In some embodiments, the plurality of human patients receiving the placebo includes both carriers of familial AD gene mutations and non-carriers of familial AD gene mutations.

[0281] IV. Kits and Manufactured Articles In another aspect of the present invention, an article of manufacture or kit contains materials useful for treating patients with preclinical ADAD. The article of manufacture comprises a container and a label or package insert affixed to or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The container may be formed from a variety of materials, such as glass or plastic. The container holds a composition to be used alone or in combination with another composition effective in treating preclinical ADAD and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is an anti-Aβ antibody. The label or package insert indicates that the composition is used to treat preclinical ADAD. In some embodiments, the article of manufacture or kit further comprises a package insert containing instructions for using the anti-Aβ antibody to treat ADAD. The article of manufacture may further comprise a second (or third) container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. [Example]

[0282] Example 1—A Clinical Study of the Safety and Efficacy of the Humanized Anti-Aβ Monoclonal Antibody, Crenezumab, Administered to PSEN1 E280A Mutation Carriers and Non-Carriers to Prevent the Onset of Autosomal Dominant Alzheimer's Disease Autosomal dominant Alzheimer's disease (ADAD; also known as familial AD or dominantly inherited AD (DIAD)) is a rare inherited form of AD caused by a single gene mutation in the APP, PSEN1, or PSEN2 gene. Fewer than 1% of all AD cases worldwide are thought to be caused by genetic mutations. ADAD has a much earlier onset than the more common sporadic AD, with symptoms typically occurring between the ages of 30 and 60. Individuals carrying one of these mutations are virtually certain to develop AD and have a 50% risk of allelic heritability. One particular mutation, the PSEN1 E280A or "Paisa" mutation, originates from a family in the Antioquia region of Colombia. Within this family, 6,000 individuals are affected, with over 1,200 confirmed carriers. Mutation carriers develop memory loss in their 30s; full dementia develops between the ages of 45 and 50.

[0283] Crenezumab (RO5490245; MABT5102A) is a fully humanized IgG4 monoclonal antibody selected for its ability to bind to monomeric, oligomeric, and fibrillar forms of Aβ in vitro (Adolfsson et al., J Neurosci, 2012;32:9677-9689). Crenezumab binds to both Aβ1-40 and Aβ1-42, inhibiting Aβ aggregation and promoting Aβ disaggregation. Because crenezumab is a human IgG4-based antibody, it has reduced Fcγ receptor (FcγR) binding affinity compared to human IgG1 or IgG2, which predicts a reduced immune effector response. These properties, coupled with the ability of systemically delivered crenezumab to reduce Aβ CNS levels in mouse models of AD, suggest that this anti-Aβ therapeutic approach may provide clinical efficacy while reducing the risk of toxicity, with the ultimate goal of correcting disease progression in AD patients at low risk for amyloid-related imaging abnormalities—edema / exudates (ARIA-E), including cerebral vasogenic edema (VE) and sulcal effusions, or amyloid-related imaging abnormalities—hemosiderin deposits (ARIA-H), including cerebral microbleeds and superficial siderosis (Sperling et al., Alzheimer's Dement., 2011;7:367-385). The promising safety profile to date provides the opportunity to administer higher doses of the drug and achieve higher brain concentrations relative to alternative monoclonal antibodies. Indeed, this safety profile allows doses exceeding 720 mg SC every 2 weeks (Q2W) to be studied in participants. Specifically, a dose of 60 mg / kg IV every 4 weeks (Q4W) was included as an option for participants in this study (GN28352, correction 6). This dose was also evaluated in a Phase 1b trial (GN29632), in a global Phase 3 study (BN29552 and BN29553) in sporadic prodromal to mild AD, and in the open-label extension (OLE) study BN40031.

[0284] The API ADAD trial (NCT01998841) was a prospective, randomized, double-blind, placebo-controlled, parallel-group trial that allowed for a phase II study of the efficacy of crenezumab versus placebo in cognitively healthy individuals without clinical symptoms of Alzheimer's disease but carrying the PSEN1 E280A autosomal dominant mutation.

[0285] Study design and objectives This clinical study consisted of two study periods, referred to as Study Periods A and B. Study Period A was a prospective, randomized, double-blind, placebo-controlled, parallel-group study of crenezumab versus placebo treatment in carriers of the PSEN1 E280A autosomal dominant PSEN1 mutation in early-onset AD who did not meet criteria for mild cognitive impairment (MCI) due to AD or dementia due to AD and therefore were in the preclinical stage of AD. This study also incorporated administration of placebo to individuals who were not PSEN1 E280A autosomal dominant mutation carriers.

[0286] PSEN1 E280A autosomal dominant mutation carriers who met study eligibility criteria were randomized in a 1:1 ratio to one of two treatment arms: crenezumab or placebo. The study was initially powered to compare the mean change from baseline in the API ADAD Composite Cognitive Test total score over 260 weeks between the active and placebo groups. Assuming a 25% dropout rate, a two-sided test at the 0.05 level overall, a placebo group CV of the change score at week 260 of 65% (= 100% × standard deviation of placebo participant change score / mean placebo participant change score), and 100 participants per arm, the study would have at least 80% power to detect a true effect of a 30% reduction in mean decline in the placebo group. To maintain genotype blinding and obtain genetically related controls, a cohort of PSEN1 E280A mutation noncarrier related family members was also enrolled in the study and administered placebo only. Thus, the study included three arms with approximately 100 participants per arm; two arms of participants with the PSEN1 E280A mutation were randomized in a 1:1 ratio to active or placebo, and the third arm of non-carriers was randomized to placebo (see Figure 1A).

[0287] Participants received randomized treatment until the final participant reached the final treatment visit at week 260. The study duration for each individual participant was approximately at least 284 weeks, which included an 8-week screening period, a double-blind treatment period at least 260 weeks long, a 4-week final dose visit, and a final safety follow-up visit 16 weeks after the final dose of study drug (crenezumab or placebo) to allow for clinical follow-up after treatment discontinuation for participants who did not continue study drug after the end of Study Period A or who terminated study drug early (see Figure 1B).

[0288] Crenezumab was administered either subcutaneously (720 mg every 2 weeks) or intravenously (60 mg / kg every 4 weeks), with a matching placebo administered by the same route and at the same frequency. Switching to a higher intravenous dose (approximately 4-fold higher exposure to crenezumab) was optional. Participants could decide whether to switch from the initial subcutaneous dose to IV dosing. However, once a given participant received intravenous dosing, they could not revert to a lower subcutaneous dose.

[0289] After completing Study Period A, participants were offered the opportunity to continue in Study Period B. In this second study period, participants continued receiving study drug until study outcomes were known, post-trial access to crenezumab was initiated through an open-label extension (OLE) or other program, or development of crenezumab was discontinued. All PSEN1 E280A mutation carriers were offered crenezumab in Study Period B, regardless of their treatment assignment during Study Period A, and all noncarriers continued on placebo. Treatment assignment for both Study Periods A and B remained blinded. Study Period B continued until approximately 9–12 months from the time participants entered Study Period B.

[0290] The target population included individuals who were members of the PSEN1 E280A mutation carriers who were related to, consented to, and willing to undergo genetic testing (e.g., APOE, PSEN1 E280A, and other genetic testing) with confirmed PSEN1 E280A mutation carrier or non-carrier status before or during the screening period. Patient demographic data are shown in Table 1 below. Patients were men and women in the age range of 30 to 60 years; had an MMSE of 24 or greater for participants with less than 9 years of education or an MMSE of 26 or greater for participants with 9 or more years of education; did not meet criteria for dementia due to AD; did not meet criteria for MCI due to AD as defined by: (a) cognitive concerns based in part on a mean subjective memory checklist score >22 (mean of participant and study partner component scores), (b) word list: recall <3 for participants with less than 9 years of education, (c) word list: recall <5 for participants with 9 or more years of education, and (d) maintenance of independence in functional activities based in part on Functional Assessment Staging (FAST) review; sufficient vision and hearing to complete the study. had a study partner who agreed to participate in the study and was able and willing to: (a) accompany the participant to all required clinic visits for subcutaneous or intravenous administration, (b) provide information for the required telephone assessment, and (c) spend sufficient time with the participant to become familiar with the participant's overall functioning and behavior and provide pertinent information about the participant, including: (i) knowledge of home activities, hobbies, daily living, social skills, and basic activities of daily living, (ii) work and education history, (iii) cognitive abilities, including memory, language, temporal and spatial orientation, judgment, and problem-solving, (iv) emotional and psychological status, and (v) general health. Participants and study partners had evidence of: (a) adequate premorbid functioning (e.g., intellectual, visual, and auditory), and (b) fluency and ability to read in the language in which the study assessments were administered.Participants were willing and able to undergo neuroimaging (PET and MRI); did not have clinically significant thyroid dysfunction or B12 deficiency as determined by the following criteria: (a) serum thyroid-stimulating hormone (TSH) and B12 levels within the normal or expected laboratory range; (b) if the participant was receiving thyroid replacement therapy, TSH levels within the normal or expected laboratory range; (c) if the participant was receiving vitamin B12 injections or oral vitamin B12 therapy, B12 levels above the lower limit of normal laboratory limits; and were in good general health with no known comorbidities that would be expected to prevent study participation.

[0291] [Table 1]

[0292] The target population excluded those with the following: (1) any significant medical, psychiatric, or neurological condition or disorder documented by medical history, physical, neurological, laboratory, or ECG testing that would expose the participant to undue risk or affect the interpretation of efficacy; (2) a history of stroke; (3) a history of severe, clinically significant CNS trauma (e.g., cerebral contusion); (4) a body weight <45 or >120 kg; (5) a history or presence of atrial fibrillation that imposed a risk of future stroke; (6) a clinically significant test (7) presence of bipolar disorder according to DSM-IV-TR or other clinically significant psychiatric disorder (recorded as an AE if diagnosed after study enrollment); (8) clinically significant depression based in part on a Geriatric Depression Scale (Short Form GDS) (15-point scale) score >9 at screening; (9) history of stroke; (10) myocardial infarction, congestive heart failure, atrial fibrillation, or uncontrolled hypertension within 2 years; (11) history of cancer within 5 years; (12) history of pulmonary embolism within the last 3 years before screening Clinically significant infection within 0 days; (13) brain MRI imaging results at baseline showing any of the following: (a) evidence of ARIA-E (cerebral VE, sulcal effusion), infection, significant cerebrovascular pathology, clinically significant lacunar infarction or multiple lacunae in cognitively important areas, or cortical infarction or clinically significant focal lesions; (b) more than four cerebral microbleeds (lesions ≤10 mm in diameter), regardless of anatomical location or diagnostic characteristics as "probable" or "definite"; or (c) Evidence of a single area of superficial siderosis in the CNS or a previous large cerebral hemorrhage (lesion >0 mm in diameter); (14) Clinically significant blood or urine screening test abnormalities that warrant further evaluation or treatment, including: (a) liver dysfunction as indicated by transaminases >2 × upper limit of normal (ULN) or clinically significant abnormalities in synthetic function tests, (b) coagulopathy (aPTT >1.2 × ULN), (c) platelet count <100,000 / μL, or (d) glycosylated hemoglobin >8.0%; (15) positive urine test for drugs of abuse at screening (cannabinoid assay results were not used to determine eligibility); (16) history of alcohol or substance dependence within the past 2 years (DSM-IV TR criteria; (17) use of any other medications that may significantly affect cognition (including, but not limited to, sedatives, narcotics (e.g., opiates / opioids), hypnotics, over-the-counter (OTC) sleep aids, and sedative antiallergics); (18) use of typical antipsychotics or barbiturates; (19) use of non-anticholinergic antidepressants or atypical antipsychotics unless maintained on a stable dose regimen for at least 6 weeks prior to screening; (20) use of any FDA / INVIMA-approved medication for the treatment of late-onset AD at screening / baseline; (21) use of anticoagulants within 4 weeks of the screening visit, or known coagulopathy or platelet count <100,000 cells / μL; (22) any biologically active substance within 5 half-lives or 3 months prior to screening, whichever is longer, except for accepted routinely recommended vaccinations (23) use of anti-seizure, anti-Parkinson's, or stimulant (e.g., methylphenidate) medications; (24) use of an investigational drug, device, or experimental drug within 60 days (or 5 half-lives, whichever is longer) of the screening visit; (25) previous treatment with crenezumab (MABT5102A) or any other Ab-targeting therapeutic; (26) history of severe allergic, anaphylactic, or other hypersensitivity reaction to chimeric, human, or humanized antibodies, or fusion proteins; (27) contraindications to MRI scanning procedures, including, possibly, medical implants or metal objects, clinically significant claustrophobia, or clinical history or laboratory findings that pose a potential risk in combination with MRI; (28) contraindications to PET scanning procedures (in some cases, if the total study-related radiation dose to participants in a given year exceeds the threshold set forth in Title 21 of the Code of Federal Regulations, Section 361 of the United States Code of Federal Regulations).(29) Any abnormal findings that may have affected the participant's response to the radiopharmaceuticals and related testing procedures required for the PET scan, including, but not limited to, current or recent (within 12 months prior to screening) participation in a study involving radioactive drugs that exceeds the limits listed in (1).

[0293] The primary objectives of this study were: (1) to evaluate the efficacy of crenezumab treatment compared with placebo for at least 260 weeks on changes in cognitive function as measured by the API ADAD cognitive composite test battery in preclinical presenilin 1 (PSEN1) E280A autosomal dominant mutation carriers; and (2) to evaluate the efficacy of crenezumab treatment compared with placebo for at least 260 weeks on changes in episodic memory function as measured by the FCSRT cueing index in preclinical PSEN1 E280A autosomal dominant mutation carriers.

[0294] Secondary objectives of this study were to evaluate the following in PSEN1 E280A mutation carriers: (1) the ability of crenezumab to affect clinical endpoints outside the primary endpoint family: the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) Cognitive Composite Test Battery and the FCSRT Cues Index; (2) the ability of crenezumab to reduce brain fibrillary amyloid burden in a defined region of interest (ROI) using florbetapir positron emission tomography (PET); (3) the ability of crenezumab to reduce the decline in regional cerebral metabolic rate of glucose (CMRgl) using fluorodeoxyglucose (FDG)-PET measurements in a ROI; (4) the ability of crenezumab to reduce brain atrophy as measured by volumetric magnetic resonance imaging (MRI); and (5) the ability of crenezumab to affect tau-based cerebrospinal fluid (CSF) biomarkers.

[0295] The safety objective of this study was to evaluate the safety and tolerability of crenezumab (comparing crenezumab to placebo) in preclinical PSEN1 E280A mutation carriers. The pharmacokinetic (PK) and pharmacodynamic (PD) objectives of this study were to collect sparse PK samples to support confirmation of crenezumab exposure and to investigate PD response (measured by plasma total Ab levels comparing crenezumab to placebo) in preclinical PSEN1 E280A mutation carriers.

[0296] The exploratory objectives of this study are: (1) to evaluate preclinical PSEN1 on additional clinical measures of efficacy and biological markers of disease not prespecified as primary or secondary endpoints in the statistical analysis plan (SAP); (2) examine pharmacogenetic effects, including but not limited to, a person's apolipoprotein E (APOE) e4 carrier status, on the cognitive, clinical, and adverse effects of active treatment; (3) examine the impact of genetic variation, including but not limited to, how genes influence the biology of Alzheimer's disease (AD) and other diseases and how genes influence biomarker response; (4) examine clinical and biomarker changes in non-carriers and compare these changes to those seen in placebo-treated carriers; (5) relate biomarker effects of treatment to clinical outcomes and examine the predictive and prognostic utility of baseline characteristics; and (6) evaluate the impact of treatment on brain tau burden over time, as measured by tau PET imaging, in an optional substudy (GN28352-1 / BN40199).

[0297] Baseline assessments for identification of outcome measures according to the study objectives as outlined above are summarized in Tables 2-3 below. [Table 2] [Table 3]

[0298] result The primary efficacy outcome measures included the annualized percentage change in API ADAD Composite Cognitive Test total score and the annualized percentage change in FCSRT Cueing Index. The results, shown in Table 4, demonstrate that both primary endpoints numerically favored crenezumab compared with placebo, although the data do not demonstrate a statistically significant benefit for crenezumab on either endpoint. [Table 4]

[0299] As noted above, treatment of patients with crenezumab reduced the annual rate of change in API ADAD composite score by 22.9% relative to treatment of patients with placebo (i.e., serving as the reference annual rate of change in API ADAD composite score). This relative reduction is determined as follows: Relative reduction (%) = -(difference in annualized percent change (SE) between treatments for crenezumab carriers and placebo carriers (e.g., 0.326 from Table 4)) / yearly percent change (SE) for placebo carriers (e.g., -1.425 from Table 4) × 100

[0300] Similar to the API ADAD composite endpoint, the data also demonstrated a numerically favorable outcome for crenezumab treatment in the FCSRT cue index by demonstrating a 19.9% reduction versus placebo treatment. This relative reduction was determined as follows: Relative reduction (%) = -(difference in annualized percent change (SE) between treatments for crenezumab carriers and placebo carriers (e.g., 0.0079 from Table 4)) / yearly percent change (SE) for placebo carriers (e.g., -0.0396 from Table 4) × 100

[0301] Unless otherwise stated, when comparing results between different patient groups (carriers vs. non-carriers) and / or treatment groups (cren-treated vs. placebo-treated), the same calculation of relative reduction as above applies.

[0302] Similar to the primary endpoint, secondary efficacy outcome measures and biomarker readouts showed mostly numerically favorable results for crenezumab treatment compared with placebo, but no statistically significant benefit was detected. Clinical secondary outcomes included (1) time to progression from preclinical AD to MCI due to AD or from preclinical AD to dementia due to AD; (2) time to progression to a non-zero score in the Clinical Dementia Rating (CDR) scale global score; (3) annual percentage change in the CDR scale box sum; and (4) annual percentage change in a measure of global neurocognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Biomarker outcomes included (1) imaging markers, namely, annual percentage change in mean brain fibrillary amyloid burden using florbetapir PET from a defined ROI, annual percentage change in regional cerebral metabolic rate of glucose (CMRgl) using FDG-PET at a defined ROI, and annual percentage change in volumetric measures using MRI; and (2) CSF biomarkers.

[0303] Safety outcome measures included analysis of the frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), discontinuation due to AEs, incidence of treatment-emergent amyloid-related imaging abnormalities (ARIA), incidence of major cerebral hemorrhage, incidence of pneumonia, incidence of infusion- and infusion-related reactions (IRRs), and incidence of anti-crenezumab antibodies. ARIAs included ARIA-E for edema or effusion (e.g., cerebral vasogenic edema (VE) or cerebral sulcal effusion) and ARIA-H for hemosiderin deposition (e.g., superficial central nervous system (CNS) siderosis or cerebral microbleeds). AEs were graded according to severity using the National Cancer Institute Common Terminology of Adverse Events, version 4.0 (NCI CTAE v4.0). This study utilized an independent data monitoring committee (iDMC), formerly known as the Data and Safety Monitoring Board (DSMB). The results of this study showed that crenezumab was generally safe and well-tolerated, which is consistent with results from other clinical trials of the investigational drug, and no new safety concerns were identified.

[0304] Additionally, this study demonstrated crenezumab PK results that are consistent with historical data for subcutaneous crenezumab and lower than expected exposures for IV crenezumab, although limited by a small sample size.

[0305] Additional exploratory outcome measures of interest included clinical indicators, body fluid biomarkers, imaging biomarkers, and other outcome measures. Clinical outcomes included change from baseline over time in the following cognitive measures: the Trail Making Test (Armitage, Psychological Monographs, 1946;60:i-48, which is incorporated herein by reference in its entirety), the Mini-Mental State Examination (MMSE) (Folstein et al., J. Psychiatr. Res., 1975;12:189-198), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Index score (Randolph, Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, TX: The Psychological Corporation, 1998), scores on each component of the API ADAD Composite Cognitive Test Battery, and the Preclinical Alzheimer's Disease Cognitive Composite (PACC) (Donohue et al., JAMA Neurology, 2014;71:961-970), which included FCSRT free and cued recall, MMSE, RBANS story recall, and RBANS coding scores. Additionally, clinical endpoints not examined in the secondary outcome measures were explored and evaluated: Neuropsychiatric Inventory (NPI) (Cummings et al., Neurology, 1994;44:2308-2314 and Cummings, Neurology, 1997;48:S10-S16) total score, item and factor change, Geriatric Depression Scale (GDS) (Sheikh and Yesavage, Clinical Gerontologist: J Aging Mental Health, 1986;5:165-173) total score change, Functional Assessment of Alzheimer's Disease Staging (FAST) (Sclan and Reisberg, Int Psychogeriatr, 1992;4:55-69) total score change, and subjective memory checklist (Acosta-Baena et al., Lancet Neurol, 2011;10:213-220) change.Additional outcomes measured include: changes in primary, secondary, and exploratory outcomes in mutation non-carriers treated with placebo; comparison of clinical and biomarker outcomes between carriers and non-carriers treated with placebo; changes in primary, secondary, and exploratory outcomes in carriers and non-carriers as a function of APOE genotype and other genetic variations; short-term changes in imaging measures as a function of initiation (e.g., from baseline to 12 weeks); and analysis of outcome measures relative to each other and to baseline characteristics.

[0306] Example 2: Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease Columbia Trial Study design and objectives This clinical study consisted of two study periods, referred to as Study Periods A and B. Study Period A was a prospective, randomized, double-blind, placebo-controlled, parallel-group study of crenezumab versus placebo treatment in carriers of the PSEN1 E280A autosomal dominant PSEN1 mutation in early-onset AD who did not meet criteria for mild cognitive impairment (MCI) due to AD or dementia due to AD and therefore were in the preclinical stage of AD. This study also incorporated administration of placebo to individuals who were not PSEN1 E280A autosomal dominant mutation carriers.

[0307] PSEN1 E280A autosomal dominant mutation carriers who met study eligibility criteria were randomized in a 1:1 ratio to one of two treatment arms: crenezumab or placebo. The study was initially powered to compare the mean change from baseline in the API ADAD Composite Cognitive Test total score over 260 weeks between the active and placebo groups. Assuming a 25% dropout rate, a two-sided test at the 0.05 level overall, a placebo group CV of the change score at week 260 of 65% (= 100% × standard deviation of placebo participant change score / mean placebo participant change score), and 100 participants per arm, the study would have at least 80% power to detect a true effect of a 30% reduction in mean decline in the placebo group. To maintain genotype blinding and obtain genetically related controls, a cohort of PSEN1 E280A mutation noncarrier related family members was also enrolled in the study and administered placebo only. The study included three arms; two arms of participants with the PSEN1 E280A mutation were randomized in a 1:1 ratio to active (n = 85) or placebo (n = 84), and the third arm of non-carriers was randomized to placebo (n = 84) (see Figure 2A).

[0308] Participants received randomized treatment until the final participant reached the final treatment visit at week 260. The study duration for each individual participant was approximately at least 284 weeks, which included an 8-week screening period, a double-blind treatment period at least 260 weeks long, a 4-week final dose visit, and a final safety follow-up visit 16 weeks after the final dose of study drug (crenezumab or placebo) to allow for clinical follow-up after treatment discontinuation for participants who did not continue study drug after the end of Study Period A or who terminated study drug early (see Figure 2B).

[0309] Crenezumab was administered either subcutaneously or intravenously every 2 weeks (60 mg / kg every 4 weeks (4200 mg for an average 70 kg person)), with a matching placebo administered by the same route and at the same frequency. The evolving science of AD led to modifications to the API trial. During the enrollment period, the approved subcutaneous dose of crenezumab was increased from 300 mg (given as two 1 mL subcutaneous injections) every 2 weeks to 720 mg (given as two 2.2 mL subcutaneous injections) every 2 weeks. Switching to the higher intravenous dose (approximately 4-fold higher exposure to crenezumab) was optional. Participants could decide whether to change from the initial subcutaneous dose to IV dosing. However, once intravenous dosing in a given participant was administered, the participant could not revert to the lower subcutaneous dose.

[0310] After completing Study Period A, participants were offered the opportunity to continue in Study Period B. In this second study period, participants continued receiving study drug until study outcomes were known, post-trial access to crenezumab was initiated through an open-label extension (OLE) or other program, or development of crenezumab was discontinued. All PSEN1 E280A mutation carriers were offered crenezumab in Study Period B, regardless of their treatment assignment during Study Period A, and all noncarriers continued on placebo. Treatment assignment for both Study Periods A and B remained blinded. Study Period B continued until approximately 9–12 months from the time participants entered Study Period B.

[0311] The target population included individuals who were members of the PSEN1 E280A mutation carriers who were related to, consented to, and willing to undergo genetic testing (e.g., APOE, PSEN1 E280A, and other genetic testing) with confirmed PSEN1 E280A mutation carrier or non-carrier status before or during the screening period. Baseline patient data are included in Table 5 below. Patients were men and women in the age range of 30 to 60 years; had an MMSE of 24 or greater for participants with less than 9 years of education or an MMSE of 26 or greater for participants with 9 or more years of education; did not meet criteria for dementia due to AD; did not meet criteria for MCI due to AD as defined by: (a) cognitive concerns based in part on a mean subjective memory checklist score >22 (mean of participant and study partner component scores), (b) word list: recall <3 for participants with less than 9 years of education, (c) word list: recall <5 for participants with 9 or more years of education, and (d) maintenance of independence in functional activities based in part on Functional Assessment Staging (FAST) review; sufficient vision and hearing to complete the study. had a study partner who agreed to participate in the study and was able and willing to: (a) accompany the participant to all required clinic visits for subcutaneous or intravenous administration, (b) provide information for the required telephone assessment, and (c) spend sufficient time with the participant to become familiar with the participant's overall functioning and behavior and provide pertinent information about the participant, including: (i) knowledge of home activities, hobbies, daily living, social skills, and basic activities of daily living, (ii) work and education history, (iii) cognitive abilities, including memory, language, temporal and spatial orientation, judgment, and problem-solving, (iv) emotional and psychological status, and (v) general health. Participants and study partners had evidence of: (a) adequate premorbid functioning (e.g., intellectual, visual, and auditory), and (b) fluency and ability to read in the language in which the study assessments were administered.Participants were willing and able to undergo neuroimaging (PET and MRI); they did not demonstrate clinically significant thyroid dysfunction or B12 deficiency, as determined by the following criteria: (a) serum thyroid-stimulating hormone (TSH) and B12 levels within the normal or expected laboratory range; (b) if participants were receiving thyroid replacement therapy, TSH levels within the normal or expected laboratory range; (c) if participants were receiving vitamin B12 injections or oral vitamin B12 therapy, B12 levels above the lower limit of normal; and they had no known comorbidities that would be expected to preclude study participation and were in good general health. At baseline, the mean age of the carrier population was approximately 37 years, approximately 7 years lower than the median age of MCI onset; nearly 50% had negative Aβ PET scans. [Table 5] TIFF2025525331000008.tif43170API Alzheimer's Prevention Initiative, APOEε4 apolipoprotein E ε4 allele, CDR-GS Clinical Dementia Rating-Global Score, CDR-SB Clinical Dementia Rating-Box Sum, CSF cerebrospinal fluid, FCSRT-CI Free and Cued Selective Association Test-Cue Index, FDG fluorodeoxyglucose, GTP1 Genentech tau probe 1, ITT intention to treat, MMSE Mini-Mental State Examination, NfL neurofilament light chain, NPI Neuropsychiatric Inventory, PET positron emission tomography, pTau181 pTau181 phosphorylated tau at threonine 181, RBANS Repeatable Battery for the Assessment of Neuropsychological Status, SD standard deviation, SUVR standardized uptake value ratio, tTau total tau, vMRI volumetric (i.e., T1-weighted) magnetic resonance imaging.

[0312] The target population excluded those with the following: (1) any significant medical, psychiatric, or neurological condition or disorder documented by medical history, physical, neurological, laboratory, or ECG testing that would expose the participant to undue risk or affect the interpretation of efficacy; (2) a history of stroke; (3) a history of severe, clinically significant CNS trauma (e.g., cerebral contusion); (4) a body weight <45 or >120 kg; (5) a history or presence of atrial fibrillation that imposed a risk of future stroke; (6) a clinically significant test (7) presence of bipolar disorder according to DSM-IV-TR or other clinically significant psychiatric disorder (recorded as an AE if diagnosed after study enrollment); (8) clinically significant depression based in part on a Geriatric Depression Scale (Short Form GDS) (15-point scale) score >9 at screening; (9) history of stroke; (10) myocardial infarction, congestive heart failure, atrial fibrillation, or uncontrolled hypertension within 2 years; (11) history of cancer within 5 years; (12) history of pulmonary embolism within the last 3 years before screening Clinically significant infection within 0 days; (13) brain MRI imaging results at baseline showing any of the following: (a) evidence of ARIA-E (cerebral VE, sulcal effusion), infection, significant cerebrovascular pathology, clinically significant lacunar infarction or multiple lacunae in cognitively important areas, or cortical infarction or clinically significant focal lesions; (b) more than four cerebral microbleeds (lesions ≤10 mm in diameter), regardless of anatomical location or diagnostic characteristics as "probable" or "definite"; or (c) Evidence of a single area of superficial siderosis in the CNS or a previous large cerebral hemorrhage (lesion >0 mm in diameter); (14) Clinically significant blood or urine screening test abnormalities that warrant further evaluation or treatment, including: (a) liver dysfunction as indicated by transaminases >2 × upper limit of normal (ULN) or clinically significant abnormalities in synthetic function tests, (b) coagulopathy (aPTT >1.2 × ULN), (c) platelet count <100,000 / μL, or (d) glycosylated hemoglobin >8.0%; (15) positive urine test for drugs of abuse at screening (cannabinoid assay results were not used to determine eligibility); (16) history of alcohol or substance dependence within the past 2 years (DSM-IV TR criteria; (17) use of any other medications that may significantly affect cognition (including, but not limited to, sedatives, narcotics (e.g., opiates / opioids), hypnotics, over-the-counter (OTC) sleep aids, and sedative antiallergics); (18) use of typical antipsychotics or barbiturates; (19) use of non-anticholinergic antidepressants or atypical antipsychotics unless maintained on a stable dose regimen for at least 6 weeks prior to screening; (20) use of any FDA / INVIMA-approved medication for the treatment of late-onset AD at screening / baseline; (21) use of anticoagulants within 4 weeks of the screening visit, or known coagulopathy or platelet count <100,000 cells / μL; (22) any biologically active substance within 5 half-lives or 3 months prior to screening, whichever is longer, except for accepted routinely recommended vaccinations (23) use of anti-seizure, anti-Parkinson's, or stimulant (e.g., methylphenidate) medications; (24) use of an investigational drug, device, or experimental drug within 60 days (or 5 half-lives, whichever is longer) of the screening visit; (25) previous treatment with crenezumab (MABT5102A) or any other Ab-targeting therapeutic; (26) history of severe allergic, anaphylactic, or other hypersensitivity reaction to chimeric, human, or humanized antibodies, or fusion proteins; (27) contraindications to MRI scanning procedures, including, possibly, medical implants or metal objects, clinically significant claustrophobia, or clinical history or laboratory findings that pose a potential risk in combination with MRI; (28) contraindications to PET scanning procedures (in some cases, if the total study-related radiation dose to participants in a given year exceeds the threshold set forth in Title 21 of the Code of Federal Regulations, Section 361 of the United States Code of Federal Regulations).(29) any abnormal findings that may have affected the participant's response to the radiopharmaceuticals and related testing procedures required for the PET scan; (30) pregnancy.

[0313] The primary objectives of this study were: (1) to evaluate the efficacy of crenezumab treatment compared with placebo for at least 260 weeks on changes in cognitive function as measured by the API ADAD cognitive composite test battery in preclinical presenilin 1 (PSEN1) E280A autosomal dominant mutation carriers; and (2) to evaluate the efficacy of crenezumab treatment compared with placebo for at least 260 weeks on changes in episodic memory function as measured by the FCSRT cueing index in preclinical PSEN1 E280A autosomal dominant mutation carriers.

[0314] Secondary objectives of this study were to evaluate the following in PSEN1 E280A mutation carriers: (1) the ability of crenezumab to affect clinical endpoints outside the primary endpoint family: the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) Cognitive Composite Test Battery and the FCSRT Cues Index; (2) the ability of crenezumab to reduce brain fibrillary amyloid burden in a defined region of interest (ROI) using florbetapir positron emission tomography (PET); (3) the ability of crenezumab to reduce the decline in regional cerebral metabolic rate of glucose (CMRgl) using fluorodeoxyglucose (FDG)-PET measurements in a ROI; (4) the ability of crenezumab to reduce brain atrophy as measured by volumetric magnetic resonance imaging (MRI); and (5) the ability of crenezumab to affect tau-based cerebrospinal fluid (CSF) biomarkers.

[0315] The safety objective of this study was to evaluate the safety and tolerability of crenezumab (comparing crenezumab to placebo) in preclinical PSEN1 E280A mutation carriers. The pharmacokinetic (PK) and pharmacodynamic (PD) objectives of this study were to collect sparse PK samples to support confirmation of crenezumab exposure and to investigate PD response (measured by plasma total Ab levels comparing crenezumab to placebo) in preclinical PSEN1 E280A mutation carriers.

[0316] The exploratory objectives of this study are: (1) to evaluate preclinical PSEN1 on additional clinical measures of efficacy and biological markers of disease not prespecified as primary or secondary endpoints in the statistical analysis plan (SAP); (2) examine pharmacogenetic effects, including but not limited to, a person's apolipoprotein E (APOE) e4 carrier status, on the cognitive, clinical, and adverse effects of active treatment; (3) examine the impact of genetic variation, including but not limited to, how genes influence the biology of Alzheimer's disease (AD) and other diseases and how genes influence biomarker response; (4) examine clinical and biomarker changes in non-carriers and compare these changes to those seen in placebo-treated carriers; (5) relate biomarker effects of treatment to clinical outcomes and examine the predictive and prognostic utility of baseline characteristics; and (6) evaluate the impact of treatment on brain tau burden over time, as measured by tau PET imaging, in an optional substudy (GN28352-1 / BN40199).

[0317] result Table 6 shows patient adherence and retention rates over the 8-year study. 94.0% of all participants completed study Period A, and 90.5% of all participants completed treatment in Period A. Treatment discontinuation was primarily due to participant decision (n=12), adverse events (n=5), and pregnancy (n=4). [Table 6]

[0318] The mean duration of treatment for patients receiving at least one dose of study drug was 6.1 years, with a maximum treatment duration of 7.9 years. The mean duration of subcutaneous treatment was 4.3 years, with a mean dose intensity of 99%. The mean duration of intravenous treatment was 2 years, with a mean dose intensity of 88%. As shown in Figure 3, some patients started on a 300 mg subcutaneous dose before switching to the 720 mg dose. Some patients continued on the 300 mg subcutaneous dose or switched to the 300 mg dose after starting on 720 mg.

[0319] Outcomes were analyzed using a random coefficient regression model (RCRM) in mutation carriers receiving at least one dose of study drug, which provides a simple and overall measure of average clinical benefit over the entire duration of the trial. See, e.g., Hu et al., Biom J. 2021;63:806-24, the entire contents of which are incorporated herein by reference. RCRM adjusts for age, education, APOE4, and CDR-GS at baseline, and for the slope, adjusts for treatment assignment. Both random intercept and slope terms are added to the model. [Table 7]

[0320] As shown in Table 7, Figure 4, and Figure 6, treatment of patients with crenezumab reduced the annual percentage change in the API ADAD composite score by 22.9% relative to treatment of the patient with placebo (i.e., serving as the reference annual percentage change in the API ADAD composite score). This relative reduction is determined as follows: Relative Reduction (%) = -(difference in annual percentage change (SE) between treatment with crenezumab and placebo carriers (e.g., 0.326 from Table 4)) / Annual percentage change (SE) of placebo carriers (e.g., -1.425 from Table 4) × 100. Figure 6 shows the breakdown of the API ADAD composite by baseline amyloid status, with amyloid-positive patients experiencing a 17.3% reduction in annual percentage change relative to placebo, while the reduction was 113.2% for amyloid-negative patients. Similar to the API ADAD composite endpoint, the data also demonstrated a numerically favorable outcome for crenezumab treatment in the FCSRT Cue Index, demonstrating a 19.9% reduction relative to placebo treatment. This relative reduction is determined as follows: Relative Reduction (%) = -(Difference in annualized percent change (SE) between treatments for crenezumab and placebo carriers (e.g., 0.0079 from Table 4)) / Annualized percent change (SE) for placebo carriers (e.g., -0.0396 from Table 4) × 100. Figure 6 shows the breakdown of FCSRT by baseline amyloid status, with amyloid-positive patients having a 24.2% reduction relative to placebo and a 31.6% reduction in amyloid-negative patients.

[0321] As shown in Figure 4, secondary efficacy outcome measures and biomarker readouts showed numerically favorable results for crenezumab treatment compared with placebo treatment, but no statistically significant benefit was detected. Clinical secondary outcomes included: (1) amyloid PET SUVr (standardized uptake value ratio); (2) time to progression from preclinical AD to MCI due to AD or time to progression from preclinical AD to dementia due to AD (see also Figure 5, which shows Kaplan-Meier curves for time to MCI or dementia due to AD); (3) annual percentage change in the box sum of the CDR scale; (4) time to progression to a non-zero score in the Clinical Dementia Rating (CDR) scale global score; and (5) annual percentage change in a measure of global neurocognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

[0322] Brain imaging and biological samples were collected as shown in Table 8, and specific biomarker modalities and measurements are shown in Table 9. All participants underwent serial amyloid-β PET, FDG PET, and MRI scans and provided annual blood samples. Half of the participants underwent serial tau PET scans (introduced later in the study). Approximately half of the participants underwent one or more lumbar punctures. [Table 8] [Table 9]

[0323] Figure 7 shows the difference in baseline Aβ levels between PSEN1 E280A mutation carriers and non-carriers. Fifty-five percent of carriers had the E280A mutation (open circles), and 45% were A- (spotted circles). The results indicate that there were approximately twice as many A- carriers as expected. The unexpectedly early AD stage in carriers led to less progression in the placebo group, reducing power in detecting significant slowing in the treatment group. However, these data provide an opportunity to investigate treatment effects in A+ and A- carriers and inform the design, size, inclusion criteria, and endpoints of future secondary and primary prevention trials.

[0324] Table 9 shows baseline brain imaging measurements. Because GTP PET was introduced later in the trial, baseline entorhinal cortex GTP1 SUVR is not available. Table 10 shows baseline CSF biomarker measurements. CSF biomarker measurements were performed using Roche's Elecsys platform. YKL-40 and S100b concentrations are in μg / mL; all other concentrations are in pg / mL. P values are not corrected for multiple comparisons. Sample size includes all participants who received at least one dose of study drug and had at least one CSF measurement at baseline. [Table 10] [Table 11]

[0325] Figures 8-17 show additional biomarker outcomes in the crenezumab- and placebo-treated PSEN1 E280A mutation carrier groups. In Figure 8, relative reductions are the average annual percentage / risk reductions in the crenezumab carrier group compared to the placebo carrier group. Amyloid-β, as determined by PET, increased in both the placebo and crenezumab carrier groups, but no statistical difference was observed between the groups (Figure 9). FDG, as determined by PET, decreased in both the placebo and crenezumab carrier groups, but no statistical difference was observed between the groups (Figure 10). CSF amyloid-β42 decreased in the placebo carrier group, but an attenuated decrease was observed in the crenezumab carrier group (Figure 11). An unexpected decrease in CSF Aβ40 was observed in the placebo carrier group, but an increase was observed in the crenezumab carrier group. Figure 12 shows an increase in CSF pTau181 in placebo-treated carriers, but no statistically significant difference was observed between the crenezumab carrier and placebo carrier groups. CSF total tau also increased in the placebo carrier group, with no statistically significant difference observed between the crenezumab carrier and placebo carrier groups (Figure 13). Furthermore, no statistically significant difference in tau between the crenezumab carrier and placebo carrier groups was observed by PET (Figure 17). CSF neurofilament light (NfL) increased in both placebo and crenezumab carriers, but no statistically significant difference was observed between the two groups (Figure 15). Finally, while no statistically significant differences were observed between the crenezumab carrier and placebo carrier groups in brain volume as measured by MRI, the cren-treated carrier group exhibited numerically more favorable results compared to or relative to the placebo-treated carrier group, at least in measures of whole brain shrinkage and hippocampal shrinkage (Figure 16).

[0326] Safety outcome measures included analysis of the frequency and severity of treatment-emergent adverse events (AEs) and serious adverse events (SAEs), discontinuation due to AEs, incidence of treatment-emergent amyloid-related imaging abnormalities (ARIA), incidence of major cerebral hemorrhage, incidence of pneumonia, incidence of infusion- and infusion-related reactions (IRRs), and incidence of anti-crenezumab antibodies. ARIAs included ARIA-E for edema or effusion (e.g., cerebral vasogenic edema (VE) or cerebral sulcal effusion) and ARIA-H for hemosiderin deposition (e.g., superficial central nervous system (CNS) siderosis or cerebral microbleeds). AEs were graded according to severity using the National Cancer Institute Common Terminology of Adverse Events, version 4.0 (NCI CTAE v4.0). This study utilized an independent data monitoring committee (iDMC), formerly known as the Data and Safety Monitoring Board (DSMB).

[0327] The results of this study demonstrated that safety and tolerability were good, with no new safety issues identified, as shown in Tables 11-13. Additionally, as shown in Table 4 above, the study had excellent adherence and retention rates over the 8-year study period. [Table 12] [Table 13] [Table 14]

[0328] Additionally, this study demonstrated crenezumab PK results that are consistent with historical data for subcutaneous crenezumab and lower than expected exposures for IV crenezumab, although limited by a small sample size.

[0329] Additional exploratory outcome measures of interest included clinical indicators, body fluid biomarkers, imaging biomarkers, and other outcome measures. Clinical outcomes included change from baseline over time in the following cognitive measures: the Trail Making Test (Armitage, Psychological Monographs, 1946;60:i-48, which is incorporated herein by reference in its entirety), the Mini-Mental State Examination (MMSE) (Folstein et al., J. Psychiatr. Res., 1975;12:189-198), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Index score (Randolph, Repeatable Battery for the Assessment of Neuropsychological Status. San Antonio, TX: The Psychological Corporation, 1998), scores on each component of the API ADAD Composite Cognitive Test Battery, and the Preclinical Alzheimer's Disease Cognitive Composite (PACC) (Donohue et al., JAMA Neurology, 2014;71:961-970), which included FCSRT free and cued recall, MMSE, RBANS story recall, and RBANS coding scores. Additionally, clinical endpoints not examined in the secondary outcome measures were explored and evaluated: Neuropsychiatric Inventory (NPI) (Cummings et al., Neurology, 1994;44:2308-2314 and Cummings, Neurology, 1997;48:S10-S16) total score, item and factor change, Geriatric Depression Scale (GDS) (Sheikh and Yesavage, Clinical Gerontologist: J Aging Mental Health, 1986;5:165-173) total score change, Functional Assessment of Alzheimer's Disease Staging (FAST) (Sclan and Reisberg, Int Psychogeriatr, 1992;4:55-69) total score change, and subjective memory checklist (Acosta-Baena et al., Lancet Neurol, 2011;10:213-220) change.Additional outcomes measured include: changes in primary, secondary, and exploratory outcomes in mutation non-carriers treated with placebo; comparison of clinical and biomarker outcomes between carriers and non-carriers treated with placebo; changes in primary, secondary, and exploratory outcomes in carriers and non-carriers as a function of APOE genotype and other genetic variations; short-term changes in imaging measures as a function of initiation (e.g., from baseline to 12 weeks); and analysis of outcome measures relative to each other and to baseline characteristics.

[0330] Example 3: Plasma biomarker findings from the Alzheimer's Prevention Initiative autosomal dominant Alzheimer's disease Columbia trial This example describes the clinical and biomarker outcomes of participants enrolled in the study described in Example 2.

[0331] Plasma assays were performed on the Roche Elecsys platform using Neurotoolkit assays to measure Aβ42, Aβ40, pTau181, pTau217, NfL, GFAP, YKL-40 and sTREM2.

[0332] Figure 18 shows baseline plasma biomarker findings in carriers and noncarriers. As shown in Figure 19, mutation carriers have elevated plasma Aβ42 concentrations and Aβ42 / Aβ40 ratios. Baseline plasma Aβ42 / Aβ40 elevations in untreated mutation carriers were unrelated to age or Aβ plaque burden. Furthermore, Log10 plasma pTau181, pTau217, NfL, and GFAP concentrations were associated with age in the mutation group. Long-term plasma biomarker changes were observed among noncarriers treated with placebo and noncarriers. As shown in Figure 20, mutation carriers had greater increases in Log10 plasma pTau181, pTau217, NfL, GFAP, and sTREM2.

[0333] Figures 21-29 show plasma biomarker outcomes in the crenezumab- and placebo-treated carrier groups. As shown in Figures 21 and 22, increases in plasma Aβ42 and Aβ40 were observed in the crenezumab-treated carrier group compared to the placebo-treated carrier group. Figure 23 shows relative decreases in plasma Log10 pTau181, pTau217, NfL, GFAP, YKL-40, and sTREM2 in the crenezumab-treated carrier group compared to the placebo-treated carrier group. Minimal but significant differences were observed between placebo- and crenezumab-treated carriers in plasma Log10 pTau181, pTau217, NfL, GFAP, YKL-40, and sTREM2, with increases in these biomarkers observed in both groups (Figures 24-29).

[0334] The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, but the illustrations and examples should not be construed as limiting the scope of the invention. The disclosures of all patent applications and publications and scientific literature cited herein are expressly incorporated by reference in their entirety for any purpose. [Table 15]

[0335] Enumerated Embodiments Embodiment 1. A method of delaying the onset of at least one symptom in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody; Administering such treatment to a plurality of human patients results in a delay in the onset of at least one symptom in the plurality of human patients relative to a reference onset of the at least one symptom; the reference onset of at least one symptom is in a plurality of human patients who received a placebo; the antibody comprises six hypervariable regions (HVRs); (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; method.

[0336] Embodiment 2. A method of slowing cognitive decline in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody; Administering such treatment to a plurality of human patients slows cognitive decline in the plurality of human patients relative to a reference cognitive decline; the reference cognitive decline is that of a plurality of human patients who received a placebo; the antibody comprises six hypervariable regions (HVRs); (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; method.

[0337] Embodiment 3. A method of preventing cognitive impairment in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody; Administering such treatment to a plurality of human patients reduces cognitive impairment in the plurality of human patients relative to the reference cognitive impairment; the reference cognitive impairment is that of a plurality of human patients who received a placebo; the antibody comprises six hypervariable regions (HVRs); (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; method.

[0338] Embodiment 4. The method of embodiment 1, wherein administering such treatment delays the onset of at least one symptom relative to a reference onset of the at least one symptom after about 5 years or more of treatment.

[0339] Embodiment 5. The method of embodiment 2, wherein administering such treatment slows cognitive decline in a plurality of human patients relative to reference cognitive decline after about 5 or more years of treatment.

[0340] Embodiment 6 The method of embodiment 3, wherein administering such treatment prevents or reduces cognitive impairment in a plurality of human patients relative to the reference cognitive impairment after about 5 or more years of treatment.

[0341] Embodiment 7. The method according to any one of embodiments 1 to 6, delaying the onset of at least one symptom, slowing cognitive decline, or preventing cognitive impairment, as measured using the API ADAD Cognitive Composite Test Battery; In an API ADAD cognitive composite test battery, administering such treatment to a plurality of human patients reduces the annual rate of change in the API ADAD composite score of the plurality of human patients relative to a reference annual rate of change in the API ADAD composite score; The reference annualized rate of change in API ADAD composite score is the annualized rate of change in API ADAD composite score in a plurality of human patients who received a placebo.

[0342] Embodiment 8. The method of embodiment 7, wherein the API ADAD composite cognitive test battery includes Word List Recall, Multilingual Naming Test, Mini-Mental State Examination (MMSE), CERAD Construct Exercises, and Raven's Progressive Matrices.

[0343] Embodiment 9. The method of any one of embodiments 7-8, wherein administering such treatment reduces the annual rate of change in API ADAD composite score after about 5 or more years of treatment.

[0344] Embodiment 10. The method of any one of embodiments 7-9, wherein administering such treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by at least 20% relative to a reference annual rate of change in API ADAD composite score.

[0345] Embodiment 11. The method of any one of embodiments 7-9, wherein administering such treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by at least 30% relative to a reference annual rate of change in API ADAD composite score.

[0346] Embodiment 12. The method of any one of embodiments 7-9, wherein administering such treatment reduces the annual rate of change in API ADAD composite score for a plurality of human patients by 20% to 40% relative to a reference annual rate of change in API ADAD composite score.

[0347] Embodiment 13. The method of any one of embodiments 1-12, wherein administering such treatment to a plurality of human patients reduces the annual rate of change in the Free and Cued Selective Association Task (FCSRT) Cueing Index of the plurality of human patients relative to a reference annual rate of change in the FCSRT Cueing Index; The reference annual rate of change in the FCSRT cue index is the annual rate of change in the FCSRT cue index of multiple human patients who received a placebo.

[0348] Embodiment 14. The method of embodiment 13, wherein administering such treatment reduces the annual rate of change in the FCSRT Cue Index in a plurality of human patients, compared to a reference annual rate of change in the FCSRT Cue Index, after about 5 or more years of treatment.

[0349] Embodiment 15. The method of any one of embodiments 13-14, wherein administering such treatment reduces the annual rate of change in the FCSRT Cue Index for a plurality of human patients by at least 10% relative to a reference annual rate of change in the FCSRT Cue Index.

[0350] Embodiment 16. The method of any one of embodiments 13-14, wherein administering such treatment reduces the annual rate of change in the FCSRT Cue Index for a plurality of human patients by at least 20% relative to a reference annual rate of change in the FCSRT Cue Index.

[0351] Embodiment 17. The method of any one of embodiments 13-14, wherein administering such treatment reduces the annual rate of change in the FCSRT Cue Index for a plurality of human patients by 10% to about 30% relative to a reference annual rate of change in the FCSRT Cue Index.

[0352] Embodiment 18. The method of any one of embodiments 13 to 17, wherein the FCSRT cueing index is assessed using controlled learning.

[0353] Embodiment 19. The method of any one of embodiments 1-18, wherein administering such treatment to a plurality of human patients increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in the plurality of human patients relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD; The method, wherein the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD is the time to progression in a plurality of human patients who received a placebo.

[0354] Embodiment 20. The method of embodiment 19, wherein administering such treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in a plurality of human patients after about 5 or more years of treatment, relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

[0355] Embodiment 21. The method of any one of embodiments 19-20, wherein administering such treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in a plurality of human patients by at least 10%, compared to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

[0356] Embodiment 22. The method of any one of embodiments 19-20, wherein administering such treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in a plurality of human patients by at least 20%, relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

[0357] Embodiment 23. The method of any one of embodiments 19-20, wherein administering such treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in a plurality of human patients by 10% to 30%, relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

[0358] Embodiment 24. The method of any one of embodiments 1 to 23, wherein administering such treatment to a plurality of human patients increases the time to progression of Clinical Dementia Rating (CDR) scale global scores to non-zero in the plurality of human patients relative to a reference time to progression of CDR scale global scores to non-zero, wherein the reference time to progression of CDR scale global scores to non-zero is the time to progression in the plurality of human patients who received a placebo.

[0359] Embodiment 25. The method of embodiment 24, wherein the CDR scale global score represents impairments in memory, orientation, judgment and problem-solving, social problems, household and hobbies, and personal care.

[0360] Embodiment 26. The method of any one of embodiments 24-25, wherein administering such treatment increases the time to progression of the CDR scale global score to a non-zero score in a plurality of human patients by 5% relative to a reference time to progression of the CDR scale global score to a non-zero score.

[0361] Embodiment 27. The method of any one of embodiments 24-25, wherein administering such treatment increases the time to progression of the CDR scale global score to a non-zero in a plurality of human patients by 10% relative to a reference time to progression of the CDR scale global score to a non-zero.

[0362] Embodiment 28. The method of any one of embodiments 24-25, wherein administering such treatment increases the time to progression of the CDR scale global score to a non-zero in a plurality of human patients by 5% to 20% relative to a reference time to progression of the CDR scale global score to a non-zero.

[0363] Embodiment 29. The method of any one of embodiments 1 to 28, wherein administering such treatment to a plurality of human patients reduces the annual rate of change in the sum of boxes on the Clinical Dementia Rating (CDR) scale for the...

Claims

1. 1. A method for delaying the onset of at least one symptom in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody; administering such treatment to a plurality of human patients results in a delay in onset of at least one symptom in said plurality of human patients relative to a reference onset of at least one symptom; wherein the reference occurrence of at least one symptom is from a plurality of human patients who received a placebo; the antibody comprises six hypervariable regions (HVRs); (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; method.

2. 1. A method of slowing cognitive decline in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody; administering such treatment to a plurality of human patients delays cognitive decline in said plurality of human patients relative to a reference cognitive decline; the reference cognitive decline is of a plurality of human patients who received a placebo; the antibody comprises six hypervariable regions (HVRs); (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; method.

3. 1. A method for preventing cognitive impairment in a human patient having a genetic mutation that causes familial Alzheimer's disease (AD), comprising administering to the human patient an effective amount of a humanized monoclonal anti-amyloid beta (Aβ) antibody; Administering such treatment to a plurality of human patients reduces cognitive impairment in said plurality of human patients relative to a reference cognitive impairment; the reference cognitive impairment is from a plurality of human patients who received a placebo; the antibody comprises six hypervariable regions (HVRs); (i) HVR-H1 comprises the amino acid sequence set forth in SEQ ID NO:2; (ii) HVR-H2 comprises the amino acid sequence set forth in SEQ ID NO:3; (iii) HVR-H3 comprises the amino acid sequence set forth in SEQ ID NO:4; (iv) HVR-L1 comprises the amino acid sequence set forth in SEQ ID NO:6; (v) HVR-L2 comprises the amino acid sequence set forth in SEQ ID NO: 7; and (vi) HVR-L3 comprises the amino acid sequence set forth in SEQ ID NO: 8; method.

4. 10. The method of claim 1, wherein administering such treatment delays the onset of at least one symptom compared to the reference onset of at least one symptom after about 5 years or more of treatment.

5. 3. The method of claim 2, wherein administering such treatment slows cognitive decline in said plurality of human patients relative to said reference cognitive decline after about 5 or more years of treatment.

6. 4. The method of claim 3, wherein administering such treatment prevents or reduces cognitive impairment in said plurality of human patients relative to said reference cognitive impairment after about 5 or more years of treatment.

7. The method according to any one of claims 1 to 6, said delay in the onset of at least one symptom, said slowing of cognitive decline, or said prevention of cognitive impairment is measured using the API ADAD Cognitive Composite Test Battery; wherein administering such treatment to said plurality of human patients reduces the annual rate of change in API ADAD composite scores of said plurality of human patients relative to a reference annual rate of change in API ADAD composite scores in said API ADAD cognitive composite test battery; The method, wherein the reference annualized rate of change in the API ADAD composite score is the annualized rate of change in the API ADAD composite score of a plurality of human patients who received the placebo.

8. 8. The method of claim 7, wherein the API ADAD Composite Cognitive Test Battery includes Word List Recall, Multilingual Naming Test, Mini-Mental State Examination (MMSE), CERAD Construct Exercises, and Raven's Progressive Matrices.

9. 9. The method of any one of claims 7-8, wherein administering such treatment reduces the annual rate of change in the API ADAD composite score after about 5 or more years of treatment.

10. 10. The method of any one of claims 7-9, wherein administering such treatment reduces the annual rate of change in the API ADAD composite scores for the plurality of human patients by at least 20% relative to the reference annual rate of change in the API ADAD composite scores.

11. The method according to any one of claims 1 to 10, administering such treatment to said plurality of human patients reduces the annual rate of change in a Free and Cued Selective Association Task (FCSRT) Cueing Index of said plurality of human patients relative to a reference annual rate of change in the FCSRT Cueing Index; The method, wherein the reference annual rate of change in the FCSRT Cue Index is the annual rate of change in the FCSRT Cue Index of a plurality of human patients who received the placebo.

12. 12. The method of claim 11, wherein administering such treatment reduces the annual rate of change in the FCSRT Cue Index of the plurality of human patients compared to the reference annual rate of change in the FCSRT Cue Index after about 5 or more years of treatment.

13. 13. The method of claim 11 or 12, wherein administering such treatment reduces the annual rate of change in the FCSRT cue index of the plurality of human patients by at least 10% relative to the reference annual rate of change in the FCSRT cue index.

14. 14. The method of any one of claims 11 to 13, wherein the FCSRT cue index is assessed using controlled learning.

15. The method according to any one of claims 1 to 14, administering such treatment to said plurality of human patients increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in said plurality of human patients relative to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD; The method, wherein the reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD is the time to progression in a plurality of human patients who received the placebo.

16. 16. The method of claim 15, wherein administering such treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in said plurality of human patients after about 5 or more years of treatment, relative to said reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

17. 17. The method of claim 15 or 16, wherein administering such treatment increases the time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD in said plurality of human patients by at least 10% compared to a reference time to progression from preclinical AD to mild cognitive impairment due to AD or from preclinical AD to dementia due to AD.

18. 18. The method of any one of claims 1-17, wherein administration of such treatment to the plurality of human patients increases the time to progression of a Clinical Dementia Rating (CDR) scale global score to a non-zero for the plurality of human patients relative to a reference time to progression of the CDR scale global score to a non-zero, wherein the reference time to progression of the CDR scale global score to a non-zero is the time to progression for the plurality of human patients who received placebo.

19. 19. The method of claim 18, wherein administration of such treatment increases the time to progression of the CDR scale global score to non-zero in the plurality of human patients by at least 5% relative to a reference time to progression of the CDR scale global score to non-zero.

20. 20. The method according to any one of claims 1 to 19, wherein administration of such treatment to said plurality of human patients reduces the annual rate of change in the sum of boxes on a Clinical Dementia Rating (CDR) scale for said plurality of human patients relative to a reference annual rate of change in the sum of boxes on the CDR scale; wherein said reference annualized rate of change in the sum of the boxes of the CDR scale is the annualized rate of change in the sum of the boxes of the CDR scale for a plurality of human patients who received a placebo.

21. 21. The method of claim 20, wherein administration of such treatment reduces the annual rate of change in the sum of boxes of the CDR scale for said plurality of human patients after about 5 or more years of treatment, compared to said reference annual rate of change in the sum of boxes of the CDR scale.

22. 22. The method of any one of claims 18-21, wherein administration of such treatment reduces the annual rate of change in the Sum of Boxes Global Score of the CDR Measure in said plurality of human patients by at least 5% relative to the reference Sum of Boxes Global Score of the CDR Measure.

23. 23. The method according to any one of claims 1 to 22, administering such treatment to said plurality of human patients reduces the annual rate of change in a measure of global neurocognitive function for said plurality of human patients relative to a reference annual rate of change in the measure of global neurocognitive function; wherein said reference annualized rate of change in a measure of global neurocognitive function is the annualized rate of change in a measure of global neurocognitive function of said plurality of human patients who received a placebo.

24. 24. The method of claim 23, wherein the annual rate of change in a measure of global neurocognitive function is determined using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score.

25. 25. The method of claim 24, wherein administering such treatment reduces the annual rate of change in RBANS score in the plurality of human patients compared to a reference annual rate of change in RBANS score, wherein the reference annual rate of change in RBANS score is the annual rate of change in RBANS score in a plurality of human patients who received a placebo.

26. 26. The method of claim 24 or 25, wherein administering such treatment reduces the annual rate of change in RBANS score in the plurality of human patients compared to the reference annual rate of change in RBANS score after about 5 or more years of treatment.

27. 27. The method of any one of claims 24 to 26, wherein administering such treatment reduces the RBANS score by at least 4% relative to a reference RBANS score.

28. 28. The method of any one of claims 1-27, wherein administration of such treatment to said plurality of human patients results in an effect on tau-based CSF biomarkers compared to a reference tau-based CSF biomarker; wherein said reference tau-based CSF biomarkers are said tau-based CSF biomarkers in a plurality of human patients who received said placebo.

29. 29. The method of claim 28, wherein the tau-based CSF biomarker is measured using positron emission tomography.

30. 30. The method of claim 28 or 29, wherein administering such treatment reduces the annualized rate of change of said tau-based CSF biomarker in said plurality of human patients compared to a reference annualized rate of change of said tau-based CSF biomarker, wherein said reference tau-based CSF biomarker is the annualized rate of change of said tau-based CSF biomarker in a plurality of human patients who received a placebo.

31. 31. The method of claim 30, wherein administration of such treatment reduces the annual rate of tau-based CSF biomarker in said plurality of human patients by at least 30% relative to said reference tau-based CSF biomarker, and wherein said tau-based CSF biomarker is a phospho-tau [ptau]-based CSF biomarker.

32. 31. The method of claim 30, wherein administration of such treatment reduces the annual rate of tau-based CSF biomarker in said plurality of human patients by at least 20% relative to said reference tau-based CSF biomarker, wherein said tau-based CSF biomarker is a total tau [ttau]-based CSF biomarker.

33. 33. The method according to any one of claims 1 to 32, administering such treatment to said plurality of human patients results in an effect on brain tau load relative to a reference brain tau load; The method, wherein the reference brain tau burden is the brain tau burden of a plurality of human patients who received the placebo.

34. 34. The method of claim 33, wherein administering such treatment reduces the annual incidence of Tau PET in said plurality of human patients by at least 50% relative to reference Tau PET.

35. 35. The method according to any one of claims 1 to 34, administering such treatment to said plurality of human patients reduces the brain fibrillary amyloid burden in predetermined regions of interest of said plurality of human patients relative to a reference brain fibrillary amyloid burden in a predetermined region of interest; The method, wherein said reference brain fibrillary amyloid burden in a predetermined region of interest is the brain fibrillary amyloid burden in a predetermined region of interest of a plurality of human patients who received said placebo.

36. 36. The method of claim 35, wherein administration of such treatment reduces the annual rate of change of amyloid burden measured by PET in said plurality of human patients by 3% relative to the reference amyloid burden measured by PET.

37. 37. The method according to any one of claims 1 to 36, administering such treatment to said plurality of human patients reduces the decrease in regional cerebral metabolic rate of glucose (CMRgI) of said plurality of human patients relative to a reference CMRgI; The method, wherein said reference CMRgI is the CMRgI of said plurality of human patients who received said placebo.

38. 38. The method of claim 37, wherein administration of such treatment reduces FDG PET measurements in the plurality of human patients relative to reference FDG PET measurements, wherein the reference FDG PET measurements are FDG PET measurements in the plurality of human patients who received the placebo.

39. 39. The method of claim 38, wherein administration of such treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in the plurality of human patients compared to a reference annualized SUVR for FDG PET, wherein the reference annualized SUVR for FDG PET is the annualized SUVR for FDG PET for the plurality of human patients who received the placebo.

40. 40. The method of claim 39, administration of such treatment reduces the annualized standardized uptake value ratio (SUVR) of FDG PET measurements in said plurality of human patients by at least 10% compared to a reference annualized SUVR for FDG PET; The method, wherein the reference annualized SUVR of FDG PET is the annualized SUVR of FDG PET of the plurality of human patients who received the placebo.

41. 41. The method according to any one of claims 1 to 40, administering such treatment to said plurality of human patients reduces the annual rate of change in brain atrophy in said plurality of human patients relative to a reference annual rate of change in brain atrophy; wherein the reference annual rate of change in brain atrophy is the annual rate of change in brain atrophy of the plurality of human patients who received the placebo.

42. 42. The method of claim 41, wherein administering such treatment reduces the annual rate of change in brain atrophy in the plurality of human patients after about 5 or more years of treatment, compared to the reference annual rate of change in brain atrophy.

43. 43. The method of claim 42, wherein administration of such treatment reduces the annual rate of change of said brain atrophy in said plurality of human patients by 5% to 20% relative to said reference brain atrophy, said reduction being measured by whole brain volumetric MRI.

44. 44. The method of claim 43, wherein the volumetric MRI is measured in bilateral hippocampi.

45. 45. The method of claim 44, wherein administering such treatment reduces the annual rate of change in said brain atrophy in said plurality of human patients by at least 1% relative to said reference brain atrophy, said reduction being measured by bilateral hippocampal volumetric MRI.

46. 46. The method according to any one of claims 1 to 45, administering such treatment results in a reduced change above baseline in the cognitive measure of said plurality of human patients compared to a reference cognitive measure; the reference cognitive measure is a cognitive measure of a plurality of human patients who received the placebo; The cognitive measure is selected from the group consisting of: i) a trial-design test, ii) the Mini-Mental State Examination (MMSE), iii) the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) index score, iv) scores on each component of the API ADAD Composite Cognitive Test Battery, v) the Preclinical Alzheimer's Disease Cognitive Composite (PACC), and vi) other clinical endpoints.

47. 47. The method of claim 46, wherein administering such treatment reduces the change over baseline in said cognitive measure in said plurality of human patients compared to said reference cognitive measure after about 5 or more years of treatment.

48. 48. The method according to any one of claims 1 to 47, administering such treatment reduces the change above baseline in a neuropsychiatric inventory (NPI) of said plurality of human patients compared to a reference NPI; The method, wherein said reference NPI is an NPI of a plurality of human patients who received said placebo.

49. 49. The method of any one of claims 1 to 48, administering such treatment reduces the change from baseline in the Geriatric Depression Scale (GDS) of said plurality of human patients compared to a reference GDS; The method, wherein the reference GDS is a GDS of a plurality of human patients who received the placebo.

50. 50. The method of any one of claims 1 to 49, administration of such treatment reduces the change from baseline in Functional Assessment of Alzheimer's Disease Staging (FAST) total score for said plurality of human patients, relative to a reference FAST total score; The method, wherein the reference FAST total scores are FAST total scores of a plurality of human patients who received the placebo.

51. 51. The method of any one of claims 1 to 50, administering such treatment reduces the change above baseline in the subject memory checklist for said plurality of human patients compared to a reference change in the subject memory checklist; The method, wherein the reference change in the subject memory checklist is the change in the subject memory checklist of a plurality of human patients who received the placebo.

52. 52. The method of any one of claims 1 to 51, wherein the genetic mutation causing familial AD is an autosomal dominant mutation causing autosomal dominant Alzheimer's disease (ADAD).

53. 53. The method of claim 52, wherein the ADAD comprises one or more mutations in one or more genes selected from the group consisting of presenilin 1 (PSEN1), presenilin 2 (PSEN2), and / or amyloid precursor protein (APP).

54. 54. The method of any one of claims 1 to 53, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered intravenously.

55. 55. The method of claim 54, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is administered at a) a dose of about 60 mg / kg or more; or b) a fixed dose of 4200 mg or more; or c) a fixed dose of about 4200 mg.

56. 56. The method of claim 54 or 55, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered about every four weeks (Q4W).

57. 56. The method of claim 54 or 55, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered about Q4W for about 5 years.

58. 58. The method of any one of claims 1-53 or 55-57, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered subcutaneously.

59. 59. The method of claim 58, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered at a dose of about 720 mg or greater.

60. 59. The method of claim 58, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered at a dose of about 300 mg.

61. 61. The method of any one of claims 58-60, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered every other week (Q2W).

62. 62. The method of any one of claims 58-61, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is delivered about Q2W for about 5 years.

63. 63. The method of any one of claims 1 to 62, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:

11.

64. 64. The method of any one of claims 1 to 63, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain comprising the amino acid sequence of SEQ ID NO:

9.

65. 65. The method of any one of claims 1-64, wherein administration of such treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in said plurality of human patients compared to a reference SUVR for amyloid PET, wherein said reference SUVR for amyloid PET is the SUVR for amyloid PET in said plurality of human patients who received said placebo.

66. 66. The method of claim 65, wherein administering such treatment reduces the standardized uptake value ratio (SUVR) of amyloid PET measurements in said plurality of human patients by at least 3% compared to said reference SUVR for amyloid PET.

67. 66. The method of claim 65, wherein administration of such treatment reduces cerebrospinal fluid (CSF) neurofilament light (CSF NfL) in the plurality of human patients compared to a reference CSF NfL, wherein the reference CSF NfL is derived from the plurality of human patients who received the placebo.

68. 68. The method of claim 67, wherein administering such treatment results in at least a 10% relative reduction in CSF NfL in said plurality of human patients relative to said reference CSF NfL.

69. 69. The method of any one of claims 1 to 68, wherein the humanized monoclonal anti-amyloid beta (Aβ) antibody is crenezumab.

70. 70. A kit comprising a humanized monoclonal anti-amyloid beta (Aβ) antibody for treating a human patient in need thereof, having a genetic mutation that causes familial Alzheimer's disease (AD), according to the method of any one of claims 1 to 69.

71. 70. A humanized monoclonal anti-amyloid beta (Aβ) antibody for use in treating a human patient in need thereof, having a genetic mutation that causes familial Alzheimer's disease (AD), according to the method of any one of claims 1 to 69.

Images