This randomized, double-blind, placebo-controlled, parallel group, adaptive study will evaluate the efficacy and safety of crenezumab versus placebo in individuals who carry the PSEN1 E280A autosomal-dominant mutation and do not meet the criteria for mild cognitive impairment due to AD or dementia due to AD and are, thus, in a preclinical phase of AD. Participants will be randomized in a 1:1 ratio to receive either crenezumab or placebo subcutaneously (every 2 weeks) or intravenously (every 4 weeks) for at least 260 weeks. The switch to the intravenous (IV) dose will be optional (as per participant decision). The study will also include a cohort of PSEN1 E280A mutation non-carriers who will be dosed with placebo only.

NCT01998841

Conditions

1. Alzheimer's Disease

Interventions

1. Drug: Crenezumab
2. Drug: Placebo

MeSH:Alzheimer Disease

HPO:Alzheimer disease

A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-Randomized, Placebo-Treated Non-Carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease. --- E280A ---

A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort This randomized, double-blind, placebo-controlled, parallel group, adaptive study will evaluate the efficacy and safety of crenezumab versus placebo in individuals who carry the PSEN1 E280A autosomal-dominant mutation and do not meet the criteria for mild cognitive impairment due to AD or dementia due to AD and are, thus, in a preclinical phase of AD. --- E280A ---

A Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer's Disease (AD), Including a Placebo-Treated Non-Carrier Cohort This randomized, double-blind, placebo-controlled, parallel group, adaptive study will evaluate the efficacy and safety of crenezumab versus placebo in individuals who carry the PSEN1 E280A autosomal-dominant mutation and do not meet the criteria for mild cognitive impairment due to AD or dementia due to AD and are, thus, in a preclinical phase of AD. --- E280A --- --- E280A ---

The study will also include a cohort of PSEN1 E280A mutation non-carriers who will be dosed with placebo only. --- E280A ---

Inclusion Criteria: - Membership in PSEN1 E280A mutation carrier kindred - Agrees to conditions of, and is willing to undergo, genetic testing (for example [e.g.], apolipoprotein E [APOE], PSEN1 E280A, and other genetic testing) - PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period - Mini-Mental Stage Examination (MMSE) greater than or equal to (>=) 24 for participants with less than (<) 9 years of education or MMSE >=26 for participants with 9 or more years of education - Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria - Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria - Adequate vision and hearing in the investigator's judgment to be able to complete testing - If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints - For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug - For men with partners of childbearing potential (that is [i.e.], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug - Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status - Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered - Willing and able to undergo neuroimaging (PET and MRI) - Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. --- E280A ---

Inclusion Criteria: - Membership in PSEN1 E280A mutation carrier kindred - Agrees to conditions of, and is willing to undergo, genetic testing (for example [e.g.], apolipoprotein E [APOE], PSEN1 E280A, and other genetic testing) - PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period - Mini-Mental Stage Examination (MMSE) greater than or equal to (>=) 24 for participants with less than (<) 9 years of education or MMSE >=26 for participants with 9 or more years of education - Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria - Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria - Adequate vision and hearing in the investigator's judgment to be able to complete testing - If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints - For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug - For men with partners of childbearing potential (that is [i.e.], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug - Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status - Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered - Willing and able to undergo neuroimaging (PET and MRI) - Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. --- E280A --- --- E280A ---

Inclusion Criteria: - Membership in PSEN1 E280A mutation carrier kindred - Agrees to conditions of, and is willing to undergo, genetic testing (for example [e.g.], apolipoprotein E [APOE], PSEN1 E280A, and other genetic testing) - PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period - Mini-Mental Stage Examination (MMSE) greater than or equal to (>=) 24 for participants with less than (<) 9 years of education or MMSE >=26 for participants with 9 or more years of education - Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria - Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria - Adequate vision and hearing in the investigator's judgment to be able to complete testing - If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints - For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug - For men with partners of childbearing potential (that is [i.e.], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug - Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status - Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered - Willing and able to undergo neuroimaging (PET and MRI) - Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. --- E280A --- --- E280A --- --- E280A ---

Short-term, peri-operative use of anti-coagulants may not result in discontinuation from the study; however, any such use must be discussed with the Medical Monitor - Treatment with any biologic therapy within five half-lives or 3 months prior to screening, whichever is longer, with the exception of routinely recommended vaccinations, which are allowed - Use of anti-seizure medication (except in childhood for febrile seizures or if used for non-seizure indications), anti-parkinsonian, or stimulant (e.g., methylphenidate) medications - Use of investigational drug, device, or experimental medication within 60 days (or five half-lives, whichever is longer) of the screening visit - Previous treatment with crenezumab or any other therapeutic that targets A-beta - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins - Contraindication to MRI scan procedures or clinically significant claustrophobia that would contraindicate a brain MRI scan - Contraindication to PET scan procedures Inclusion Criteria: - Membership in PSEN1 E280A mutation carrier kindred - Agrees to conditions of, and is willing to undergo, genetic testing (for example [e.g.], apolipoprotein E [APOE], PSEN1 E280A, and other genetic testing) - PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period - Mini-Mental Stage Examination (MMSE) greater than or equal to (>=) 24 for participants with less than (<) 9 years of education or MMSE >=26 for participants with 9 or more years of education - Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria - Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria - Adequate vision and hearing in the investigator's judgment to be able to complete testing - If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints - For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug - For men with partners of childbearing potential (that is [i.e.], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug - Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status - Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered - Willing and able to undergo neuroimaging (PET and MRI) - Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. --- E280A ---

Short-term, peri-operative use of anti-coagulants may not result in discontinuation from the study; however, any such use must be discussed with the Medical Monitor - Treatment with any biologic therapy within five half-lives or 3 months prior to screening, whichever is longer, with the exception of routinely recommended vaccinations, which are allowed - Use of anti-seizure medication (except in childhood for febrile seizures or if used for non-seizure indications), anti-parkinsonian, or stimulant (e.g., methylphenidate) medications - Use of investigational drug, device, or experimental medication within 60 days (or five half-lives, whichever is longer) of the screening visit - Previous treatment with crenezumab or any other therapeutic that targets A-beta - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins - Contraindication to MRI scan procedures or clinically significant claustrophobia that would contraindicate a brain MRI scan - Contraindication to PET scan procedures Inclusion Criteria: - Membership in PSEN1 E280A mutation carrier kindred - Agrees to conditions of, and is willing to undergo, genetic testing (for example [e.g.], apolipoprotein E [APOE], PSEN1 E280A, and other genetic testing) - PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period - Mini-Mental Stage Examination (MMSE) greater than or equal to (>=) 24 for participants with less than (<) 9 years of education or MMSE >=26 for participants with 9 or more years of education - Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria - Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria - Adequate vision and hearing in the investigator's judgment to be able to complete testing - If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints - For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug - For men with partners of childbearing potential (that is [i.e.], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug - Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status - Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered - Willing and able to undergo neuroimaging (PET and MRI) - Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. --- E280A --- --- E280A ---

Short-term, peri-operative use of anti-coagulants may not result in discontinuation from the study; however, any such use must be discussed with the Medical Monitor - Treatment with any biologic therapy within five half-lives or 3 months prior to screening, whichever is longer, with the exception of routinely recommended vaccinations, which are allowed - Use of anti-seizure medication (except in childhood for febrile seizures or if used for non-seizure indications), anti-parkinsonian, or stimulant (e.g., methylphenidate) medications - Use of investigational drug, device, or experimental medication within 60 days (or five half-lives, whichever is longer) of the screening visit - Previous treatment with crenezumab or any other therapeutic that targets A-beta - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins - Contraindication to MRI scan procedures or clinically significant claustrophobia that would contraindicate a brain MRI scan - Contraindication to PET scan procedures Inclusion Criteria: - Membership in PSEN1 E280A mutation carrier kindred - Agrees to conditions of, and is willing to undergo, genetic testing (for example [e.g.], apolipoprotein E [APOE], PSEN1 E280A, and other genetic testing) - PSEN1 E280A mutation carrier or non-carrier status has been confirmed prior to or during the screening period - Mini-Mental Stage Examination (MMSE) greater than or equal to (>=) 24 for participants with less than (<) 9 years of education or MMSE >=26 for participants with 9 or more years of education - Does not meet criteria for dementia due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (McKhann et al. 2011) criteria - Does not meet criteria for mild cognitive impairment (MCI) due to AD per the National Institute on Aging and the Alzheimer's Association Workgroup (Albert et al. 2011) criteria - Adequate vision and hearing in the investigator's judgment to be able to complete testing - If female, and not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, willing to undergo pregnancy tests at protocol-specific timepoints - For women who are not documented (by medical records or physician's note) to be surgically sterile (absence of ovaries and/or uterus) or postmenopausal, agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of <1 percent (%) per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner, tubal ligation) during the treatment period and for at least 16 weeks after the last dose of study drug - For men with partners of childbearing potential (that is [i.e.], women who are not surgically sterile and are not postmenopausal), agreement to remain abstinent or use a condom as a method of contraception during the treatment period and for at least 8 weeks after the last dose of study drug - Study partner who agrees to participate in the study and is capable of and willing to: accompany the participant to all required visits; provide information for required telephone assessments; spend sufficient time with the participant to be familiar with his/her overall function and behavior and be able to provide adequate information about the participant including knowledge about domestic activities, hobbies, routines, social skills and basic activities of daily life; work and educational history; cognitive performance including memory abilities, language abilities, temporal and spatial orientation, judgment and problem solving; emotional and psychological state; and general health status - Participant and study partner have evidence of adequate premorbid functioning (e.g., intellectual, visual, and auditory) and are fluent in, and able to read, the language in which study assessments are administered - Willing and able to undergo neuroimaging (PET and MRI) - Serum thyroid stimulating hormone (TSH) and B12 levels within normal or expected ranges for the testing laboratory or if TSH and B12 values are out of range they are judged by the investigator not to be clinically significant. --- E280A --- --- E280A --- --- E280A ---

This substudy will evaluate the effect of crenezumab on the longitudinal tau burden in a subgroup of preclinical Presenilin1 (PSEN1) E280A mutation carriers and non-carriers, who were enrolled in study NCT01998841 (GN28352). Participants will receive up to three intravenous (IV) injections of [^18F] Genentech Tau Probe 1 (GTP1) and will undergo a tau positron emission tomography (PET) scan after each IV injection of [18^F]GTP1. The purpose of this substudy is to increase the understanding of disease progression in the preclinical stage of familial Alzheimer's Disease (AD).

NCT03977584

Conditions

1. Alzheimer Disease

Interventions

1. Drug: Crenezumab
2. Drug: Placebo
3. Other: [^18F]GTP1

MeSH:Alzheimer Disease

HPO:Alzheimer disease

Tau PET Longitudinal Substudy Associated With: A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-randomized, Placebo-treated Non-carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease. --- E280A ---

Tau Positron Emission Tomography (PET) Longitudinal Substudy Associated With: Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers in the Treatment of Autosomal-Dominant Alzheimer's Disease This substudy will evaluate the effect of crenezumab on the longitudinal tau burden in a subgroup of preclinical Presenilin1 (PSEN1) E280A mutation carriers and non-carriers, who were enrolled in study NCT01998841 (GN28352). --- E280A ---

Tau Positron Emission Tomography (PET) Longitudinal Substudy Associated With: Study of Crenezumab Versus Placebo in Preclinical Presenilin1 (PSEN1) E280A Mutation Carriers in the Treatment of Autosomal-Dominant Alzheimer's Disease This substudy will evaluate the effect of crenezumab on the longitudinal tau burden in a subgroup of preclinical Presenilin1 (PSEN1) E280A mutation carriers and non-carriers, who were enrolled in study NCT01998841 (GN28352). --- E280A --- --- E280A ---