Longitudinal Early-onset Alzheimer's Disease Study Protocol

Study Overview
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Brief Summary
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The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a non-randomized, natural history, non-treatment study designed to look at disease progression in individuals with early onset cognitive impairment. Clinical, cognitive, imaging, biomarker, and genetic characteristics will be assessed across three cohorts: (1) early onset Alzheimer's Disease (EOAD) participants, (2) early onset non-Alzheimer's Disease (EOnonAD) participants, and (3) cognitively normal (CN) control participants.

Detailed Description
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The LEADS study is a non-randomized, natural history, non-treatment study. Enrolled participants must be 40 - 64 (inclusive) years of age, with MCI due to AD or probable AD dementia (cognitively impaired participants) or have no significant memory impairment (cognitively normal [CN] participants). Approximately 600 participants with cognitive impairment (400 with early onset Alzheimer's Disease [EOAD] and 200 with early onset non-Alzheimer's Disease [EOnonAD]) and 100 CN participants will be enrolled at approximately 20 sites in the United States. Cognitively impaired participants will take part in the study for 48+ months; CN participants will take part in the study for 24+ months. Participants will undergo longitudinal clinical and cognitive assessments, computerized cognitive tests, biomarker and genetic tests, PET (FDG, amyloid and tau) and MRI brain scans, and optional cerebrospinal fluid (CSF) collection. Participants will be invited to consider autopsy brain donation The primary objectives of the LEADS study are to: collect longitudinal assessments and biomarker data in individuals with early onset cognitive impairment (EOAD / EOnonAD) and cognitively normal (CN) controls; to compare baseline and longitudinal cognitive and functional characteristics, between EOAD and CN, and EOAD and Late Onset Alzheimer's Disease (LOAD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI); and to study the associations of longitudinal clinical and cognitive assessments with multimodal imaging and biofluid markers that capture different elements of the AD pathophysiological cascade

Official Title
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Longitudinal Early-onset Alzheimer's Disease Study Protocol

Conditions
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Early Onset Alzheimer Disease, Alzheimer Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Flortaucipir
* Drug: Florbetaben
* Drug: Fluorodeoxyglucose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Cognitively Impaired (EOAD and EOnonAD) Cohorts Only: Meets NIA-AA criteria for MCI due to AD or probable AD dementia Have a global CDR score ≤ 1.0 Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC Age between 40-64 years (inclusive) at the time of consent Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends at least 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan Fluent in English or Spanish Inclusion Criteria for Cognitively Normal (CN) Cohort Only: Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living Have a global CDR score = 0 Have capacity to provide informed consent Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made for participant with less than 8 years of education at the discretion of the Site PI Age between 40-64 years (inclusive) at the time of consent Must have a study partner (informant) who spends a minimum average of 10 hours per week with the participant (e.g., family member, significant other, friend, caregiver) who is generally aware of the participants' daily activities and can provide information about the participant's cognitive and functional performance. If the participant does not have a study partner who spends 10 face-to-face hours per week, other arrangements for identifying a viable study partner will be granted on a case-by-case basis by the Site PI Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure Not pregnant or lactating. Women must be two years post-menopausal, be surgically sterile, or have a negative pregnancy test prior to each PET scan Fluent in English or Spanish Exclusion Criteria for all (EOAD, EOnonAD and CN) cohorts: Meets core clinical criteria for non-AD dementia Two or more first degree relatives with a history of early-onset dementia suggestive of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1, PSEN2, MAPT, GRN and C9ORF72 have been excluded Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72) Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip, artificial heart valve, select ear implants, select stents incompatible with 3T MRI, metal fragments or foreign objects in the eyes, skin or body, etc.) Lifetime medical history of a brain disorder other than the disorder causing dementia except for headache (exceptions are allowed at the discretion of the Site PI - e.g., seizure disorder thought to be due to EOAD). MRI scan with evidence of infection or focal lesions, cortical strokes, multiple lacunes (single lacune is allowable unless it meets criteria for strategic lacune affecting cognition) Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI) Research radiation exposure will be assessed by the study physician. If the candidate participant has had more than one nuclear medicine study in the prior 12 months for research-related purposes, study inclusion will require approval from the PET Core Investigational agents are prohibited 30 days prior to entry Previous enrollment in a therapeutic trial targeting amyloid or tau Participation in other clinical studies with neuropsychological measures, with the exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS) protocol (Note: This criterion is intended to reduce repeat measures effects during neuropsychological testing. Exceptions are allowed at the discretion of the Site PI) Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria) Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed) Suicidal behaviors in the past 12 months or active suicidal ideations Residing in a 24-hour care skilled nursing facility (at the time of screening) (For optional lumbar puncture procedure only): a. Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be not clinically significant by the Site PI i. Platelet count <100,000/ul ii. INR>1.2 iii. Abnormal PT or PTT at screening b. Contraindications to the procedure, including but not limited to severe degenerative joint disease, deformity of the spine, history of a bleeding disorder c. Suspected elevated intracranial pressure, Arnold Chiari malformation or mass lesion d. Use of the anticoagulant medications such as but not limited to warfarin, rivaroxaban, dabigatran Deemed ineligible by the Site PI for any other reason

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Early Onset Alzheimer's Disease (EOAD)<br>Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia Amyloid positive status (florbetaben PET scan with evidence of elevated amyloid as determined by a central read) CDR score ≤ 1.0 flortaucipir (18F-AV-1451) PET scanning | Drug: Flortaucipir<br>* All participants will receive a single bolus intravenous injection of approximately 10 mCi (+/- 10%, 20μg mass dose) of flortaucipir (18F-AV-1451). At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.<br>* Other names: 18F-AV-1451 (also known as [F-18]T807 or LY3191748);Drug: Florbetaben<br>* All participants will receive a single bolus intravenous injection of approximately 8 mCi +/- .8mCi of florbetaben (AV-45). At approximately 90-minutes (+/- 10 minutes) post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.<br>* Other names: AV-45, Neuraceq;|
| Cognitively Normal (CN) Controls<br>Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions and activities of daily living Mini-Mental State Exam score between 26-30 CDR score = 0 flortaucipir (18F-AV-1451) PET scanning | Drug: Flortaucipir<br>* All participants will receive a single bolus intravenous injection of approximately 10 mCi (+/- 10%, 20μg mass dose) of flortaucipir (18F-AV-1451). At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.<br>* Other names: 18F-AV-1451 (also known as [F-18]T807 or LY3191748);Drug: Florbetaben<br>* All participants will receive a single bolus intravenous injection of approximately 8 mCi +/- .8mCi of florbetaben (AV-45). At approximately 90-minutes (+/- 10 minutes) post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.<br>* Other names: AV-45, Neuraceq;Drug: Fluorodeoxyglucose<br>* All participants will receive a single bolus intravenous injection of approximately 5 mCi (+/- 10%, 0.5 mCi) of fluorodeoxyglucose. At approximately 30 minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.<br>* Other names: FDG;|
| Early Onset non-Alzheimer's Disease (EOnonAD)<br>Diagnosis of NIA-AA criteria of MCI due to AD or probable AD dementia Amyloid negative status (florbetaben PET scan with no evidence of elevated amyloid as determined by a central read) CDR score ≤ 1.0 flortaucipir (18F-AV-1451) PET scanning | Drug: Flortaucipir<br>* All participants will receive a single bolus intravenous injection of approximately 10 mCi (+/- 10%, 20μg mass dose) of flortaucipir (18F-AV-1451). At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.<br>* Other names: 18F-AV-1451 (also known as [F-18]T807 or LY3191748);Drug: Florbetaben<br>* All participants will receive a single bolus intravenous injection of approximately 8 mCi +/- .8mCi of florbetaben (AV-45). At approximately 90-minutes (+/- 10 minutes) post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.<br>* Other names: AV-45, Neuraceq;Drug: Fluorodeoxyglucose<br>* All participants will receive a single bolus intravenous injection of approximately 5 mCi (+/- 10%, 0.5 mCi) of fluorodeoxyglucose. At approximately 30 minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.<br>* Other names: FDG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13) | The ADAS-Cog is an in-person examiner-administered, structured scale that evaluates memory (word recall, word recognition), reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions are also obtained. | Month 0, Month 12, Month 24, Month 36 (EOAD/EOnonAD only) and Month 48 (EOAD/EOnonAD only) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change in cognition as measured by the Clinical Dementia Rating - Sum of Boxes (CDR-SB) | The CDR is a semi-structured interview of the informant and participant that assesses for impairment in 8 areas of functioning - memory, orientation, judgment and problem solving, community affairs, home and hobbies, personal care, behavior, personality, and language. | CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48 | 
| Change in tau deposition as measured by flortaucipir (18F-AV-1451) Positron Emission Tomography (PET) imaging |  | Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD and EOnonAD amyloid positive participants only) | 
| Change in amyloid deposition as measured by florbetaben using Positron Emission Tomography (PET) imaging |  | Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD/EOnonAD only | 
| Neurodegeneration as measured by fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) imaging compared to magnetic resonance imaging (MRI) |  | Month 12 (EOnonAD only) and Month 24 (CN only) | 
| Change in brain structure using magnetic resonance imaging (MRI) |  | CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24 and Month 36 | 
| Change in cerebrospinal fluid (CSF) biomarkers |  | CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 | 
| Change in plasma biomarkers |  | CN participants: Month 0, Month 12 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tau, Cognitively Normal, Amyloid, Plaques, Neuroimaging, Biomarkers, Cognition Disorder, Dementia, Early Onset Alzheimer's Disease, Alzheimer's Disease, Mild Cognitive Impairment