Longitudinal Early-onset Alzheimer's Disease Study Protocol (LEADS)

March 18, 2024 updated by: Indiana University
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

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

Study Type

Observational

Enrollment (Estimated)

700

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Sun City, Arizona, United States, 85351
        • Recruiting
        • Banner Sun Health Research Institute
        • Principal Investigator:
          • Alireza Atri, MD
        • Contact:
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • University of California, Los Angeles
        • Contact:
        • Principal Investigator:
          • Mario Mendez, MD, PhD
      • Palo Alto, California, United States, 94304
        • Recruiting
        • Stanford University
        • Principal Investigator:
          • Sharon Sha, MD
        • Contact:
      • San Francisco, California, United States, 94121
        • Recruiting
        • University of California, San Francisco
        • Contact:
        • Principal Investigator:
          • Gil Rabinovici, MD
    • District of Columbia
      • Washington, District of Columbia, United States, 20057
        • Recruiting
        • Georgetown University
        • Contact:
        • Principal Investigator:
          • R. Scott Turner, MD, PhD
    • Florida
      • Jacksonville, Florida, United States, 32224
        • Recruiting
        • Mayo Clinic, Jacksonville
        • Principal Investigator:
          • Gregory Day, MD
        • Contact:
      • Miami Beach, Florida, United States, 33140
        • Recruiting
        • Wien Center
        • Principal Investigator:
          • Ranjan Duara, MD
        • Contact:
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory University
        • Contact:
        • Principal Investigator:
          • Thomas Wingo, MD
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Northwestern University
        • Contact:
        • Principal Investigator:
          • Ian Grant, MD
    • Indiana
      • Indianapolis, Indiana, United States, 47405
        • Recruiting
        • Indiana University
        • Principal Investigator:
          • David Clark, MD
        • Contact:
    • Maryland
      • Baltimore, Maryland, United States, 21218
        • Recruiting
        • Johns Hopkins University
        • Principal Investigator:
          • Chiadi Onyike, MBBS, MD
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Massachusetts General Hospital
        • Principal Investigator:
          • Brad Dickerson, MD
        • Contact:
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic, Rochester
        • Contact:
        • Principal Investigator:
          • David Jones, MD
    • Missouri
      • Saint Louis, Missouri, United States, 63130
        • Recruiting
        • Washington University, St. Louis
        • Contact:
        • Principal Investigator:
          • Kyle Womack, MD
    • New York
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University
        • Contact:
        • Principal Investigator:
          • Lawrence Honig, MD, PhD
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
    • Rhode Island
      • Providence, Rhode Island, United States, 02906
        • Recruiting
        • Butler Hospital
        • Principal Investigator:
          • Meghan Riddle, MD
        • Contact:
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • Houston Methodist Hospital
        • Contact:
        • Principal Investigator:
          • Joseph Masdeu, MD, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 64 years (Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Probability Sample

Study Population

Cognitively Impaired Participants (ie: Early Onset Alzheimer's Disease (EOAD) and Early Onset non-Alzheimer's Disease (EOnonAD)) and Cognitively Normal (CN) Control Participants

Description

Inclusion Criteria for Cognitively Impaired (EOAD and EOnonAD) Cohorts Only:

  1. Meets NIA-AA criteria for MCI due to AD or probable AD dementia
  2. Have a global CDR score ≤ 1.0
  3. Have capacity to provide informed consent (IC) or has a legal authorized representative or guardian who provides IC
  4. Age between 40-64 years (inclusive) at the time of consent
  5. 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
  6. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
  7. 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
  8. Fluent in English or Spanish

Inclusion Criteria for Cognitively Normal (CN) Cohort Only:

  1. Meets criteria for cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
  2. Have a global CDR score = 0
  3. Have capacity to provide informed consent
  4. 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
  5. Age between 40-64 years (inclusive) at the time of consent
  6. 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
  7. Willing and able to complete longitudinal study procedures aside from LP which is an optional procedure
  8. 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
  9. Fluent in English or Spanish

Exclusion Criteria for all (EOAD, EOnonAD and CN) cohorts:

  1. Meets core clinical criteria for non-AD dementia
  2. 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
  3. Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72)
  4. 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.)
  5. 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).
  6. 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)
  7. Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol (at the discretion of the Site PI)
  8. 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
  9. Investigational agents are prohibited 30 days prior to entry
  10. Previous enrollment in a therapeutic trial targeting amyloid or tau
  11. 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)
  12. Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria)
  13. Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder with or without psychotic features
  14. Current history (in previous 6 months) of moderate or severe substance abuse (nicotine or caffeine is allowed)
  15. Suicidal behaviors in the past 12 months or active suicidal ideations
  16. Residing in a 24-hour care skilled nursing facility (at the time of screening)

  17. (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

  18. Deemed ineligible by the Site PI for any other reason

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Early Onset Alzheimer's Disease (EOAD)
  • 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
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.
Other Names:
  • 18F-AV-1451 (also known as [F-18]T807 or LY3191748)
Drug: Florbetaben
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.
Other Names:
  • AV-45, Neuraceq
Cognitively Normal (CN) Controls
  • 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
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.
Other Names:
  • 18F-AV-1451 (also known as [F-18]T807 or LY3191748)
Drug: Florbetaben
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.
Other Names:
  • AV-45, Neuraceq
Drug: Fluorodeoxyglucose
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.
Other Names:
  • FDG
Early Onset non-Alzheimer's Disease (EOnonAD)
  • 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
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.
Other Names:
  • 18F-AV-1451 (also known as [F-18]T807 or LY3191748)
Drug: Florbetaben
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.
Other Names:
  • AV-45, Neuraceq
Drug: Fluorodeoxyglucose
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.
Other Names:
  • FDG

What is the study measuring?

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)
Time Frame: Month 0, Month 12, Month 24, Month 36 (EOAD/EOnonAD only) and Month 48 (EOAD/EOnonAD only)
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)
Time Frame: CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48
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
Time Frame: Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD and EOnonAD amyloid positive participants only)
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
Time Frame: Month 0, Month 12 (EOAD only), Month 24 (EOAD only) and Month 36 (EOAD/EOnonAD only
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)
Time Frame: Month 12 (EOnonAD only) and Month 24 (CN only)
Month 12 (EOnonAD only) and Month 24 (CN only)
Change in brain structure using magnetic resonance imaging (MRI)
Time Frame: CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24 and Month 36
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
Time Frame: CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36
CN participants: Month 0 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36
Change in plasma biomarkers
Time Frame: CN participants: Month 0, Month 12 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48
CN participants: Month 0, Month 12 and Month 24; EOAD/EOnonAD participants: Month 0, Month 12, Month 24, Month 36 and Month 48

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Indiana University

Collaborators

National Institute on Aging (NIA)
Alzheimer's Therapeutic Research Institute
Alzheimer's Association

Investigators

  • Principal Investigator: Liana Apostolova, MD, Indiana University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 30, 2018

Primary Completion (Estimated)

May 31, 2024

Study Completion (Estimated)

May 31, 2024

Study Registration Dates

First Submitted

April 4, 2018

First Submitted That Met QC Criteria

April 23, 2018

First Posted (Actual)

April 25, 2018

Study Record Updates

Last Update Posted (Actual)

March 19, 2024

Last Update Submitted That Met QC Criteria

March 18, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ATRI-003
  • R56AG057195 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Study data will be shared broadly through the Laboratory of NeuroImaging (LONI), with aggregate data sharing through the Global Alzheimer's Association Interactive Network (GAAIN). MRI and PET data will also be available for download from the LEADS Image and Data Archive (IDA) website. Genetics, genomics, and related data will be shared with other researchers pursuant to the NIA Genetics Sharing Policy. National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site, with other NIA-approved sites, will make genetic, genomic and related data and associated phenotypic data available to qualified investigators for secondary analysis in accordance with standards established by NIA.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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