Clinical trial NCT05617014: Alzheimer's Disease Neuroimaging Initiative 4
Official title: Alzheimer's Disease Neuroimaging Initiative 4 (ADNI4)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mild Cognitive Impairment
Alzheimer Disease
Dementia
Keywords: amyloid
plaques
neuroimaging
biomarkers
cognition disorder
early detection
pre-dementia
dementia
Alzheimer's disease
tau
observational
Lead sponsor: University of Southern California
Sponsor class: OTHER
Collaborators: name: Northern California Institute of Research and Education
name: National Institute on Aging (NIA)
name: Alzheimer's Therapeutic Research Institute
First posted: 2022-11-15
Enrollment: 1500
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Cognitively normal (CN), mild cognitive impairment (MCI), and dementia (DEM) participants.

Brief summary: Since its launch in 2004, the overarching aim of the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study has been to validate biomarkers for Alzheimer's disease (AD) clinical trials. ADNI4 continues the previously funded ADNI1, ADNI-GO, ADNI2, and ADNI3 studies that have combined public/private collaborations between academia and industry to determine the relationships between the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of AD.

Detailed description: The ADNI4 Study is a multi-center, non-randomized, natural history, non-treatment study. 1,150 participants will be enrolled across three cohorts: cognitively normal (CN), mild cognitive impairment (MCI) and dementia (DEM).

Participants between the ages of 55-90 (inclusive) will be enrolled at 59 sites in the United States and Canada. Approximately, 750 participants will be newly enrolled into the ADNI4 Study, while 750 participants will be rollover participants, continuing their participation from previous ADNI studies. Clinical/cognitive, imaging, biomarker, and genetic characteristics will be assessed across the three cohorts.

Participants enrolled in the ADNI4 Study will undergo longitudinal clinical and cognitive assessments, computerized cognitive batteries, biomarker and genetic tests, PET (amyloid and tau) and MRI scans and cerebral spinal fluid (CSF) collection for up to 5 years.

For more information, please visit the ADNI4 Study website: https://www.adni4.org/

Eligibility criteria: Inclusion Criteria for Newly Enrolled Participants, CN Cohort:

1. Participant may or may not have a significant subjective memory concern as reported by participant, study partner, or clinician.
2. Normal memory function documented by scoring above demographically-adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale - Revised (the maximum score is 25):

   1. ≥9 for 16 or more years of education
   2. ≥ 5 for 8-15 years of education
   3. ≥ 3 for 0-7 years of education
   4. Note: cut-offs may be modified over time as the field evolves in this area
3. Mini-Mental State Exam score between 24 and 30 (inclusive) (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director and/or Clinical Core)
4. Clinical Dementia Rating = 0. Memory Box score must be 0.
5. Cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living.
6. Stability of Permitted Medications for 4 weeks. In particular, participants may:

   1. Take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 years)
   2. Estrogen replacement therapy is permissible
   3. Gingko biloba is permissible, but discouraged
   4. Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria for Newly Enrolled Participants, MCI Cohort

1. Participant must have a subjective memory concern as reported by participant, study partner, or clinician.
2. Abnormal memory function documented by scoring within the demographically- adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale - Revised (the maximum score is 25):

   1. ≤11 for 16 or more years of education
   2. ≤9 for 8-15 years of education
   3. ≤6 for 0-7 years of education.
   4. Note: cut-offs may be modified over time as the field evolves in this area.
3. Mini-Mental State Exam score between 24 and 30 (inclusive) (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director and/or Clinical Core)
4. Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5
5. General cognition and functional performance sufficiently preserved such that a diagnosis of dementia cannot be made by the site physician at the time of the screening visit.
6. Stability of Permitted Medications for 4 weeks. In particular, participants may:

   1. Take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 year)
   2. Estrogen replacement therapy is permissible
   3. Gingko biloba is permissible, but discouraged
   4. Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening
   5. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screen
   6. Aducanumab and any other approved treatments for the neurobiology of AD if stable for 24 weeks prior to screen

Inclusion Criteria for Newly Enrolled Participants, DEM Cohort

1. Participant must have a subjective memory concern as reported by participant, study partner, or clinician.
2. Abnormal memory function documented by scoring within the demographically- adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale - Revised (the maximum score is 25):

   1. ≤11 for 16 or more years of education
   2. ≤9 for 8-15 years of education
   3. ≤6 for 0-7 years of education.
   4. Note: cut-offs may be modified over time as the field evolves in this area.
3. Mini-Mental State Exam score between 20 and 28 (inclusive) (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director and/or Clinical Core)
4. Clinical Dementia Rating = 0.5 or 1.0.
5. Meets the National Institute on Aging/Alzheimer's Association Diagnostic Guidelines for Dementia (2011)
6. Stability of Permitted Medications for 4 weeks. In particular, participants may:

   1. Take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 1 year)
   2. Estrogen replacement therapy is permissible
   3. Gingko biloba is permissible, but discouraged
   4. Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening
   5. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screen
   6. Aducanumab and any other approved treatments for the neurobiology of AD if stable for 24 weeks prior to screen

Inclusion Criteria for Newly Enrolled Participants, All Cohorts

1. Geriatric Depression Scale score less than 10.
2. Age between 55-90 years (inclusive).
3. Study partner who has frequent contact with the participant (i.e., minimum average of 2 hours per week) and may be able to accompany the participant to clinic visits or provide information remotely (e.g. over the phone).
4. Visual and auditory acuity adequate for neuropsychological testing.
5. Good general health with no diseases expected to interfere with the study.
6. Participant is not pregnant, lactating, or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile).
7. Willing and able to participate in a longitudinal imaging study.
8. Must be literate and speak English or Spanish fluently.
9. Agrees to collection of blood for GWAS, APOE testing, DNA and RNA testing
10. Agrees to collection of blood for biomarker testing.
11. The Administrative Core, described in section 9.1.1, will collaborate with leadership from all Cores to review the blood biomarker data from the remote blood cohort and select participants to join the in-clinic cohort. See ADNI4: Remote protocol.
12. Agrees to participate in the ADNI study which includes cognitive evaluation, MRI and PET scans.
13. Flexibility can be made to all criteria for those with at least 8 years in a low socio-economic status (SES) neighborhood.

Inclusion Criteria for Rollover Participants, All Cohorts

The following additional inclusion criteria apply to all diagnostic categories for rollover participants only:

1. Must have been enrolled and followed in one of the following previous ADNI studies: ADNIGO, ADNI2, ADNI3 for at least one year.
2. Willing and able to continue to participant in an ongoing longitudinal study. A reduced battery of tests is allowable.
3. Study partner may be available who has frequent contact with the participant (i.e., minimum average of 2 hours per week), and may be able to accompany the participant to clinic visits or provide information remotely (e.g. over the phone).

Exclusion Criteria for Newly Enrolled Participants, CN Cohort:

1.Any significant neurologic disease, such as Parkinson's disease, vascular cognitive impairment/dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities

Exclusion Criteria for Newly Enrolled Participants, MCI and DEM Cohorts:

1.Any significant neurologic disease other than suspected Alzheimer's disease, such as Parkinson's disease (Parkinsonian symptoms complicating MCI/AD are acceptable), vascular cognitive impairment dementia (multiple lacunes less than or equal to 1.5 cm and/or extensive white matter changes are acceptable), Huntington's disease, normal pressure hydrocephalus, brain tumor (clinically insignificant meningioma acceptable), progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.

Exclusion Criteria for Newly Enrolled Participants, All Cohorts:

Additional exclusion criteria apply to all diagnostic categories for newly enrolled participants:

1. Screening/Baseline MRI brain scan with evidence of infection, or other clinically significant focal lesions. Participants with cortical strokes, not large enough to distort anatomy, multiple lacunar infarctions or extensive white matter disease are allowed.
2. Screening/Baseline MRI brain scan with evidence of large structural abnormalities that would corrupt image analytical pipelines - e.g. large hemispheric infarcts, large areas of encephalomalacia, large arachnoid cysts
3. Unable to complete MRIs for any reason (e.g. pacemaker or other implanted metal devices, severe claustrophobia, anxiety which prevents MRI scans, too large to fit, etc.).
4. Current major depression, bipolar disorder as described in DMS-IV within the past 1 year. Psychotic features, agitation or behavioral problems within the last 3 months which could lead to difficulty complying with the protocol.
5. Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder.
6. History of schizophrenia (DSM-5 criteria).
7. History of alcohol or substance disorder within the past 2 years (DSM-5 criteria).
8. Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol.
9. Clinically significant abnormalities in B12, or thyroid function tests that might interfere with the study. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.
10. Residence in skilled nursing facility
11. Current use of specific psychoactive medications (e.g. certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.), at the discretion of the clinician.
12. Current use of any other exclusionary medications.
13. Investigational agents are prohibited for five half-lives or one month, whichever time period is longer, prior to entry and for the duration of the trial.
14. Participation in clinical studies involving neuropsychological measures being collected more than once time per year.
15. Female that is pregnant, lactating, or of childbearing potential.
16. Flexibility can be made to all criteria for those with at least 8 years in a low socio-economic status (SES) neighborhood.

Primary outcomes:
measure: Rate of enrollment of Underrepresented Populations (URPs)
timeFrame: 5 years
Secondary outcomes:
measure: Rate of change in cognition as measured by the Category Fluency (Animals) Tests
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Measurement of Everyday Cognition 12-item (12-Item ECog)
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Logical Memory Test I and II (immediate and delayed paragraph recall)
timeFrame: CN Cohorts: Screening/Initial, Months 24 and 48. MCI Cohorts: Screening/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Screening/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Montreal Cognitive Assessment (MoCA)
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Multilingual Naming Test (MINT)
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Perceived Stress (PSS)
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Rey Auditory Verbal Learning Test (AVLT)
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Trail Making Test: A and B
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Clinical Dementia Rating (CDR)
timeFrame: CN Cohorts: Screening/Initial, Months 24 and 48. MCI Cohorts: Screening/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Screening/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Activities of Daily Living (ADL) Functional Assessment Questionnaire (FAQ)
timeFrame: CN Cohorts: Baseline/Initial, Months 24 and 48. MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12 and 24.
measure: Rate of change in cognition as measured by the Neuropsychiatric Inventory (NPI)
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12, 24 and 36.
measure: Rate of change in cognition as measured by the Neuropsychiatric Inventory Q (NPI-Q)
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Baseline/Initial, Months 12, 24 and 36.
measure: Rate of change in cognition as measured by the Geriatric Depression Scale (GDS) Short Form
timeFrame: CN Cohorts: Screening/Initial, Months 24 and 48. MCI Cohorts: Screening/Initial, Months 12, 24, 36 and 48. DEM Cohorts: Screening/Initial, Months 12 and 24.
measure: Change in amyloid deposition as measured by florbetaben
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in amyloid deposition as measured by NAV4694
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in amyloid deposition as measured by florbetapir
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in tau deposition as measured by flortaucipir
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in tau deposition as measured by MK-6240
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in tau deposition as measured by PI-2620
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in amyloid β-peptide (Aβ) 40 (Aβ40) in Cerebrospinal Fluid (CSF)
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in amyloid β-peptide (Aβ) 42 (Aβ42) in Cerebrospinal Fluid (CSF)
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in Cerebrospinal Fluid (CSF) Levels of Total Tau
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in Cerebrospinal Fluid (CSF) Levels of Phospho-Tau 181
timeFrame: CN and MCI Cohorts: Baseline/Initial, Months 24 and 48. DEM Cohorts: Baseline/Initial and Month 24 and 36.
measure: Change in brain structure using magnetic resonance imaging (MRI)
timeFrame: CN and MCI Cohorts: Screening/Initial, Months 24 and 48. DEM Cohorts: Screening/Initial and Month 24 and 36.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Walnut Creek
country: United States
facility: University of California, Davis
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Miami Beach
country: United States
facility: Wien Center
state: Florida
city: Miami
country: United States
facility: Gonzalez MD & Aswad MD Health Services
state: Florida
city: Tampa
country: United States
facility: University of South Florida Health Byrd Alzheimer's Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Memory Clinic
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Fairway
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Ann Arbor
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Alzheimer's Disease Research Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University, St Louis
state: Missouri
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas
state: Nevada
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Buffalo
country: United States
facility: Dent Neurological Institute
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Orangeburg
country: United States
facility: Nathan Kline Institute for Psychiatric Research
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Tulsa
country: United States
facility: Central States Research
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Butler Hospital, Memory and Aging Program
state: Rhode Island
city: Charleston
country: United States
facility: Ralph H. Johnson VA Health Care System
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center Center for Cognitive Medicine
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: London
country: Canada
facility: Parkwood Institute
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: University of California, San Francisco
name: Michael Weiner, MD
role: STUDY_DIRECTOR
affiliation: USC Alzheimer's Therapeutic Research Institute (ATRI)
name: Paul Aisen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Ronald Petersen, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References: