Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3)

Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3)

Since its launch in 2004, the overarching aim of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been realized in informing the design of therapeutic trials in AD. ADNI3 continues the previously funded ADNI-1, ADNI-GO, and ADNI-2 studies that have been 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 Alzheimer's disease (AD). The overall goal of the study is to continue to discover, optimize, standardize, and validate clinical trial measures and biomarkers used in AD research.

Study Overview

• Status: Completed
• Conditions: Mild Cognitive Impairment (MCI); Alzheimer's Disease (AD)

Detailed Description

The overall goal of ADNI3 is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD), as the pathology evolves from normal aging through very mild symptoms, to mild cognitive impairment (MCI), to dementia. ADNI3 continues the previously funded AD Neuroimaging Initiative (ADNI1, ADNI-GO, and ADNI-2), and remains a public/private collaboration between academia and industry to study biomarkers of AD. ADNI will continue to inform the neuroscience of AD, identify diagnostic and prognostic markers, identify outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios.

This is multi-center, a non-randomized, natural history, non-treatment study. 1,070-2,000 total participants will be enrolled across three cohorts: cognitively normal* (CN), mild cognitive impairment (MCI) and mild Alzheimer's Disease (AD) dementia. Participants between the ages of 55-90 (inclusive) will be enrolled at 59 sites in the United States and Canada. Approximately, 700 - 800 will be rollover participants from previous ADNI studies, and 370 - 1200 will be newly enrolled. Clinical/cognitive, imaging, biomarker, and genetic characteristics will be assessed across the three cohorts.

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

*currently recruiting non-Caucasian participants only for the cognitively normal cohort.

• Study Type: Observational
• Enrollment (Actual): 1141

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6T1Z3
      • University of British Columbia, Clinic for AD & Related
  • Ontario
    • London, Ontario, Canada, N6C 0A7
      • Parkwood Institute
    • London, Ontario, Canada, N6C 4R3
      • St. Joseph's Health Center - Cognitive Neurology
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital Memory Clinic
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama, Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner Alzheimer's Institute
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
    • Sun City, Arizona, United States, 85351
      • Banner Sun Health Research Institute
  • California
    • Irvine, California, United States, 92697
      • University of California, Irvine
    • La Jolla, California, United States, 920371707
      • University of California, San Diego
    • Long Beach, California, United States, 90822
      • Long Beach VA Neuropsychiatric Research Program
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Los Angeles, California, United States, 900335310
      • University of Southern California
    • Palo Alto, California, United States, 94304
      • VA Palo Alto HSC / Stanford School of Medicine
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
    • Walnut Creek, California, United States, 945985900
      • University of California, Davis
  • Connecticut
    • New Haven, Connecticut, United States, 65103330
      • Yale University School Of Medicine
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 200072145
      • Georgetown University
    • Washington D.C., District of Columbia, United States, 200600001
      • Howard University
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic, Jacksonville
    • Miami Beach, Florida, United States, 331402877
      • Wien Center for Clinical Research
    • Tampa, Florida, United States, 336134808
      • University of South Florida - Health Byrd Alzheimer Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 606113010
      • Northwestern University
    • Chicago, Illinois, United States, 606123806
      • Rush University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Fairway, Kansas, United States, 66205
      • University of Kansas
  • Kentucky
    • Lexington, Kentucky, United States, 405042681
      • University Of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 212242764
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 21155804
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 21182307
      • Boston University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 481052967
      • University of Michigan, Ann Arbor
  • Minnesota
    • Rochester, Minnesota, United States, 559050001
      • Mayo Clinic, Rochester
  • Missouri
    • St Louis, Missouri, United States, 631082215
      • Washington University, St. Louis
  • Nevada
    • Las Vegas, Nevada, United States, 891060100
      • Cleveland Clinic Lou Ruvo Center for Brain Health
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Buffalo, New York, United States, 142261727
      • Dent Neurologic Institute
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 100166055
      • New York University Medical Center
    • New York, New York, United States, 100296552
      • Mount Sinai School of Medicine
    • Orangeburg, New York, United States, 109621159
      • Nathan Kline Institute for Psychiatric Research
    • Rochester, New York, United States, 14620
      • University of Rochester
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Beachwood, Ohio, United States, 441224312
      • Case Western Reserve University
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 972393011
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
    • Providence, Rhode Island, United States, 02906
      • Butler Hospital Memory and Aging Program
  • South Carolina
    • Charleston, South Carolina, United States, 29401
      • Ralph H. Johnson VA Health Care System
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas, Southwestern MC at Dallas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Houston Methodist
  • Wisconsin
    • Madison, Wisconsin, United States, 537920001
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Cognitively normal (CN), mild cognitive impairment (MCI), and mild AD dementia participants.

Description

Inclusion Criteria (all CN participants):

1. Participant with or without subjective memory complaints, verified by a study partner, beyond what one would expect for age

2. Normal memory function documented by scoring above education 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
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)
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 at least 4 weeks:

   1. Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms 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 (all MCI participants):

1. Participant must express a subjective memory concern as reported by participant, or recalled by study partner or clinician.

2. Abnormal memory function documented by scoring below education 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):

   a. < 11 for 16 or more years of education b. ≤ 9 for 8-15 years of education c. ≤ 6 for 0-7 years of education

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)
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 Alzheimer's disease cannot be made by the site physician at the time of the Screening Visit

6. Stability of Permitted Medications for at least 4 weeks:

   1. Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
   2. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit
   3. Estrogen replacement therapy is permissible
   4. Gingko biloba is permissible, but discouraged
   5. 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 (all AD participants):

1. Participant must express a subjective memory concern as reported by participant, or recalled by study partner or clinician.n.

2. Abnormal memory function documented by scoring below education 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. ≤ 8 for 16 or more years of education
   2. ≤ 4 for 8-15 years of education
   3. ≤ 2 for 0-7 years of education
3. Mini-Mental State Exam score between 20 and 26 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
4. Clinical Dementia Rating = 0.5 or 1.0
5. NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) -ADRDA (Alzheimer's Disease and Related Disorders Association) criteria for probable AD

6. Stability of Permitted Medications for at least 4 weeks:

   1. Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
   2. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit
   3. Estrogen replacement therapy is permissible
   4. Gingko biloba is permissible, but discouraged
   5. 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 Specific to Newly Enrolled Participants

1. Geriatric Depression Scale score less than 6.
2. Age between 55-90 years (inclusive).
3. Study partner who has frequent contact with the participant (i.e., minimum average of 10 hours per week) and is available to accompany the participant to all clinic visits for the duration of the protocol.
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. Modified Hachinski Ischemic Score less than or equal to 4.
9. Completed six grades of education or has a good work history (sufficient to exclude mental retardation).
10. Must speak English or Spanish fluently.
11. Willing to undergo repeated MRIs (3Tesla) and at least two PET scans
12. Agrees to collection of blood for genomic analysis (including GWAS (genome-wide association study) sequencing and other analysis), APOE (Apolipoprotein E) testing and biospecimen banking.
13. Agrees to collection of blood for biomarker testing.
14. Agrees to at least one lumbar puncture for the collection of CSF.
15. Agrees to share genomic data and biomarker samples. Inclusion Criteria Specific to Rollover Participants"

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

1. Must have been enrolled and followed in ADNI-1, ADNI-GO, or ADNI-2 for at least one year.
2. Willing and able to continue to participate in an ongoing longitudinal study. A reduced battery of tests is allowable if the participant is not able/willing to complete the full battery.

Exclusion Criteria (all CN participants):

1. Any significant neurologic disease, such as Parkinson's disease, multi-infarct 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 deficits or known structural brain abnormalities

Exclusion Criteria (all MCI participants):

1. Any significant neurologic disease other than suspected incipient Alzheimer's disease, such as Parkinson's disease, multi-infarct 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 deficits or known structural brain abnormalities.

Exclusion Criteria (all AD participants):

1. Any significant neurologic disease other than Alzheimer's disease, such as Parkinson's disease, multi-infarct 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 deficits or known structural brain abnormalities.

Exclusion Criteria (all participants):

The following additional exclusion criteria apply to all diagnostic categories:

1. Screening/Baseline MRI brain scan with evidence of infection, infarction, or other focal lesions or multiple lacunes or lacunes in a critical memory structure
2. Subjects that have any contraindications for MRI studies, including the presence of cardiac pacemakers, or metal fragments or foreign objects in the eyes, skin or body.
3. Major depression, bipolar disorder as described in DSM-IV within the past 1 year. Psychotic features, agitation or behavioral problems within the last 3 months that could lead to difficulty complying with the protocol.
4. Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder.
5. History of schizophrenia (DSM IV criteria).
6. History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
7. Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol.
8. Clinically significant abnormalities in B12 or thyroid function tests (TFTs) 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.
9. Residence in a skilled nursing facility.
10. Current use of specific psychoactive medications (e.g., certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics). Current use of warfarin or other anticoagulants such as dabigatran, rivaroxaban and apixaban (exclusionary for lumbar puncture).
11. Current use of any other exclusionary medications
12. Investigational agents are prohibited one month prior to entry and for the duration of the trial.
13. Participation in clinical studies involving neuropsychological measures being collected more than one time per year.

Exclusion Criteria Specific to AV-1451 PET:

The following criteria are exclusionary only for the AV-1451 scanning portion of the study:

1. History of risk factors for torsades de pointes (a cardiac dysrhythmia associated with sudden death) or taking medications known to prolong the QT interval. A list of restricted medications will be provided.
2. Have an ECG obtained prior to the AV-1451 PET scan that in the opinion of the investigator is clinically significant with regard to the subject's participation in the study. Bazett's corrected QT (QTcB) interval must be evaluated and must not exceed 458 msec in males, or 474 msec in females.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Cognitively Normal (CN); 135-500 newly enrolled participants with no apparent memory problems, and 295-300 cognitively normal participants followed from the ADNI2 study. Currently recruiting non-Caucasian participants only for the normal cognition group.
Mild Cognitive Impairment (MCI); 150 - 515 newly enrolled participants with mild cognitive impairment (MCI), and 275-320 MCI participants followed from the ADNI2 study.
Mild Alzheimer's Disease (AD) dementia; 85 - 185 newly enrolled participants with mild Alzheimer's disease (AD) dementia, and 130 - 150 mild AD participants followed from the ADNI2 study.

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)	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.	5 years
Rate of change in cognition as measured by the Logical Memory Test I and II		5 years
Rate of change in cognition as measured by the Mini-Mental State Examinations (MMSE)	The MMSE scale evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two overlapping pentagons.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of change in cognition as measured by the Cogstate Brief Battery (CBB)	The Cogstate Brief battery (CBB) is a brief (10-15 minute) computerized cognitive battery developed by Cogstate (Cogstate Ltd. New Haven, CT, USA) that measures attention, speed of information processing, working memory and learning.	5 years
Rate of change in cognition as measured by the American National Adult Reading Test (ANART)	The ANART estimates premorbid verbal intelligence (VIQ) in patients with dementia.	5 years
Rate of change in cognition as measured by the Montreal Cognitive Assessment (MoCA)	The Montreal Cognitive Assessment test (MoCA) is a cognitive assessment designed to detect participants at the MCI stage of cognitive dysfunction.	5 years
Rate of change in cognition as measured by the Rey Auditory Verbal Learning Test	The AVLT is a list-learning task, which assesses multiple cognitive parameters associated with learning and memory.	5 years
Rate of change in cognition as measured by the Trail Making Test: A and B		5 years
Change in tau deposition as measured by 18F-AV-1451		5 years
Change in amyloid deposition as measured by Florbetapir		5 years
Change in amyloid deposition as measured by Florbetaben		5 years
Rate of conversion to MCI or dementia due to AD		5 years
Rates of change of glucose metabolism (FDG-PET)		5 years
Change in Cerebral Spinal Fluid (CSF) Tau Biomarkers		5 years
Change in brain structure using magnetic resonance imaging (MRI)		5 years

Collaborators and Investigators

• Sponsor: University of Southern California
• Collaborators: National Institute on Aging (NIA); Northern California Institute of Research and Education; Alzheimer's Therapeutic Research Institute
• Investigators: Principal Investigator: Paul Aisen, MD, USC Alzheimer's Therapeutic Research Institute (ATRI); Study Director: Michael W. Weiner, MD, University of California, San Francisco; Principal Investigator: Ronald Peterson, MD, PHD, Mayo Clinic

Publications and helpful links

General Publications

• Rauchmann BS, Schneider-Axmann T, Perneczky R; Alzheimer's Disease Neuroimaging Initiative (ADNI). Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Abeta-PET and cognition. J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1289-1295. doi: 10.1136/jnnp-2020-325537. Epub 2021 Jun 29.
• Bullich S, Roe-Vellve N, Marquie M, Landau SM, Barthel H, Villemagne VL, Sanabria A, Tartari JP, Sotolongo-Grau O, Dore V, Koglin N, Muller A, Perrotin A, Jovalekic A, De Santi S, Tarraga L, Stephens AW, Rowe CC, Sabri O, Seibyl JP, Boada M. Early detection of amyloid load using 18F-florbetaben PET. Alzheimers Res Ther. 2021 Mar 27;13(1):67. doi: 10.1186/s13195-021-00807-6.
• Miller AA, Sharp ES, Wang S, Zhao Y, Mecca AP, van Dyck CH, O'Dell RS; Alzheimer's Disease Neuroimaging Initiative (ADNI). Self-reported hearing loss is associated with faster cognitive and functional decline but not diagnostic conversion in the ADNI cohort. Alzheimers Dement. 2024 Nov;20(11):7847-7858. doi: 10.1002/alz.14252. Epub 2024 Sep 26.
• Howe MD, Caruso MR, Manoochehri M, Kunicki ZJ, Emrani S, Rudolph JL, Huey ED, Salloway SP, Oh H; Alzheimer's Disease Neuroimaging Initiative. Utility of cerebrovascular imaging biomarkers to detect cerebral amyloidosis. Alzheimers Dement. 2024 Oct;20(10):7220-7231. doi: 10.1002/alz.14207. Epub 2024 Sep 1.
• Howe MD, Caruso MR, Manoochehri M, Kunicki ZJ, Emrani S, Rudolph JL, Huey ED, Salloway SP, Oh H; Alzheimer's Disease Neuroimaging Initiative. Utility of cerebrovascular imaging biomarkers to detect cerebral amyloidosis. medRxiv [Preprint]. 2024 May 28:2024.05.28.24308056. doi: 10.1101/2024.05.28.24308056.

Helpful Links

• List of Alzheimer's Disease Neuroimaging Initiative Publications
• Alzheimer's Therapeutic Research Institute
• Alzheimer's Disease Neuroimaging Initiative
• Laboratory of Neuro Imaging (LONI)
• Brain Health Registry (BHR)

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2016
• Primary Completion (Actual): May 28, 2024
• Study Completion (Actual): May 28, 2024

Study Registration Dates

• First Submitted: July 27, 2016
• First Submitted That Met QC Criteria: August 2, 2016
• First Posted (Estimated): August 3, 2016

Study Record Updates

• Last Update Posted (Actual): March 11, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: dementia; amyloid; plaques; neuroimaging; biomarkers; cognition disorder; early detection; pre-dementia; Alzheimer's disease; tau
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathological Conditions, Anatomical; Neurocognitive Disorders; Tauopathies; Neurodegenerative Diseases; Frontotemporal Lobar Degeneration; Frontotemporal Dementia; Pathological Conditions, Signs and Symptoms; Cognitive Dysfunction; Alzheimer Disease; Dementia; Pick Disease of the Brain; Plaque, Amyloid; Cognition Disorders
• Other Study ID Numbers: ATRI-001; U01AG024904 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES