Alzheimer's Disease Neuroimaging Initiative 4

Alzheimer's Disease Neuroimaging Initiative 4 (ADNI4)

The Alzheimer's Disease Neuroimaging Initiative 4 (ADNI4) is a non-randomized, longitudinal, natural history study designed to validate biomarkers, improve clinical trial design, and advance understanding of Alzheimer's disease across the full disease spectrum. Building on the success of ADNI1, ADNI-GO, ADNI2, and ADNI3, ADNI4 integrates clinical, cognitive, imaging, genetic, and fluid biomarker data to characterize disease progression and predict cognitive decline.

ADNI4 includes both in-clinic and remote cohorts and a small complementary sub-cohort, Together Exploring Aging Minds (TEAM-ADNI), which evaluates community-based recruitment and longitudinal data collection approaches.

Since its launch in 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been a landmark public-private partnership focused on developing and validating biomarkers for Alzheimer's disease (AD) and improving clinical trial design. ADNI4 continues the previously funded ADNI1, ADNI-GO, ADNI2, and ADNI3 studies and integrates clinical, cognitive, imaging, genetic, and biochemical biomarker data to characterize the full spectrum of Alzheimer's disease, from normal cognition through dementia.

The ADNI4 study is a multi-center, non-randomized, longitudinal, natural history, non-treatment study. Approximately 1,500 participants will be enrolled across three cohorts: cognitively normal (CN), mild cognitive impairment (MCI), and dementia (DEM). Participants between the ages of 55 and 90 years will be enrolled at sites across the United States and Canada. Approximately 750 participants will be newly enrolled into ADNI4, and approximately 750 participants will be rollover participants continuing from prior ADNI studies. Clinical, cognitive, imaging, biomarker, and genetic characteristics will be assessed longitudinally across the three cohorts.

Participants enrolled in ADNI4 will undergo longitudinal clinical and cognitive assessments, computerized cognitive batteries, biomarker and genetic testing, positron emission tomography (PET) imaging for amyloid and tau, magnetic resonance imaging (MRI), and collection of cerebrospinal fluid (CSF) for up to five years.

ADNI4 incorporates both in-clinic and remote approaches, including web-based cognitive assessments and blood-based biomarkers, to support scalable identification and longitudinal monitoring of individuals across the disease continuum and to inform future clinical trial design.

ADNI4 also includes the Together Exploring Aging Minds (TEAM-ADNI) cohort, a small complementary sub-cohort that evaluates community-based recruitment and flexible approaches to participant identification, enrollment, and longitudinal data collection.

Across cohorts, ADNI4 aims to validate imaging and fluid biomarkers, improve clinical trial design, characterize longitudinal cognitive and biomarker changes, and identify predictors of disease progression.

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

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.