Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3)

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):

3. 9 for 16 or more years of education

4. 5 for 8-15 years of education

5. 3 for 0-7 years of education

6. 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)

7. Clinical Dementia Rating = 0. Memory Box score must be 0

8. Cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living

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

10. 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)

11. Estrogen replacement therapy is permissible

12. Gingko biloba is permissible, but discouraged

13. 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:

7. 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)

8. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit

9. Estrogen replacement therapy is permissible

10. Gingko biloba is permissible, but discouraged

11. 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):

3. ≤ 8 for 16 or more years of education

4. ≤ 4 for 8-15 years of education

5. ≤ 2 for 0-7 years of education

6. 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)

7. Clinical Dementia Rating = 0.5 or 1.0

8. NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) -ADRDA (Alzheimer's Disease and Related Disorders Association) criteria for probable AD

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

10. 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)

11. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit

12. Estrogen replacement therapy is permissible

13. Gingko biloba is permissible, but discouraged

14. 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.