Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3) Protocol

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.

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 24 inclusive (Exceptions for scores of 24
and 25 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.