Longitudinal Early-onset Alzheimer's Disease Study Protocol

The LEADS study is a non-randomized, natural history, non-treatment study. Enrolled
participants must be 40 - 64 (inclusive) years of age, with MCI due to AD or probable AD
dementia (EOAD / EO-nonAD), or have no significant memory impairment (CN).

Approximately 500 participants with cognitive impairment (EOAD / EO-nonAD) and 100 CN
participants will be enrolled at approximately 15 sites in the United States. Cognitively
impaired participants will take part in the study for 24 months; CN participants will take
part in the study for 12 months.

Participants will undergo longitudinal clinical and cognitive assessments, computerized
cognitive batteries, biomarker and genetic tests, PET (amyloid and tau) and MRI brain scans,
and cerebrospinal fluid (CSF) collection.

The primary objectives of the LEADS study are to:

- collect longitudinal assessments and biomarker data in individuals with early onset
cognitive impairment (EOAD / EO-nonAD) and cognitively normal (CN) controls;

- to compare baseline and longitudinal cognitive and functional characteristics, between
EOAD and CN, and EOAD and Late Onset Alzheimer's Disease (LOAD) from the Alzheimer's
Disease Neuroimaging Initiative (ADNI); and

- to study the associations of longitudinal clinical and cognitive assessments with
multimodal imaging and biofluid markers that capture different elements of the AD
pathophysiological cascade

Inclusion Criteria (Cognitively Impaired (EOAD and EO-nonAD) Cohorts Only):

1. Meets NIA-AA criteria for MCI due to AD or probable AD dementia

2. Have a global CDR score ≤ 1.0

3. Have capacity to provide informed consent (IC) or has a legal authorized
representative or guardian who provides IC

4. Age between 40-64 years (inclusive) at the time of consent

5. Must have a study partner (informant) who spends a minimum average of 10 hours per
week with the participant (e.g., family member, significant other, friend, caregiver)
who is generally aware of the participants' daily activities and can provide
information about the participant's cognitive and functional performance. If the
participant does not have a study partner who spends 10 face-to-face hours per week,
other arrangements for identifying a viable study partner will be granted on a
case-by-case basis by the Site PI

6. Willing and able to complete longitudinal study procedures aside from LP which is an
optional procedure

7. Not pregnant or lactating. Women must be two years post-menopausal, be surgically
sterile, or have a negative pregnancy test prior to each PET scan

8. Fluent in English

Inclusion Criteria (Cognitively Normal (CN) Cohort Only):

1. Meets criteria for cognitively normal, based on an absence of significant impairment
in cognitive functions or activities of daily living

2. Have a global CDR score = 0

3. Have capacity to provide informed consent

4. Have a Mini-Mental State Exam score between 26-30 (inclusive). Exceptions may be made
for participant with less than 8 years of education at the discretion of the Site PI

5. Age between 40-64 years (inclusive) at the time of consent

6. Must have a study partner (informant) who spends a minimum average of 10 hours per
week with the participant (e.g., family member, significant other, friend, caregiver)
who is generally aware of the participants' daily activities and can provide
information about the participant's cognitive and functional performance. If the
participant does not have a study partner who spends 10 face-to-face hours per week,
other arrangements for identifying a viable study partner will be granted on a
case-by-case basis by the Site PI

7. Willing and able to complete longitudinal study procedures aside from LP which is an
optional procedure

8. Not pregnant or lactating. Women must be two years post-menopausal, be surgically
sterile, or have a negative pregnancy test prior to each PET scan

9. Fluent in English

Exclusion Criteria (All (EOAD, EO-nonAD and CN) Cohorts):

1. Meets core clinical criteria for non-AD dementia

2. Two or more first degree relatives with a history of early-onset dementia suggestive
of autosomal dominant transmission, unless known pathogenic mutations in APP, PSEN1,
PSEN2 have been excluded

3. Known mutation in an ADAD gene (APP, PSEN1, PSEN2) or other autosomal dominant genes
associated with other neurodegenerative disorders

4. Contraindications to 3T MRI (e.g., claustrophobia, pacemaker, select aneurismal clip,
artificial heart valve, select ear implants, select stents incompatible with 3T MRI,
metal fragments or foreign objects in the eyes, skin or body, etc.)

5. Lifetime medical history of a brain disorder other than the disorder causing dementia
except for headache (exceptions are allowed at the discretion of the Site PI - e.g.,
seizure disorder thought to be due to EOAD).

6. MRI scan with evidence of infection or focal lesions, cortical strokes, multiple
lacunes (single lacune is allowable unless it meets criteria for strategic lacune
affecting cognition)

7. Any significant systemic illness or unstable medical condition, which could lead to
difficulty complying with the protocol (at the discretion of the Site PI)

8. Medical radiation exposure will be assessed by the study physician. If the candidate
participant has had more than one nuclear medicine study in the prior 12 months, study
inclusion will require approval from the PET Core

9. Investigational agents are prohibited 30 days prior to entry

10. Previous enrollment in a therapeutic trial targeting amyloid or tau

11. Participation in other clinical studies with neuropsychological measures, with the
exception of participants who are co-enrolled in the NACC Uniform Data Set (UDS)
protocol (Note: This criterion is intended to reduce repeat measures effects during
neuropsychological testing. Exceptions are allowed at the discretion of the Site PI)

12. Lifetime history of schizophrenia spectrum disorders (DSM-5 criteria)

13. Current history (in previous 12 months) of DSM-5 diagnosis of mania, bipolar disorder
with or without psychotic features

14. Current history (in previous 6 months) of moderate or severe substance abuse (nicotine
or caffeine is allowed)

15. Suicidal behaviors in the past 12 months or active suicidal ideations

16. Residing in a 24-hour care skilled nursing facility (at the time of screening)

17. History of torsades de pointes or taking medications known to prolong the QT interval

18. Corrected QT (QTc) interval ≥ 458 msec in males or ≥ 474 msec in females

19. (For optional lumbar puncture procedure only):

a. Clinical laboratory values must be within normal limits or, if abnormal, must be
judged to be not clinically significant by the Site PI i. Platelet count <100,000/µl
ii. INR>1.2 iii. Abnormal PT or PTT at screening b. Contraindications to the
procedure, including but not limited to severe degenerative joint disease, deformity
of the spine, history of a bleeding disorder c. Suspected elevated intracranial
pressure, Arnold Chiari malformation or mass lesion d. Use of the anticoagulant
medications such as but not limited to warfarin, rivaroxaban, dabigatran

20. Deemed ineligible by the Site PI for any other reason