Longitudinal Early-onset Alzheimer's Disease Study Protocol

Inclusion Criteria for Cognitively Impaired (EOAD and EOnonAD) 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 at least 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 or Spanish if enrolled in the U.S. 9. Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to site's spoken language(s). Inclusion Criteria for 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 or Spanish if enrolled in the U.S. 10. Fluent in English, Spanish, Dutch or Swedish for sites outside the U.S., according to site's spoken language(s). Exclusion Criteria for all (EOAD, EOnonAD 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, MAPT, GRN and C9ORF72 have been excluded 3. Known CLIA certified mutation in an ADAD gene (APP, PSEN1, PSEN2), or other autosomal dominant genes associated with other neurodegenerative disorders (MAPT, GRN, C9ORF72) 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. Research 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 for research-related purposes, 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. (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/ml 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 18. Deemed ineligible by the Site PI for any other reason