Predicting Pre-dementia in Older Adults

Inclusion Criteria: Age Age 55 years or older at enrollment. APOE Genotype Documented carrier of at least one APOE ε4 allele, based on prior testing (e.g., clinical APOE testing, prior genetic panel, research cohort genotyping, or direct-to-consumer testing). Existing Genomic Data for PRS Whole-genome sequencing (WGS) data already completed, with willingness to provide existing WGS data files (e.g., VCF, FASTQ, or equivalent) to the study team for Alzheimer's disease polygenic risk score (PRS) calculation; or If WGS is not available, prior high-density or targeted genotyping array data covering Alzheimer's disease risk loci, with willingness to provide these data for PRS calculation (feasibility of array-based PRS will be evaluated case-by-case). Note: The study does not perform APOE genotyping or WGS as part of the research; these must be completed before enrollment. Cognitive Status at Baseline Cognitively normal or very mildly impaired at baseline, defined by: Digital cognitive assessment and/or Punto Test consistent with a Global Clinical Dementia Rating (CDR) of 0 or 0.5. No clinical diagnosis of dementia. For cognitively normal (CN) and subjective cognitive decline (SCD) participants, staging by the Progression and Risk (P\&R) model (combining PRS, biomarker, and cognitive data) will be applied for risk stratification. Absence of Baseline AD-MCI by Biomarkers Does not currently qualify for Alzheimer's disease-related MCI (AD-MCI), operationalized as no evidence of MCI with plasma or CSF pTau217 level above a validated cutoff for AD-MCI pathology. Capacity and Participation Ability Able to provide informed consent (with capacity assessments and, where applicable, involvement of a legally authorized representative per institutional policy and IRB approval). Able and willing to comply with study procedures, including clinic visits, cognitive testing, and biospecimen collection. Willingness to Use Digital Monitoring Tools Willing to wear and/or carry digital devices for continuous or frequent monitoring (e.g., smartphone app, wearable sensors such as Oura Ring, sleep device), and to participate in app-based cognitive and speech assessments. Data-Sharing Authorizations Willingness to sign data release authorizations allowing the study to obtain existing genomic data (WGS or array) and relevant electronic medical record (EMR) data needed for risk modeling and outcome adjudication. Exclusion Criteria: Baseline Dementia Diagnosis Clinical diagnosis of dementia of any cause at baseline. Major Neurological Disorders Affecting Cognition History of major neurological conditions that in the investigator's judgment may confound cognitive assessment or outcomes, such as: Parkinson's disease. Stroke with residual neurological deficits. Epilepsy with frequent seizures. Major Psychiatric Illness Major psychiatric disorders that significantly interfere with participation or data interpretability, such as uncontrolled major depressive disorder or schizophrenia, as judged by the investigator. Serious or Unstable Medical Conditions Uncontrolled systemic medical illness expected to limit life expectancy to less than approximately 3 years, including but not limited to unstable cardiac, hepatic, or renal disease. Recent Investigational or Disease-Modifying AD Treatments Use of investigational drugs or disease-modifying Alzheimer's therapies within 6 months prior to baseline, if such treatments are likely to confound biomarker trajectories or cognitive outcomes. Inability or Unwillingness to Use Required Digital Tools Lack of Required Genomic Documentation or Refusal to Share Data No prior APOE genotype documenting at least one ε4 allele; or No available WGS or suitable genotyping array data; or Refusal to share existing APOE/genomic data and necessary EMR data with the study team. Baseline MCI with Positive pTau217 Vulnerable Populations Not Targeted Children, prisoners, and pregnant individuals are not specifically targeted and will be excluded from enrollment.