Abstract/Summary Progress in understanding Alzheimer’s disease and related disorders (ADRD) is close to producing more effective treatments, creating an urgent need for disease-predictive biomarkers to guide their use. Using cerebrospinal fluid (CSF) measurements of beta-amyloid and Tau and positron-emission tomography tracers, we can detect AD pathology in cognitively normal individuals. However, current tools do not allow us to predict when or even if an individual with asymptomatic pathology will develop symptoms. To address this need, we propose to longitudinally study ≥3000 cognitively normal individuals (50-75 years at enrollment) in the Emory Healthy Brain Study to define the frequency of asymptomatic AD and rates of cognitive decline in a racially diverse cohort of healthy individuals (Specific Aim 1). An important goal of Aim 1 is to achieve ≥33% African- American participants to provide sufficient power to address questions regarding race- and sex-dependent differences in biomarkers and risk of cognitive decline. Participants will be phenotyped biennially with cognitive testing, cardiovascular physiology, brain MRI, and blood and CSF collection. Cross-sectional (Specific Aim 2) and longitudinal analyses (Specific Aim 3) will test the hypothesis that biomarkers of synaptic, vascular, myelination, glial immunity, and metabolic functions will identify subgroups who are at greatest risk of progressing to symptomatic AD. Candidate biomarkers will be identified through state-of-the-art proteomics, MR imaging, and statistical methods. A highly collaborative data and biospecimen sharing plan will allow other investigators to leverage these resources to advance a broad spectrum of ADRD research.