Abstract The Mexican-American (MA) Hispanic community is the most rapidly growing minority and is disproportionately affected by Alzheimer’s disease and related dementias (ADRDs). Nonetheless, the prevalence, predictors, biology and clinical course of dementia, and the care needs of this population remain understudied. The Clinical Core (CC) of the South Texas Alzheimer Center (STAC) will establish a new culturally, socioeconomically, and geographically diverse cohort in this underserved region. Recruitment will be done at 3 core sites (San Antonio, Laredo and Harlingen, TX) using identical protocols. The CC will collect all the prescribed Uniform Dataset (UDS) data and collaborate with the Imaging (IC), Biomarker (BC), Genetics and Multiomics (GMC) and Neuropathological (NPC) cores to establish the brain morphology (ADNI3 protocol MRI, amyloid and tau PET), biomarker (blood, CSF, sensory-motor), genomic (clinical tests, APOE, GWAS, WGS) and pathological correlates of clinical syndromes to advance our understanding of the heterogeneous pathophysiological processes underlying ADRDs, especially in MA, using precision medicine approaches. In partnership with the Population Neuroscience Core (PNC), the CC will define risk and resilience factors for dementia by examining the impact of vascular, lifestyle, medical comorbidities, environment, culture, and social determinants (UDS+ data) on the transition from normal cognitive aging to dementia. In addition, the CC will create a trial-ready caregiver registry, examine a caregiver sample (same tests as patients except for PET and LP), and will study the interactional effect of the patient/caregiver dyad on disease course, care needs, and health outcomes. The CC will annually enroll 140 individuals with MCI or dementia and 60 cognitively normal controls; >50% will be of MA ancestry and at least 30% from underserved areas to establish a diverse longitudinal clinical cohort of ~700- 800 persons by year 4 (Aim 1a). The CC will also recruit all care partners of individuals in the clinical cohort into the caregiver registry and intensively study all willing caregivers, ~45/year from dyad and ~20 who provide care to ADRD patients who may be too advanced to enroll (Aim 1b). Within these cohorts, the CC will assess the prevalence of novel and established ADRD biomarkers of pathology, risk, and resilience with disease course and prognosis (Aim 2a). The CC will provide comprehensive care throughout illness, enabling deep longitudinal phenotyping and annual collection of biospecimens (BC, NPC), assessing serial change in imaging (IC), and clinicopathological correlations at autopsy (NPC). The approach will promote engagement (OREC), education (REC), and clinical trials for all disease stages (Aim 2b). The CC will also genetically characterize the cohort (Aim 3) and identify biomarkers for biological characterization of Suspected Non-Alzheimer Pathology (SNAP, A-/N+) in persons with and without diabetes (Aim 4). The D...