Summary Abstract (30 lines): Existing cerebrospinal fluid (CSF) and neuroimaging measures of amyloid ß, tau and neurodegeneration (A,T,N) serve as useful diagnostic biomarkers for Alzheimer’s disease (AD), however there remains an urgent, unmet need for blood based biomarkers in AD. First, multi-omic studies discovered many perturbed biological pathways in AD, however, systematic studies for biomarkers that capture these diverse biological facets of AD are limited. Second, AD is a heterogeneous disorder but biomarkers that can distinguish the biological subtypes of AD are lacking. Third, core AD neuropathology often co-exists with other neuropathologies such as vascular disease (V). These co-morbidities and co-pathologies need to be considered in biomarker discovery. Fourth, existing biomarker studies are heavily focused on non-Hispanic Whites (NHW). Similar studies in underrepresented populations (URP) are needed. This U19, bringing together >40 experts across 13 institutions, aims to bridge these knowledge gaps for discovery and validation of Centrally-linked Longitudinal pEripheral biomARkers of AD (CLEAR-AD) in multi-ethnic populations. CLEAR-AD U19 is based on the premise that AD is a complex disorder in which many biological pathways are disrupted due to multi-omic perturbations, which can be detected in brain and reflected in blood, i.e. centrally-linked peripheral molecular signatures (CLPMS). The specific aims of CLEAR-AD U19 are: 1) To discover CLPMS of the complex and heterogeneous AD pathophysiology and its co-pathologies. 2) To identify longitudinal CLPMS that detect and predict dynamic neuroimaging, fluid biomarker, and clinical changes across AD spectrum. 3) To characterize differences and similarities in CLPMS profiles across NHW, African American (AA) and Latino American (LA) participants to uncover biomarker patterns in multi-ethnic groups. 4) To make these vast resources available to the scientific community to amplify and accelerate its impact. In this U19 managed by the Administrative Core, we will leverage NIH-funded ADNI, MCSA and ADRC cohorts of >3,700 multi-ethnic participants to generate >20,000 multi-omics measures (Omics Core) that will be processed and integrated with >48,000 harmonized AD cognitive, neuroimaging and fluid endophenotypes (Analytic Core). Using these data, we will identify brain region and cell-type specific CLPMS, which reflect biological subtypes of AD and disease stage (Project 1). We will discover longitudinal changes in CLPMS that predict cognitive and A/T/N/V progression (Project 2). We will define longitudinal cognitive and A/T/N/V changes and CLPMS in URP that are either conserved with NHW or population-specific (Project 3). This U19 will a) Identify the next generation of AD biomarkers with mechanistic insights; b) Establish a precision medicine approach for rigorous multi-omics biomarker discovery and validation in AD; c) Discover molecules that can serve as biomarkers and therapeutic targets...