SUMMARY Despite a higher prevalence of Alzheimer’s disease (AD) among African Americans (AA) and Latino Americans (LA) compared to non-Hispanic whites (NHW), these populations remain underrepresented in AD biomedical research, particularly in biomarker studies and clinical trials. The overarching goal of Project 3 of this U19 is to leverage existing “trial-ready” AA and LA cohorts with longitudinal blood collections, clinical, neuroimaging and cognitive data in order to identify centrally-linked peripheral molecular signatures (CLPMS) that may serve as novel blood biomarkers that will improve diagnosis and the development of treatments in these underserved and understudied populations. Based on preliminary data from our group and others, we hypothesize that genetic variation, transcriptomic and epigenetic changes predisposing to dementia risk in AA and LA will reveal novel mechanisms associated with disease, as well as similarities with those identified in NHW. Project 3 will leverage existing AA and LA samples and data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, 66 AA 59 LA) and five Alzheimer’s Disease research Centers (ADRCs, 564 AA, 219 LA): Mayo Clinic, Indiana, 1Florida, Michigan and Knight ADRCs, plus an additional 300 AA and LA projected participants from these ADRC. Data from a sixth ADRC (Emory) collected from another 300 AA participants will also be incorporated. This project aims to: (1) identify blood multi-omic CLPMS in AA and LA that will improve AD diagnosis by effectively discriminating, with high specificity and sensitivity, between individuals clinically diagnosed with AD and who have amyloid, tau, neurodegeneration and vascular endophenotype changes characteristic of AD based on neuroimaging/CSF/plasma biomarker data, versus those who do not have these endophenotype changes characteristic of AD; (2) identify blood CLPMS that can predict the development, and that track with progression of AD, by analyzing longitudinal blood multi-omics data-matched to clinical, neuroimaging, neuropsychometric data from cognitively unimpaired, mild cognitive impairment and AD patients; (3) identify blood CLPMS that are specific to these populations, based on genetic variants, transcripts or epigenetic changes that may impact the development of AD, differentially in AA and LA vs. those of NHW ancestry (by comparison to findings from Project 2); (4) to determine if these blood CLPMS exhibit similar patterns in the brain (by comparison to findings from Project 1); (5) to determine novel pathways, genes and genetic variants involved in AD by using results from these multi-omics signatures identified in this project. Using a 3-tiered approach to analyze our findings and Roadmap to Translation to prioritize them, we expect to identify CLPMS in AA and LA in a comparative fashion with NHWs and will enhance knowledge on biomarker research, thus enabling precision medicine in these underrepresented populations. These studies will integrate...