PROJECT SUMMARY (APOE U19 Core F: Multi-Omics Core) This Multi-Omics Core (Core F) aims to develop and apply state-of-the-art proteomics, metabolomics and lipidomics technologies to investigate the mechanisms of APOE genotype on Alzheimer’s disease (AD) risk at the molecular, cellular and pathogenic levels. Given the dysfunction of complex and synergistic pathways contributes to AD heterogeneity, identifying clinically relevant molecules (DNAs, RNAs, proteins, metabolites and lipids) is essential to predict, diagnose, treat, and prevent AD. As such, this Core seeks to develop and apply technologies based on mass spectrometry (MS), coupled with transcriptome studies, to uncover proteomic, metabolomic, and lipidomic changes. Omics assessments will be made directly using human tissues and biofluids, human organoids, mouse and cell models, as well as isolated cellular compartments and protein complexes linked to AD in an apoE isoform-dependent manner. To achieve this goal, we have assembled a strong multidisciplinary team with established and renowned investigators in proteomics (Peng), metabolomics (Peng) and lipidomics (Han), both having extensive expertise in studying neurodegeneration. The Core will apply the latest proteomics, metabolomics and lipidomics strategies across U19 components, specifically Projects 2, 3, and 4, and Cores B, C, D, E, and G; the Core will also further advance these technologies to address unmet needs of the apoE research community in the following aims: (i) develop and apply a nanoscale, 27- plex MS-based platform for analyzing apoE-related proteome, protein modifications and protein interactome; (ii) develop and apply untargeted and targeted metabolomics technologies with evaluation of false discovery rate for analyzing apoE-affected metabolome; (iii) develop and apply the lipidomics technologies to serve the apoE research community; and (iv) apply multi-omics approaches to define the effects by APOE genotype, sex, and disease status. In summary, this Core will develop and provide the cutting edge MS-based multi-omics approaches for discovering novel, crucial apoE-related molecules/ networks during aging and AD pathogenesis in this U19 application.