The long-term goal of this project is to define dysfunctional molecular networks underlying the pathogenesis of Lewy body Dementia (LBD) disease, and the synergistic interaction of amyloid-beta and alpha-synuclein, primarily by omics-based systems biology approaches, focusing on proteomics and lipidomics using cutting- edge mass spectrometry (MS) in Project 2. LBD is the second most common cause of progressive dementia and shares characteristics with Alzheimer's disease (AD) and Parkinson's disease (PD). It is characterized by the manifestation of Lewy body (alpha-synuclein) pathology and amyloid plaques (amyloid-beta) in the brain. Clinically, LBD is associated with dementia, psychosis, and features of PD. Identifying clinically relevant molecules (DNAs, RNAs, proteins, or metabolites) is essential to predict, diagnose, treat, and prevent LBD. Complementary to the genome and transcriptome profiling in Project 1, Project 2 seeks to fully characterize the whole proteome, aggregated proteome, posttranslational modifications, and lipidome directly from well- characterized LBD and control brain specimens with different pathologies (provided by Core B). To achieve this goal, we have assembled a strong multidisciplinary team with established and renowned investigators in proteomics (Peng) and lipidomics (Han), both also having extensive expertise in studying neurodegeneration including analyzing human brain tissues. We will focus on three specific aims: (i) to identify aberrant protein networks in LBD with different pathologies by profiling the whole proteome; (ii) to integrate multiple-tier proteomics approaches to define LBD by profiling aggregated proteome, phosphoproteome and ubiquitinome; and (iii) to determine LBD pathways by lipidomics profiling. The acquired omics data will provide a rich resource for hypothesis-driven research, and will be integrated for generating a precise molecular signature shared in LBD cases, categorizing possible LBD subtypes, revealing key molecular dysfunction, especially linking the interaction of amyloid-beta and alpha-synuclein.