Multiomic and Functional Characterization of sTREM2 Modifiers

Alzheimer’s disease (AD) is the most common neurodegenerative disease, but currently, there is no effective means of prevention or treatment. Characterization of genes implicated in disease pathogenesis increases our mechanistic understanding of the pathways involved, thereby leading to the identification of novel biomarkers and druggable targets. One of the most relevant genes implicated in AD is TREM2, but the downstream pathways dysregulated by TREM2 risk variants are still unknown. Our team has integrated genetics and proteomic data to identify additional genes (TGFBR2 and NECTIN2) that are part of the TREM2 pathway. In this proposal, we will leverage high-throughput, unbiased multi-tissue (brain, CSF and plasma) proteomics and metabolomics data to identify what proteins, metabolites and pathways are dysregulated due to the expression of TREM2 risk variants. We will also use novel cell models (induced microglia cells) to determine the mechanism by which those new genes influence TREM2 biology.