The complex molecular events that underlie the development of Alzheimer’s disease (AD) are poorly understood and are the key to developing targeted therapies. Our group and others have shown that rare variants in the triggering receptor expressed on myeloid cells 2 gene (TREM2) are associated with increased susceptibility to AD. TREM2 encodes a membrane protein that is part of a receptor-signaling complex that modulates inflammatory responses, phagocytosis and cell survival in myeloid cells, such as microglia. However, the specific role of TREM2 in AD pathogenesis remains unclear. CSF sTREM2 levels are increased in patients with symptomatic AD compared to cognitively normal controls. We have recently discovered that common variants in the MS4A locus are a major regulator of CSF sTREM2 levels. Importantly, the same allele associated with higher CSF sTREM2 levels is associated lower AD risk and delayed age at onset. We also identified a second, independent signal in the MS4A locus that encodes MS4A4A p.M159V, which has the opposite effect on CSF sTREM2 levels and AD risk. Our findings that two independent signals in the MS4A gene region have opposing effects on CSF sTREM2 levels and AD risk points to the connection between MS4A and TREM2 biology in AD pathogenesis. The goal of this project is to elucidate the mechanisms by which MS4A genes alter TREM2 function and drive AD pathogenesis. We hypothesize that MS4A4A is involved in TREM2 trafficking and cleavage and that disrupted interaction between MS4A4A and TREM2 leads to microglial dysfunction and neurodegeneration. To test this hypothesis, we will use genomic and biochemical approaches in human brains and stem cell models. The results of this project will provide the mechanistic framework needed to develop treatments that restore or enhance TREM2 functions in order to prevent neurodegenerative disease.