The identification of the association of the TREM2 p.R47H varienat with Alzheimer's disease (AD) risk highlighted the impact of the immune response and inflammation in (AD). However, the role of TREM2 in health and in AD as well as what other genes are part of the TREM2 pathway are not totally known. We have demonstrated that soluble TREM2 (sTREM2) levels may reflect biological events that link amyloid deposition and neurofibrillary tangle formation to cognitive decline, and that can be used to genetic studies. Using CSF sTREM2 levels as endophenotype we demonstrated that MS4A4A is the major regular of sTREM2 and a potential target. In a more recent study in almost 3,000 CSF samples, we identified four loci, including MS4A4A, TREM2, TGFBR2 and NECTIN2. In this proposal, we will perform the first multi-tissue genetic screening of sTREM2 regulators. We will analyze very large datasets in brain (n=5,164), CSF (n=6,800) and plasma (n=56,900) from well-characterized cohorts with extensive pre-existing CSF biomarker (Aβ, Tau, ptau and sTREM2), clinical and genetic data. The aims of the project are: 1) to identify single (common and rare) variants, genes and pathways associated with sTREM2 levels; 2) to identify multi-tissue multi-omic signatures of TREM2 risk variants and 3) to perform functional analyses in iPSC-derived human microglia to determine the mechanisms by which TGFBR2 and NECTIN2 affect sTREM2 levels and microglia function.