Research in our laboratory focuses on dementia (Alzheimer's disease & frontotemporal dementia) and addiction (alcohol dependence). In each of these projects our goal is to understand the molecular basis of disease in order to identify novel targets for therapeutic development. We use genetic and genomic approaches to identify susceptibility alleles, this work includes integration of multiple levels of OMICs data with genetic data from genome wide association studies and whole genome/exome sequencing in families multiply affected by disease and in case control cohorts. Through these studies we have demonstrated an enrichment of AD risk variants in microglial enhancers. Interestingly variants within the SPI1 (PU.1) locus, a gene which regulates myeloid cell differentiation, influence risk for AD and for alcoholism, demonstrating the importance of neuroimmune communication in both disorders. We are currently pursuing these observations in cell and animal models with the goal of developing PU.1 inhibitors for treatment of AD. In combination with our genetic studies we use induced pluripotent stem cells in vitro and in vivo to study the mechanisms of risk underlying the AD risk genes. To date we have performed functional studies of APOE, SPI1 and MS4A4A/6A in induced microglia. We also have an extensive program studying the functional consequences of MAPT mutations and haplotypes in tauopathies such as PSP and FTD, using iPSC-derived neurons and organoids.