ABSTRACT Alzheimer disease (AD) is the leading cause of age-related dementia, affecting over 5 million people in the United States alone. Unfortunately, current therapies are largely palliative and several promising drug candidates have failed in late-stage clinical trials. Hence, there is an urgent need to improve our understanding of the mechanisms that drive the development and progression of AD. As the primary innate immune cell of the brain, microglia have been implicated in the pathogenesis of AD for several decades. But precisely how microglia contribute to AD and the degree to which this changes with disease duration remains unclear. Recent genetic studies have uncovered several AD risk genes that are highly expressed in microglia. By studying these genes in induced pluripotent stem cell (iPSC)-derived human microglia, we and others aim to advance our understanding of both the normal and disease-associated functions of these AD risk genes. One recently discovered mutation occurs in the microglia-enriched gene PLCG2 (Phospholipase C Gamma 2) and codes for a protective allele associated with a reduced chance of developing AD. This mutation is particularly interesting as PLCG2 encodes a transmembrane signaling enzyme that plays a critical role in calcium signaling. Calcium signaling is in turn central to nearly every facet of microglial function including phagocytosis, directed migration, inflammasome activation, and induction of two master regulators of immune gene transcription; NFAT and NfkB. We therefore propose to use CRISPR gene editing to produce isogenic iPSCs that express the AD protective mutation in PLCG2. We will then differentiate these cells into microglia and examine the impact of PLCG2 manipulations on microglial gene expression, calcium signaling and function. By combining CRISPR gene editing, microglial differentiation, and a novel chimeric model of AD we aim to overcome several critical barriers to microglial research and determine the impact of PLCG2 mutations on human microglial gene expression and function both in vitro and in vivo. !