Genome-wide association meta-analysis studies (GWAS) have identified more than 200 genes in strong correlation with Alzheimer’s disease (AD), most of which are expressed in brain immune cells (microglia). However, the intrinsic role of AD risk genes in the regulation of microglia phenotype and functions is unknown. We recently reported that APOE4, the strongest AD risk gene, plays a negative role in regulation of microglial response to neurodegeneration in AD mice and humans. We also identified a similar effect in microglia expressing another AD risk gene, INPP5D, to induce a response to neurodegeneration, which was restored following the genetic deletion of INPP5D or APOE4. Microglial deletion of APOE4 or INPP5D harnessed astrocytes to encapsulate amyloid beta plaques associated with reduced pathology and neurodegeneration in mice. We hypothesize that multiple GWAS-identified AD risk factors expressed in microglia impair MGnD-astrocyte crosstalk, promoting the initiation and progression of the disease. Therefore, identifying AD genetic risk factors that impair microglia-astrocyte functional interactions has a translational potential as a therapeutic intervention for AD. In collaboration with Dr. Rudolph Tanzi, we obtained an updated list of the more than 200 identified GWAS hits, and we have prioritized 122 AD risk factors based on mouse and human orthologues and druggability, which will be investigated using microglia-specific genetic perturbations in AD mice. Utilizing our newly developed approach to genetically perturb multiple microglia clones in the same brain, each perturbed for a single gene deletion, we will be able to identify regulators of inflammatory microglial states. The top ten microglial risk genes whose deletion boosts or suppresses the MGnD signature in AD mice will be validated as a single gene perturbation using the platform that we have established. This project will have considerable impact on advancing both basic science and microglia-based therapeutic interventions for AD.