Microglia, the primary immune cells and the sensor of the brain’s health, play a pivotal role in the maintenance of brain homeostasis, but lose their functions during the course of aging and neurodegenerative diseases. There is a gap in our knowledge about how microglial function is maintained in a healthy brain and is prone to dysregulation in an Alzheimer’s disease brain. We previously discovered a new role of Apolipoprotein E (APOE) in the microglial phenotype switch during neurodegeneration. However, there is a lack of understanding in how human APOE allele variants, specifically APOE4 allele, regulate microglia in AD. APOE4 is the major genetic risk factor for sporadic late-onset AD, with women being more affected than men. The functional mechanisms underlying the genetic association of APOE4 with AD remain elusive. Our preliminary data demonstrate a negative role of the APOE4 allele in regulating microglia response to neurodegeneration by employing novel tools, including new mouse models and techniques to specifically target APOE in microglia. These findings provide new directions to target APOE4 signaling to restore microglial functions in AD. This follow-on proposal is to understand the role of human APOE variants in neurodegeneration in microglia as well as peripheral immune cells, including neutrophils and monocytes, and to validate our findings in a human AD cohort with different APOE alleles.