The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer disease. APOE4 increases risk and APOE2 decreases risk. The Holtzman lab recently found that, in addition to the effect of APOE on amyloid beta, APOE exacerbates tau pathology and tau-mediated brain damage. We have preliminary data that APOE produced by a particular cell type in the brain called astrocytes is intervening APOE4-mediated brain injury. One goal of the current grant is to better characterize how APOE4 derived from astroctyes is leading to tau-mediated brain injury via another glial cell type called microglia. Recently, we have found that specific types of lipids and cholesterol accumulate in microglial cells in the presence of APOE4 and tau pathology. We think this lipid accumulation may be detrimental to the brain. A second goal of this grant is to better characterize these APOE4-mediated changes in lipids and cholesterol as well as to determine whether decreasing this lipid/cholesterol accumulation will ameliorate tau-mediated brain injury.