The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer’s disease (AD). APOE4increases risk and APOE2 decreases risk. The Holtzman lab found that in addition to the effect of APOE on amyloid beta, APOE exacerbates tau pathology and tau-mediated brain damage. Tau-dependent neurodegeneration is accompanied by a strong inflammatory response in the brain. Further, buildup of post-translationally modified forms of tau, neurodegeneration and inflammation are exacerbated by the presence of APOE in the order E4>E3>E2, with the absence of APOE being very neuroprotective. The regional progression of brain injury in AD highly correlates with tau accumulation but not amyloid deposition, and the underlying mechanisms of tau-mediated neurodegeneration are not entirely clear. Certain cells in the brain called microglia are part of what is termed the brain’s innate immune system, and we have found that these cells are required for tau-mediated neurodegeneration. However, there are other types of immune cells in the brain, and their role in APOE and tau-mediated neurodegeneration is not clear. We recently compared all of the immune cells in the brain in models of amyloid beta deposition (APP/PS1) without nerve cell loss, as well as in a mouse model of tau accumulation in which there is marked neuronal loss (P301S). We found that P301S mice, but not APP/PS1 mice, develop a more severe inflammatory response in the brain with both distinct and more activated microglia and infiltrated T-cells (part of the adaptive immune system). T-cells were markedly increased in areas with tau pathology in P301S mice and in the AD brain. Of note, T-cells consistently correlated with the extent of neuronal loss, and T-cells dynamically transformed their cellular characteristics in the P301S brain with greater changes in the presence of APOE4. We also found that T-cells are required for the brain injury in the P301S mice. Based on these data, we hypothesize that APOE plays an important role in facilitating the ability of specific types of T-cells to become activated, and contribute to tau-mediated neurodegeneration. This hypothesis will be tested in a series of experiments in animal models and in collaboration with other members of the APOE consortium.