Carriers of the APOE4 gene are at significantly increased risk for developing Alzheimer’s disease. We have shown that aging mice that express the APOE4 gene have increased activity in a region of the brain that is implicated in the development of Alzheimer’s disease, and we believe this increased activity may be an important link between APOE4 and Alzheimer’s disease pathology. In order to understand why this increased activity occurs, we will perform a series of experiments. In addition, we will study the effect of this APOE4-linked brain activity on the spread of tau, an important protein whose accumulation and spread in the brain plays a vital role in Alzheimer’s disease. We anticipate that the results of this study will yield significant insights into the biology of APOE4 and Alzheimer’s disease, as well as how Alzheimer’s disease may be treated or prevented in these individuals.