Project Summary Carriers of the apolipoprotein E (APOE) ε4 gene are at a significantly increased risk of developing Alzheimer’s disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear. Our own research has uncovered novel effects of APOE4 expression on important processes in the brain, including neuronal activity, the endosomal-lysosomal system and bioenergetic regulation. However, substantial questions remain about these effects of APOE4 expression. Most importantly, it is unclear what effects these and other APOE4-associated pathway deficits have on the development of the hallmark pathologies that are observed in the brains of AD patients. In order to answer this question effectively, the AD field requires new mouse models that more faithfully replicate both the genetics and the pathology of AD patients. As a first step in that direction, we are proposing to generate and characterize a novel mouse model that expresses either the APOE2, APOE3 or APOE4, alongside KI versions of a pro-aggregating humanized mutant APP gene and a human MAPT gene. These APOE/hAPP/hTau mice will be aged and characterized using both traditional experiments, such as immunohistochemistry (IHC) and behavior, as well as cutting-edge structural and functional MRI (sfMRI)-based techniques. We anticipate that the full study proposed herein will result in the creation of a valuable new AD mouse model and that the characterization studies will elucidate the effects of differential APOE isoform expression on the development of AD pathology and the behavioral changes they induce. In total, this study will be an important breakthrough in our quest to understand how APOE isoform differences affect an individual’s susceptibility to AD, potentially leading to new therapeutic strategies for AD, especially among APOE4 carriers.