APOE4 is the strongest identified genetic risk factor for late-onset Alzheimer’s disease. Strong evidence from Abeta-deposition mouse models and humans indicate that APOE4 influences the metabolism of Abeta within the brain, which promotes Abeta plaque pathology. The precise mechanism(s) by which APOE isoforms influence Abeta are not completely clear, although numerous in vivo and in vitro studies suggest that APOE4 slows the clearance of Abeta from the brain and facilitates the aggregation of monomeric Abeta. There are a variety of other effects that APOE may have in the both the normal brain as well as in the setting of AD and other neurological diseases. Studies on the effects of APOE4 on amyloid pathology in mouse models have relied on targeted replacement mice, where exons 2-4 of murine APOE were replaced with exons 2-4 of human APOE isoforms and a neomycin selection cassette. Recently, Cure Alzheimer’s Fund supported the generation of new human APOE targeted replacement mice containing floxed alleles to support the study of cell-type specific roles for human APOE or temporal control of APOE expression. These next-generation human APOE replacement mice will accelerate research into the mechanism by which APOE4 influences the onset and progression of AD, and APOE2 is protective.