Based on what is known about the genetics and pathology of Alzheimer's disease (AD), our research focuses on the interaction between two proteins within the brain called apolipoprotein E (apoE) and amyloid-beta peptide (Aβ). There are three naturally occurring forms of apoE: apoE2, apoE3 and apoE4. Individuals that possess apoE4 have up to a 15-fold greater risk of developing AD. Aggregates of Aβplaques, are a requisite hallmark of AD, and apoE levels are thought to modulate the levels and neurotoxicity of Aβ. However there is much debate on whether to raise or lower apoE levels as an AD therapeutic approach. Recently, Bexarotene (BEX), an anti-cancer drug, was demonstrated to increase mouse-apoE levels and reduce Aβ levels in a mouse model of AD. However, experimental evidence suggests that increasing human-apoE4 will increase Aβ levels, thus actually increasing AD pathology. Despite this major contraindication, BEX is entering clinical trials for treating AD patients. Thus, it is imperative that the effects of BEX on the human forms of apoE are tested, specifically apoE4. Thus, the purpose of this proposal is to evaluate the effects of BEX in a new AD mouse model that specifically human apoE2, E3, or E4 and over-express human Aβ, the EFAD mice. The EFAD mice are a tractable model, with significant Aβ accumulation occurring between 2 and 6 months, mirroring human pathology but at an accelerated rate that allows for efficient evaluation of both drug prevention and treatment paradigms.