The principle objective of this application is the development of safer and more effective combinatorial therapy for AD. ReXceptor, Inc. is developing new therapeutics for the treatment of AD based on stimulating the physiological clearance mechanisms of soluble forms of A from the brain. Bexarotene is an agonist of the ligand-activated transcription factor, retinoid X receptor (RXR), and stimulates the transcription of ApoE and its lipid transporters, leading to elevated levels of high density lipoproteins (HDL) i the brain. ApoE-based HDLs act to promote the proteolysis of A peptides, resulting in restoration of normal neural network function and improved memory and cognition. Bexarotene is an FDA approved drug for the treatment of cutaneous T-cell lymphoma with a favorable safety profile. However, oral administration of bexarotene is associated with hypertriglyceridemia and hypercholesterolemia. Thus, minimizing the side effects associated with cardiovascular risk is of importance in the use of this drug for the treatment of AD. We propose to use the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), in conjunction with bexarotene to decrease plasma dyslipidemia in a mouse model of AD. DHA acts to suppress plasma triglyceride levels. Importantly, DHA is an endogenous ligand for RXR and stimulates the transcription of RXR target genes within the brain. Indeed, dietary supplementation with DHA ameliorates AD pathogenesis in mouse models of AD. The primary objective of this proposal is to identify a combinatorial therapy based on the therapeutic effects of bexarotene and DHA in AD models. This approach is anticipated to allow the reduction in bexarotene dosage and total drug exposure. We believe that this is an innovative approach to provide a more effective therapeutic and provide ReXceptor with commercially viable product. The specific aims of this proposal are: 1: To determine the dose dependency of bexarotene, DHA, and the combination, on LXR and PPAR?-target genes and plasma lipid levels in a mouse model of Alzheimer's disease; and, 2: To ascertain the therapeutic effect of combinatorial treatment of bexarotene and DHA on A levels and behavior in a mouse model of AD.