(300 WORDS MAX.)Alzheimer's disease (AD) is typified by accumulation of amyloid peptides within the brain that is associated with impaired -Amyloid (Aβ) clearance. We now know the greatest genetic risk factor for AD is possession of one form of the gene for Apolipoprotein E (APOE), owing to its association with impaired clearance from the brain. It is now known that ApoE plays a critical role in the clearance of Aβ from the brain through its ability to promote the proteolytic degradation of Aβ peptides. APOE expression is controlled by two related receptor pairs in the nucleus of glial cells, PPAR:RXR and LXR:RXR. Drugs that bind to RXR activates both receptor pairs resulting in the synergistic stimulation of APOE expression. We reasoned that activation of RXR would increase brain ApoE levels and promote A clearance. We demonstrate that oral administration of the FDA-approved RXR activator, bexarotene (TargretinTM) to murine models of AD results in the very rapid reduction in small, soluble forms of Aβ.. We observed the rapid loss of >60% of preexisting amyloid plaques that was accompanied by complete reversal of the impairment of cognition and memory and restoration of cortical neural network function. This proposal requests support for a randomized, placebo-controlled clinical study to evaluate the effect of bexarotene on Aβ and apoE kinetics of 12 healthy subjects. This study will be conducted through a collaboration with C2N Diagnostics and will employ proprietary stable isotope labeling kinetic (SILK) technology together with C2N's method of absolute peptide/protein quantification (SISAQ) to measure the synthesis and clearance rate of amyloid peptides and apoE in the cerebrospinal fluid (CSF). The primary endpoint of the study will be quantitation of Aβ clearance from the CSF. Secondary endpoints are measurements of ApoE biosynthesis. This study will establish if bexarotene acts in humans to regulate important AD biomarkers.