Since 1993, apolipoprotein E (apoE) has been recognized to play a key role in the pathogenesis of Alzheimer's disease (AD). ApoE is the major cholesterol carrier in the brain and the only validated genetic risk factor for late-onset AD. Exactly how apoE participates in the development of AD neuropathology is not entirely understood, and putative roles in the deposition and clearance of amyloid plaques have been proposed. Previous work from our laboratory has identified ATP-binding cassette transporter A1 (ABCA1) as a key regulator of apoE levels in the brain and have demonstrated that ABCA1-mediated transfer of lipids to apoE is a critical parameter in determining amyloid burden in vivo. These studies have provided an important advance in our understanding of apoE function in AD and have identified ABCA1 as an important factor known to regulate apoE lipidation in vivo. LXR agonists have shown efficacy in APP23 and Tg2576 models of AD for both reducing Ab levels and protecting against cognitive deficits. Expression array data also suggests a role for LXR agonists in reducing neuroinflammation. Female APP/PS1 mice with and without ABCA1 will be administered GW3965 starting at 16 weeks and 32 weeks of age until sacrifice at 40 weeks. At monthly intervals plasma Ab and lipids and body weight are measured. CSF, plasma, fixed and frozen brain tissue, liver are collected at sacrifice. Cognitive analysis including the Morris water maze and novel object recognition will be assessed. Neuropathology at 40 weeks will assess Protein lysates and Thio-T Histology. We have initiated studies using the LXR agonist GW3965 to reduce both behavioural and neuropathological phenotypes in APP/PS1 mice with and without ABCA1 using both prophylactic and therapeutic approaches. Final behavior assessment is due for completion by May 2008. This work may lead to a clearer understanding of the role of cholesterol transporters in AD, and highlight them as potential therapeutic targets.