We propose to further develop small molecule partial inhibitors of mitochondrial complex I (MCI) as a disease-modifying therapy for AD.  This strategy targets neuronal metabolic dysfunction, the earliest pathophysiological change in AD patients, which is discernible decades before the deposition of amyloid beta plaques or phospho-Tau tangles and the onset of dementia.  We have demonstrated that the tricyclic pyrone compound CP2 and proprietary analogues developed using rational design selectively and mildly inhibit the activity of MCI. New compounds are allowed and protected by a patent. Our compounds enhance the efficiency of the electron transport chain and resistance to oxidative stress in vitro and in vivo.  We have confirmed these effects in a range of systems (primary mouse neurons, multiple mouse models of familial AD, wild-type mice fed with a high fat diet, mitochondria isolated from mouse and human brain, human lymphocytes and fibroblasts), supporting the high transnational potential of this approach.  Our compounds are orally bioavailable, centrally penetrant, and appear to be safe and well-tolerated in multiple mouse models of AD. Treatment was efficacious in both pre- and symptomatic AD mice. Results in presymptomatic AD mice have been published.