Thiazolidinedione drugs were originally developed for the treatment of type 2 diabetes because they increase insulin action and appear to protect the pancreatic beta cells from dying. These compounds, such as Actos (also called piolgitazone) and Avandia (also called rosiglitazone) also have antiinflammatory actions in preclinical animals and in man. There are data indicating that even though rosiglitazone circulates at low levels and is not able to enter the brain at significant levels, it still is able to reduce amyloid in transgenic mice and may have some efficacy in AD patients. Both pioglitazone and rosiglitazone can activate a nuclear receptor called PPARgamma. This results in several side effects, including expansion of plasma volume that can lead to edema and in some cases may cause congestive heart failure. It is generally believed that compounds with this "insulin sensitizing" and anti-inflammatory activity also exert their good effects through this same receptor. We at Metabolic Solutions Development Company were involved in the original development of pioglitazone and understand that new therapeutic agents can be constructed that are good anti-diabetic and anti-inflammatory compounds without activating this nuclear receptor. In fact, the primary action of these compounds is through a direct effect on the mitochondria that can result in increased numbers of mitochondria. We are currently evaluating our lead compound in phase II clinical trials for the treatment of type II diabetes. The funding of this proposal would help us to test the concept that this lead compound will have the potential to treat AD. This research will also allow us to test whether our new analogs designed to gain greater access to the brain have the potential to have greater benefit. These studies will pave the way for the testing of our clinical lead compound and/or newer analogs in AD patients.