Alzheimer's disease (AD) is one of the leading causes of death in United States, suggesting the lack of therapies to prevent the progression of the disease. Continuous increase in the mortality rate due to AD indicates the urgent need for new drug discovery and further establishing the need for novel molecular targets for therapeutic potential. Many reports verify direct pathological links between AD and diabetes, which highlights the contribution of diabetes to the development of AD. Thiazolidinediones (TZDs) are insulin sensitizing peroxisomal proliferator activating receptor gamma (PPAR?) agonists, have been recognized as promising agents for memory in patients with AD. However the exact signaling mechanism remains relatively unknown. Although currently available PPAR? agonists show promise for improving memory deficits in AD, poor blood brain barrier permeability results in inadequate bio-availability in the brain requiring high dosing with chronic time frames that are associated with increased incidences of myocardial infarction. The innovation of our proposed research is based on the development of novel selective PPAR? modulators with high blood brain barrier permeability. These selective PPAR? modulators are used as tools to better understand how central PPAR? activation alters synaptic plasticity and cognition in animal models of AD without the deleterious side effects on the heart. We have identified a novel signaling mechanism in which PPAR? transcriptionally regulates an increase in expression of the neurotrophin BDNF, which is known to induce synaptogenesis and improve memory consolidation. Although our preliminary data in which our lead compound improves memory deficits and increases post synaptic receptor expression is in a diabetic type 2 (db/db) mouse model will extend these findings into a 3xTg-Ad mouse model in the current proposal. Our central hypothesis will test that our lead compound improves cognitive deficits and pathologies associated from Alzheimer's disease better than current TZDs in a 3x Tg-AD mouse with the following aims: (compound 9) 1. To compare the beneficial effects of compound 9 to Pio on improving memory deficits and synaptic plasticity in the 3xTg-AD mouse. 2. To evaluate possible mechanisms for how compound 9 rescues cognitive deficits and pathologies vs Pio. We expect that further evaluation of these compounds will lead to increased knowledge base for identifying molecular targets that will ameliorate memory deficits associated with AD. Findings from this study will advance the knowledge base and beneficial mechanistic insights into PPAR? modes of action against AD.