PROJECT SUMMARY Alzheimer’s disease (AD) is characterized by progressive cognitive dysfunction and widespread neuronal loss, accumulation of amyloid b plaques and aggregation of hyperphosphorylated tau into neurofribrillary tangles. There has been extensive interest in the use of antioxidants to treat AD and other neurodegenerative pathologies. Normal brains are replete with glucose and ascorbate, both of which are sources of advanced glycation end-products (AGE) via autooxidation in the presence of redox metal-ion catalysts. AGE levels and carboxymethyl lysine, a predominant AGE modification, are increased in the brain of AD patients. AGEs modify and crosslink proteins and AGEs were identified in both plaques and tangles of AD brains. Indeed, glycation has the potential to be a driving influence in formation of both plaques and tangles. Furthermore, AGEs induce toxic effects with formation of reactive oxygen species through interaction with AGE receptors (RAGE), which are increased in AD brains. Preventing AGE formation therefore represents a rational approach for the treatment of AD. There is increasing recognition that there are similarities between the progression of neurodegeneration in AD and diabetes with AGE formation being one suspected common causative factor. In our current Phase II grant, we are comprehensively testing the in vivo efficacy of our lead compound, a proprietary atypical antioxidant that inhibits redox metal-ion catalysis of oxidation, against diabetic peripheral neuropathy using rodent models of type 1 and type 2 diabetes. In this supplement, we will use two different animal models of AD to explore the therapeutic potential of our lead compound. This application offers a propitious and synergistic opportunity to extend the investigation of our most potent lead compound to non-diabetic AD models.