PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) and other forms of dementia are rapidly increasing with the aging of the population, and show a clear preponderance among people with insulin resistance. Metformin, an insulin sensitizer, is being examined in clinical trials as an anti-aging drug. However, very little objective data is available regarding metformin's effect on the brain, a major organ affected by aging. Insulin receptors are widely distributed in the brain and their disruption causes neuronal dysfunction and AD like changes. Pre-clinical studies suggest that metformin ameliorates many AD-related changes and stimulate mitochondrial biogenesis. However, observational human studies among type 2 diabetics (T2D) show either conflicting or equivocal results which could be related to other co-morbidities. Metformin is a drug with a long track-record showing an excellent safety profile among elderly people with insulin resistance. We therefore submit the current exploratory/developmental research proposal to investigate whether metformin enhances brain mitochondrial function (ATP production) by nuclear Magnetic Spectroscopy (NMRS) and blood flow and the functional network by functional MRI (fMRI) of different regions of brain, especially those rich in insulin receptors. As a secondary measurement, we will measure structural changes in the white and grey matter areas of the brain by MRI. Cognitive function will be assessed by utilizing the computerized NIH Toolbox. This 40 week placebo controlled double-blind human study will randomize 40 elderly people >65 years with abdominal adiposity and impaired fasting glucose to either metformin or placebo intervention. This project represents a new direction for the PI and is a collaborative effort with colleagues at the Mayo Clinic with expertise in MRI, NMRS, and AD. The study results may lead to a breakthrough in providing either definitive data or sufficiently strong preliminary data regarding metformin's effect on elderly people with insulin resistance, on whether the drug enhances their brain mitochondrial function in conjunction with improvement of brain functional network and cognitive functions. The proposed research is the essential step needed to pursue a larger grant application involving the use of metformin as an adjutant to other established life style changes with beneficial effects on the brain.