Diabetes and insulin resistance are known risk factors for Alzheimer's disease (AD). PPAR-gamma agonists (e.g., Troglitazone, Rosiglitazone, and Pioglitazone) have been examined as insulin sensitizers for the treatment of diabetes, and for the treatment of AD, but have adverse side effect profiles. MSDC (Dr. Jerry Colca) received ADDF funding to examine a new type of insulin sensitizer (Mitoglitazone) on change in biochemical, cognitive, and FDG-PET metabolism in a phase II study of non-diabetic AD patients. Twelve weeks of Mitoglitazone was associated with increased high molecular weight (HMW) adiponectin (p<0.0001) and decreased high sensitivity C-reactive protein (p=0.067). Importantly, in comparison to the placebo group, brain metabolism via FDG-PET was improved in regions associated with AD (e.g., parietal and temporal lobes and the posterior cingulate/precuneus region) suggesting a central effect on insulin sensitivity which might prove to be disease modifying. The beneficial effects of Mitoglitazone could be through enhanced mitochondrial functioning, but additional research is needed to understand the underlying mechanisms. In other research, Dr. Mielke has also received ADDF and NIH funding and has found that high blood ceramides are associated with risk of AD among cognitively normal individuals, cognitively decline and hippocampal volume loss among patients with mild cognitive impairment, cognitive decline in AD patients. In pathology-confirmed AD patients, plasma ceramides were also higher. Notably, ceramides can lead to mitochondrial dysfunction and are thought to play a critical role in insulin resistance. The aim of this proposal is to merge these two lines of ADDF-funded research to measure plasma ceramides and amino acids at baseline and 12 weeks to determine whether Mitoglitazone modifies ceramide levels. This information will help to better understand the mechanisms by which Mitoglitazone may be associated with FDG metabolism in AD patients.