Project Summary The impaired glycemic control associated with pre-diabetes increases risk for type 2 diabetes, which is a known risk factor for Alzheimer’s Disease (AD). Mechanisms such as impaired energy metabolism, cellular bioenergetic function, reduced intracellular protein homeostasis (proteostasis), and inflammation are all potential contributors to AD etiology. Therefore, a novel therapy that simultaneously improves glycemic control and cellular chaperone systems (i.e. Heat Shock Proteins, HSPs) may prove particularly effective in preventing and treating AD. Heat therapy has been independently shown to improve blood glucose regulation, insulin resistance, and inflammation. Importantly, heat therapy also activates inter-organ crosstalk via endocytic vesicles and increases HSPs to improve both mitochondrial function and proteostasis in a variety of tissues. Given the potential contribution of these factors to brain health, heat therapy could offer immense clinical benefit to individuals at risk for AD. Here, we will determine if heat therapy can improve blood (Aim 1) and brain (Aim 2) glucose metabolism in cognitively healthy older adults (65+) who are at risk for AD. We will also examine the degree to which changes in blood and brain glucose metabolism track together and explore several additional potential mechanisms that are critical to understanding the brain benefits of heat therapy (Aim 3). These aims will provide a comprehensive understanding of the impact of heat therapy on glucose homeostasis and brain health.