Alzheimer’s disease and associated dementia caused by neurological impairment have become an increasing health burden. Exercise has been shown in animal models and clinical studies in humans to be neuroprotective in AD. The mechanisms by which exercise protects the brain are diverse and complex. We found that exercise increases a hormone called fibronectin-domain III containing 5 (FNDC5) and its secreted form, irisin. In our pilot studies, we also found that irisin reduces amyloid beta pathology and cell loss in our cell culture system. This research will test the hypothesis that the novel exercise hormone irisin is neuroprotective in AD; we already have been testing our hypothesis in our cell culture and animal models of AD. Our study will provide a potential promising way to generate novel therapeutic targets for AD.