Alzheimer’s disease (AD) and associated dementia caused by neurological impairment have become an increasing health burden. Exercise has been shown in animal models and human clinical studies to be neuroprotective in AD. The mechanisms by which exercise protects the brain should be diverse and complex. Particularly, exercise increases a hormone called FNDC5 (fibronectin-domain III containing 5) and its secreted form, irisin. In our studies, we found that irisin treatment decreased the level of amyloid beta (Aβ) peptide, a protein that causes AD, in our three-dimensional (3D) cell culture systems by increasing an Aβ-degrading enzyme called neprilysin. We also found that irisin is responsible for the beneficial effects of exercise on cognitive function, and that injection of irisin was able to improve cognitive deficits and neuropathology in AD transgenic mice. Our findings suggest that irisin could be considered and developed as a therapeutic target for AD.