ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disease with no cure that affects >50 millions of people worldwide. Emerging evidence supports that accumulation of damaged/dysfunctional mitochondria in the central nervous system is an early, central pathology. Reactive oxygen species (ROS) produced by dysfunctional mitochondria cause oxidative damages to proteins, lipids and DNA and exacerbate the key pathologies of amyloid-β (Aβ) accumulation and hyperphosphorylation of Tau protein in a vicious cycle. In stark contrast, endurance exercise (i.e., running) or resistance exercise (i.e., weightlifting) have significant preventive and therapeutic impacts on AD. However, the underlying mechanisms are poorly understood. AMP-dependent protein kinase (AMPK), a master energy sensor, has emerged as a promising regulator underlying the superb benefits of exercise. AMPK is primarily expressed in neurons in the hippocampus, and its activity is reduced in animal models of AD. Importantly, endurance exercise restores AMPK activity with reduced Aβ deposition along with restored spatial learning and memory. A promising but untested mechanism is exercise-induced mitophagy, a selective degradation of damaged/dysfunctional mitochondria under the control of AMPK and its downstream unc-51-like autophagy activating kinase (Ulk1), resulting in improved mitochondrial quality. We hypothesize that endurance and/or resistance exercise promotes AMPK-Ulk1 activation and mitophagy, hence removing damaged/dysfunctional mitochondria in adult hippocampal neurons and preventing neurodegeneration and cognitive decline in AD. To test this hypothesis, we propose: 1. To determine whether AMPK-Ulk1 activation is required for exercise-mediated protection against AD. 2. To ascertain whether AMPK activation is sufficient to protect against AD. The proposed studies are hypothesis-driven and supported by previously published and preliminary findings with strong scientific premises. We have also developed unique exercise and genetic models along with mitochondrial reporter mice to address the importance and regulation of exercise-induced mitophagy against AD. The findings will pave the way for developing effective therapeutics targeting AMPK and mitophagy for AD.