The impact of exercise on brain mitochondrial health and its relevance to Alzheimer's disease

• Mitochondrial dysfunction is a pathological hallmark of Alzheimer’s Disease (AD). • Mitochondrial dysfunction in AD is associated with loss of mitochondrial quality control processes. • Exercise has been shown to modulate mitochondrial quality control processes in the brain. • Exercise could benefit AD as a preventative measure, but more research is required to fully understand mechanisms of exercise on mitochondrial function. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Mounting evidence implicates mitochondrial dysfunction as an upstream driver of AD pathogenesis, contributing to bioenergetic deficits, oxidative stress, impaired calcium homeostasis, and chronic neuroinflammation. Given the high energy demand of the brain, the preservation of mitochondrial function is critical for neuronal health. Physical exercise is recognized for its neuroprotective effects, with growing support that it may attenuate AD progression through enhancing mitochondrial quality control. This review explores how exercise influences key mitochondrial quality control processes in the brain—including mitochondrial-biogenesis, -dynamics, and mitophagy—and how these adaptations counteract AD-related pathologies. We further examine the dual role of reactive oxygen species, the impact of exercise-induced signaling molecules such as brain-derived neurotropic factor, irisin, and insulin-like growth factor 1, and the importance of cardiorespiratory fitness in fostering mitochondrial resilience. Finally, we highlight critical gaps in our understanding of how different exercise modalities uniquely affect brain mitochondria and AD pathology. Collectively, this underscores the potential of exercise as a non-pharmacological strategy to enhance brain mitochondrial health and promote cognitive resilience in aging and AD.