Physical Exercise as Disease-Modifying Alternative against Alzheimer’s Disease: A Gut–Muscle–Brain Partnership

Alzheimer’s disease (AD) is a common cause of dementia characterized by neurodegenerative dysregulations, cognitive impairments, and neuropsychiatric symptoms. Physical exercise (PE) has emerged as a powerful tool for reducing chronic inflammation, improving overall health, and preventing cognitive decline. The connection between the immune system, gut microbiota (GM), and neuroinflammation highlights the role of the gut–brain axis in maintaining brain health and preventing neurodegenerative diseases. Neglected so far, PE has beneficial effects on microbial composition and diversity, thus providing the potential to alleviate neurological symptoms. There is bidirectional communication between the gut and muscle, with GM diversity modulation and short-chain fatty acid (SCFA) production affecting muscle metabolism and preservation, and muscle activity/exercise in turn inducing significant changes in GM composition, functionality, diversity, and SCFA production. This gut–muscle and muscle–gut interplay can then modulate cognition. For instance, irisin, an exercise-induced myokine, promotes neuroplasticity and cognitive function through BDNF signaling. Irisin and muscle-generated BDNF may mediate the positive effects of physical activity against some aspects of AD pathophysiology through the interaction of exercise with the gut microbial ecosystem, neural plasticity, anti-inflammatory signaling pathways, and neurogenesis. Understanding gut–muscle–brain interconnections hold promise for developing strategies to promote brain health, fight age-associated cognitive decline, and improve muscle health and longevity.