Exercise as a multidomain intervention in aging and Alzheimer’s disease: State of the evidence

Alzheimer’s disease is a multifactorial and aging-related neurodegenerative disorder characterized by progressive cognitive decline driven by amyloid-β accumulation, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Despite decades of pharmacological efforts, effective disease-modifying therapies remain elusive, positioning physical exercise as a promising multidomain intervention capable of addressing aging-related phenotypes and multiple pathophysiological layers simultaneously. In this narrative review, we investigate the molecular, cellular, and systemic mechanisms by which physical exercise exerts neuroprotective effects in aging and Alzheimer’s disease. The reviewed evidence highlights that exercise enhances hippocampal neurogenesis and synaptic plasticity via brain-derived neurotrophic factor upregulation, promotes myokine-mediated signaling (e.g., irisin and insulin growth factor-1), mitigates oxidative and inflammatory cascades, and modulates microRNA networks and transposable element activity linked to genomic stability and brain plasticity. Preclinical data consistently demonstrate that both voluntary and forced exercise paradigms attenuate amyloid and tau pathology and improve cognition in transgenic mouse models, whereas clinical trials confirm cognitive and functional benefits primarily in prevention and early intervention contexts. The convergence of aerobic and resistance training emerges as the most effective approach, acting through complementary vascular, metabolic, and anabolic pathways. Collectively, this review integrates molecular and translational insights to propose that regular, multimodal exercise—beyond cardiovascular health—constitutes a potent and accessible neuroprotective strategy against aging and Alzheimer’s disease, with epigenetic and network-level effects that may redefine the boundaries between prevention and therapy.