Beyond the brain-centric view: A systems physiology framework for exercise-induced neuroprotection in Alzheimer's...

Alzheimer's disease (AD) is regarded as a multifactorial disease that combines central pathological changes and peripheral organ dysfunction. Its core features include Aβ protein deposition, tau protein pathology, synaptic dysfunction, and neuroinflammation. Exercise has been proven to be one of the most effective non-pharmacological intervention measures. However, its mechanism of action in AD has not been fully elucidated from the traditional brain-centered research perspective. Moreover, most existing studies focus on isolated organ systems or a single signaling pathway, failing to fully reflect the overall peripheral-cerebral physiological interaction mechanism required for neuroprotective effects of exercise. This article provides a structured narrative synthesis of current evidence regarding how exercise may influence AD-related pathological processes through multiple peripheral organ systems. It clarifies the communication mechanisms between these systems and the central nervous system through endocrine, immune, metabolic, neural, and vascular pathways. The study shows that exercise functions by coordinating the regulation of peripheral physiological functions, rather than relying on a single target mechanism. Exercise can regulate multiple signaling pathways such as muscle-brain, gut-brain, liver-brain, adipose-brain, bone-brain, and immune-brain, improving overall metabolic flexibility, inflammation regulation, vascular function, and neuroimmune homeostasis; these peripheral adaptive changes further act on the central nervous system, regulating blood-brain barrier(BBB) integrity, microglial cell activity, neuronal energy metabolism, neurovascular coupling, and synaptic plasticity. In summary, the neuroprotective effect induced by exercise stems from the integration of multiple systems' physiology, rather than isolated molecular signal transduction. This review synthesizes current evidence on exercise-induced peripheral-central interactions in AD from a systems physiology perspective, highlighting the significance of integrating peripheral biomarkers, multi-organ interactions, and central outcomes. It provides a theoretical framework for future personalized and mechanism-oriented exercise intervention studies.