Mechanistic Investigation of Exercise Interventions in Rodent Models of Alzheimer's Disease and Prospects for Clinical Translation.

Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder for which existing pharmacotherapies are inadequate to arrest pathological progression, highlighting the imperative to identify safe and effective nonpharmacological interventions. Exercise, as a multi-target therapeutic modality, has been shown to reverse multiple facets of AD-related neuropathology through diverse mechanisms. In this systematic review, we synthesize evidence on the effects of voluntary running, structured swimming, and modulation of the gut microbiota in transgenic murine models of AD. Exercise was found to ameliorate AD pathology by modulating amyloid precursor protein (APP) processing and β-amyloid (Aβ) production/clearance, restoring mitochondrial integrity and function, attenuating neuroinflammatory responses, enhancing synaptic plasticity, and upregulating neurotrophic factors. Moreover, exercise reshapes the intestinal microbiome and thereby modulates the gut-brain axis, further promoting neuroimmune homeostasis and cognitive resilience. Through RNA sequencing data analysis, key genes such as Tlr4, Cdc42, and F13a1 were identified, which may play significant roles in neuroimmune regulation and cognitive protection. By integrating multi-omics evidence, we propose a coordinated "exercise-microbiota-brain" mechanistic framework that offers theoretical support for personalized, exercise-based therapeutic strategies and translational applications in AD. We also emphasize the necessity of future studies combining exercise with complementary interventions to accelerate the clinical translation of multimodal therapeutic approaches.