Abstract

Background Physical activity (PA) is strongly associated with enhanced cognitive resilience and a lower risk of Alzheimer’s disease (AD) in the aging population. However, the molecular mechanisms linking exercise-induced neuroprotection to epigenetic remodeling remain poorly defined. Methods A total of 1,511 participants from the National Health and Nutrition Examination Survey (NHANES) 2013–2014 cohort were included to assess the association between PA and cognitive performance. Mendelian randomization (MR) analysis was further employed to infer the causal relationship between PA and the risk of various dementias. Differential gene enrichment analysis was performed using the Gene Expression Omnibus (GEO) dataset (GSE110298) to compare transcriptomic profiles between sedentary and high PA groups in patients with AD. For mechanistic exploration, APP/PS1 transgenic mice underwent an 8-week treadmill-based aerobic exercise (AE) intervention (5 days/week, 40 min/day), followed by comprehensive assessments, including behavioral tests, pathological examinations, epigenetic and molecular biological analyses, and single-cell RNA sequencing. Results Epidemiological analysis of the NHANES cohort revealed a nonlinear, dose-dependent relationship between PA and cognitive performance. MR supported a causal effect of genetically predicted higher PA on reduced AD risk. Transcriptomic profiling from GEO identified synaptic signaling and neurogenesis as key pathways modulated by exercise. In APP/PS1 mice, AE alleviated Aβ pathology and cognitive deficits, restored synaptic plasticity, and normalized synaptic protein expression. Mechanistically, AE activated ADRB2, triggering AMPKα phosphorylation and its interaction with the N-terminal (1–200 aa) region of p300. This interaction facilitated p300 nuclear translocation and subsequent enhanced histone H4K5 and H4K12 acetylation, promoting synaptic gene (e.g., GluN1) transcription. The AE-induced nuclear translocation of p300 and the i