Effectiveness of exercise training on hippocampal mitochondrial regulation in Alzheimer's disease: A mechanistic systematic review.

Abstract

Alzheimer's disease (AD) is associated with hippocampal mitochondrial dysfunction, including impaired mitophagy, biogenesis, dynamics, bioenergetics, and redox homeostasis, which may contribute to amyloid-β (Aβ) accumulation, tau pathology, and cognitive decline. This systematic review examined whether exercise training is associated with changes in hippocampal mitochondrial regulation and cognitive function in transgenic AD rodent models. Following PRISMA 2020 guidelines, PubMed, EMBASE, and Web of Science were searched up to July 2, 2026. Twenty-one studies met inclusion criteria. Exercise modalities included treadmill running, voluntary wheel running, and swimming, with durations from 4 weeks to 8 months. Risk of bias was assessed using the SYRCLE tool. Due to heterogeneity, meta-analysis was not appropriate; a narrative synthesis was performed. Exercise training was associated with changes in markers of mitophagy, biogenesis, dynamics, and function, as well as reduced oxidative stress, decreased Aβ and tau pathology, and improved spatial learning and memory. However, most studies assessed static markers rather than functional flux, and risk of bias was unclear in several domains. The evidence suggests that exercise training may be associated with hippocampal mitochondrial modulation and cognitive benefits in AD models, but conclusions are limited by heterogeneity and incomplete reporting. Further studies with functional mitochondrial assays and clear reporting of methods and results are needed.