Candidate neurobiological pathways linking physical exercise to cognition in Parkinson's disease: a hypothesis-generating translational framework

Cognitive impairment is a major nonmotor symptom of Parkinson's disease (PD), yet effective strategies for preserving cognitive function remain limited. Although physical exercise may confer cognitive benefits, the biological pathways linking exercise to cognition in PD remain incompletely established. This narrative review presents a hypothesis-generating translational framework for 4 candidate mechanistic domains that may contribute to exercise-related cognitive effects in PD. First, exercise-responsive neurotrophic signaling, particularly through brain-derived neurotrophic factor-tropomyosin receptor kinase B, insulin-like growth factor 1, and vascular endothelial growth factor pathways, may support synaptic plasticity, neuronal survival, and neurovascular function. Second, exercise may modulate dopaminergic, cholinergic, and noradrenergic systems and influence corticostriatal plasticity relevant to cognitive function. Third, muscle-derived factors and exercise-induced metabolites may affect neurotrophic signaling, neuronal metabolism, and autophagy-lysosomal clearance of α-synuclein. Fourth, exercise may regulate systemic and central inflammatory responses through cytokine signaling, glial activation, inflammasome pathways, and complement-mediated synaptic remodeling. The evidence supporting these pathways is derived from basic, preclinical, observational, and exercise-intervention studies, but the strength of evidence varies considerably across stages of translation. Direct evidence that exercise-induced biological changes mediate cognitive improvement in patients with PD is lacking. These pathways should therefore be regarded as candidate mechanisms for hypothesis-driven investigation of the cognitive effects of exercise in PD.