The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis

While exercise is shown to reduce hippocampal atrophy, the underlying molecular mechanisms remain to be fully elucidated. Animal studies suggest the myokine irisin underlies exercise-related hippocampal benefits, though human evidence is lacking. We cross-sectionally examined 74 healthy older adults (age 65.47 ± 8.56 years). Participants completed Godin Leisure-Time exercise questionnaires, provided fasting blood for irisin measurement and underwent structural MRI with hippocampal subfield segmentation. Hierarchical regression and mediation analyses tested irisin-mediated exercise-hippocampus relationships, controlling for age, sex and education. Exercise positively associated with circulating irisin (β = 0.365, p = 0.003). Irisin positively associated with bilateral hippocampal volumes (right: β = 0.353, p = 0.001; left: β = 0.275, p = 0.012), strongest in right-CA3 (β = 0.530), right-CA4/dentate gyrus (β = 0.471), and bilateral CA1 (β = 0.336-0.373) subfields. Mediation analysis revealed all exercise-hippocampus relationships operated indirectly through irisin. This study provides first human evidence that irisin is a molecular mechanism linking exercise to hippocampal volume, particularly in subfields critical for memory, neurogenesis and Alzheimer's pathology. Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12620000054910.