Targeting Brain Energy Metabolism: Novel Mechanisms and Therapeutic Potential of Exercise Mimetics in Alzheimer’s Disease

Impaired brain energy metabolism is an early pathological hallmark of Alzheimer’s disease (AD) and persists throughout disease progression. Regular physical exercise has been shown to restore energy homeostasis and improve cognitive function. However, advanced age, frailty, and multiple comorbidities substantially often limit the ability of patients to engage in sufficient physical activity. These limitations underscore the need for alternative approaches capable of reproducing the systemic benefits of exercise. Consequently, exercise mimetics, a class of bioactive compounds that reproduce these benefits, have attracted growing attention. This review examines how exercise mimetics ameliorate AD-associated pathologies by modulating energy metabolism. Particular emphasis is placed on specific mechanisms, including irisin and metformin, and the molecular pathways through which they regulate energy homeostasis and confer neuroprotective effects.