Targeting insulin resistance with exercise mimetics: A potential therapeutic strategy for Alzheimer's disease

Insulin resistance (IR) has emerged as a key pathological mechanism underlying Alzheimer's disease (AD). This resistance accelerates AD progression by promoting amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Although regular physical exercise can slow cognitive decline in AD by improving insulin sensitivity through multiple pathways, many patients experience progressive physical decline. This reduces adherence to exercise programs and limits their long-term effectiveness. Exercise mimetics have therefore attracted attention. These bioactive agents can reproduce or enhance selected health benefits of exercise by targeting exercise-related molecular signaling pathways, without requiring direct physical exertion. This review summarizes the mechanisms by which exercise mimetics improve AD pathology through the regulation of IR. It also provides a theoretical basis for the development of targeted exercise mimetics.