Peripheral Insulin Resistance and Alzheimer's Disease: Possible Mediators Including Extracellular Vesicles

Epidemiological studies consistently indicate that type 2 diabetes mellitus increases the risk of Alzheimer's disease (AD). Accumulating evidence suggests that insulin resistance, rather than hyperglycemia per se, is the principal metabolic factor associated with AD development. Population-based longitudinal studies show that insulin resistance is strongly linked to earlier amyloid β (Aβ) accumulation, whereas its association with tau pathology remains inconsistent. Importantly, insulin resistance-related cognitive decline and earlier disease onset cannot be fully explained by the extent of Aβ deposition alone, implying the involvement of additional pathogenic pathways. Animal studies further support a role for insulin resistance independent of sustained hyperglycemia. Genetic models of systemic insulin resistance demonstrate impairments in cognition, cerebral blood flow regulation, and emotional behavior, distinct from phenotypes observed in models with brain-specific disruption of insulin signaling. Together with clinical observations showing preserved central insulin responsiveness in individuals with type 2 diabetes, these findings highlight peripheral insulin resistance as a key contributor to brain vulnerability in AD. How peripheral insulin resistance influences the brain remains incompletely understood. Emerging evidence suggests that extracellular vesicles may act as a possible mediator of peripheral-central communication by conveying bioactive molecules across tissues. In this review, we summarize epidemiological and experimental evidence linking peripheral insulin resistance to AD and discuss the potential, yet still speculative, role of extracellular vesicles in this process.