Insulin Resistance in Alzheimer's: Exploring the Type 3 Diabetes Hypothesis

Alzheimer’s disease (AD), long defined by amyloid-beta plaques and neurofibrillary tangles, is increasingly recognized as a metabolic disorder, with insulin resistance (IR) emerging as a central pathological feature. This has led to the “Type 3 Diabetes” hypothesis, highlighting the brain-specific disruption of insulin signaling and glucose metabolism in AD. Epidemiological studies link type 2 diabetes, obesity, and peripheral IR to increased AD risk, independent of vascular factors. Mechanistically, impaired insulin and IGF signaling in the brain contributes to synaptic loss, mitochondrial dysfunction, tau hyperphosphorylation, and amyloid accumulation. Both experimental models and postmortem analyses show consistent disruptions in insulin receptor signaling pathways in AD. Therapeutic strategies targeting insulin pathways—such as intranasal insulin and GLP-1 receptor agonists—have demonstrated cognitive benefits in some studies, though clinical trial outcomes remain mixed. This review examines the epidemiological, mechanistic, and therapeutic evidence underpinning the Type 3 Diabetes model and outlines future research priorities in diagnostics and treatment.