Diabetes mellitus is a well-recognized risk factor for dementia. In prospective studies, diabetes confers a greater than 80% increase in risk for all-cause dementia and Alzheimer's disease, and greater than 180% increase in risk for vascular dementia.[1] One in seven adults in the United States are estimated to have diabetes, and more than 90% of them have type 2 diabetes (T2D).[2] With an aging population and increasing obesity, the incidence and prevalence of T2D is expected to continue to increase worldwide.[3]
Insulin resistance, which is a metabolic hallmark of T2D, has been postulated as a pathophysiologic connection between diabetes and dementia. Hyperinsulinemia, a biomarker of peripheral insulin resistance, is a risk factor for Alzheimer's disease even in the absence of diabetes.[4] At the same time, ex-vivo studies have shown evidence of brain insulin resistance in people with Alzheimer's disease who did not have diabetes.[5] While insulin signaling in the brain has an important role in neuronal and glial metabolism, synaptic neurotransmission, neuroinflammation and neurovascular coupling, it is presently unclear whether the observed associations between T2D and dementia are caused by insulin resistance in the brain or metabolic consequences of peripheral insulin resistance (as reviewed in Reference[6]). T2D is also characterized by endothelial dysfunction and microvascular insufficiency, which can lead to vascular dementia even in the absence of macrovascular insults, through mechanisms involving ischemia, blood–brain barrier leakage, and disruptions in white matter integrity.
