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13 November 2018
Insulin Resistance in Alzheimer's Disease
Laís S. S. Ferreira
2 more and 
Fernanda G. De Felice
A possible cascade of events connecting peripheral metabolic dysregulation to dementia. In diabetic and/or obese subjects, dyslipidemia, and increased circulating free fat acids as well as hyperglycemia and elevated peripheral AGEs levels (1) may increase blood-brain barrier permeability, allowing the influx of FFAs into the brain (2). Disrupted BBB along with high levels of brain FFAs and AGEs, in turn, would cause activation of microglia and astrocytes and the release of proinflammatory cytokines (3). Low-grade, chronic brain inflammation leads to detrimental events in neurons, including insulin resistance (4), priming the brain to cognitive impairment and Alzheimer's disease.

The epidemiological connection between diabetes, obesity, and dementia represents an important public health challenge but also an opportunity to further understand these conditions. The key intersection among the three diseases is insulin resistance, which has been classically described to occur in peripheral tissues in diabetes and obesity and has recently been shown to develop in Alzheimer's disease (AD) brains. Here we review encouraging preclinical and clinical data indicating the potential of targeting impaired insulin signaling with antidiabetic drugs to treat dementia. We further discuss biological mechanisms through which peripheral metabolic dysregulation may lead to brain malfunction, providing possible explanations for the connection between diabetes, obesity, and AD. Finally, we briefly discuss how lifelong allostatic load may interact with aging to increase the risk of dementia in late life.

55,315 views
177 citations
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