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The Role of Insulin Resistance in the Pathogenesis of Alzheimer’s Disease

Implications for Treatment

Abstract

An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in Alzheimer’s disease may contribute to the disease pathophysiology and clinical symptoms. It has long been known that insulin is essential for energy metabolism in the periphery. In the past 2 decades, convergent findings have begun to demonstrate that insulin also plays a role in energy metabolism and other aspects of CNS function. Investigators reported 20 years ago that insulin and insulin receptors were densely but selectively expressed in the brain, including the medial temporal regions that support the formation of memory. It has recently been demonstrated that insulin-sensitive glucose transporters are localised to the same regions supporting memory and that insulin plays a role in memory functions. Collectively, these findings suggest that insulin may contribute to normal cognitive functioning and that insulin abnormalities may exacerbate cognitive impairments, such as those associated with Alzheimer’s disease.

Insulin may also play a role in regulating the amyloid precursor protein and its derivative β-amyloid (Aβ), which is associated with senile plaques, a neuro-pathological hallmark of Alzheimer’s disease. It has been proposed that insulin can accelerate the intracellular trafficking of Aβ and interfere with its degradation. These findings are consistent with the notion that insulin abnormalities may potentially influence levels of Aβ in the brains of patients with Alzheimer’s disease.

The increased occurrence of insulin resistance in Alzheimer’s disease and the numerous mechanisms through which insulin may affect clinical and pathological aspects of the disease suggest that improving insulin effectiveness may have therapeutic benefit for patients with Alzheimer’s disease. The thiazolidinedione rosiglitazone has been shown to have a potent insulin-sensitising action that appears to be mediated through the peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ agonists, such as rosiglitazone, also have anti-inflammatory effects that may be of therapeutic benefit in patients with Alzheimer’s disease.

This review presents evidence suggesting that insulin resistance plays a role in the pathophysiology and clinical symptoms of Alzheimer’s disease. Based on this evidence, we propose that treatment of insulin resistance may reduce the risk or retard the development of Alzheimer’s disease.

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Acknowledgements

This work was supported in part by the Department of Veterans Affairs, USA, and grants (AG00258, AG05136 and AG10880) from the National Institutes of Health, USA, and from GlaxoSmithKline. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Watson, G.S., Craft, S. The Role of Insulin Resistance in the Pathogenesis of Alzheimer’s Disease. Mol Diag Ther 17, 27–45 (2003). https://doi.org/10.2165/00023210-200317010-00003

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Keywords

  • Insulin Resistance
  • Insulin Receptor
  • Amyloid Precursor Protein
  • Improve Insulin Sensitivity
  • Healthy Control Individual