How does diabetes accelerate Alzheimer disease pathology?

Abstract

Diabetes and Alzheimer disease (AD)—two age-related diseases—are both increasing in prevalence, and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood. Abnormal protein processing, abnormalities in insulin signaling, dysregulated glucose metabolism, oxidative stress, the formation of advanced glycation end products, and the activation of inflammatory pathways are features common to both diseases. Hypercholesterolemia is another factor that has received attention, owing to its potential association with diabetes and AD. This Review summarizes the mechanistic pathways that might link diabetes and AD. An understanding of this complex interaction is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases.

Key Points

  • Alzheimer disease (AD) and diabetes are both associated with enormous and increasing socioeconomic effects

  • Diabetes affects the processing of amyloid-β and tau, and might increase the rate of formation of senile plaques and neurofibrillary tangles, the main neuropathological hallmarks of AD

  • Hyperinsulinemia is associated with amyloid-β accumulation and regulates tau phosphorylation

  • Oxidative stress activates inflammatory pathways and, hence, might exacerbate AD neuropathology

  • Mitochondrial dysfunction is associated with both diabetes and AD, and leads to intracellular calcium dysregulation and abnormal processing of the amyloid precursor protein

  • Induction of diabetes exacerbates AD neuropathology in mouse models of this neurodegenerative disease

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Figure 1: Altered insulin signaling in diabetes might contribute to Alzheimer disease pathophysiology.
Figure 2: Pathological mechanisms associated with diabetes might cause AD.

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Acknowledgements

The authors greatly appreciate the helpful discussion with Dr. K. A. Sullivan (University of Michigan, Ann Arbor, MI, USA). This work was supported by an Aging Training Grant (NIA T32-AG000114), and grants from the Animal Models of Diabetic Complications Consortium (NIH U01-DK076160), the Taubman Institute and the Program for Neurology Research and Discovery.

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C. Sims-Robinson researched the data for the article, provided substantial contributions to discussions of the content, and contributed to the writing, reviewing and editing of the manuscript. B. Kim researched the data for the article and contributed to the writing, reviewing and editing of the manuscript. A. Rosko researched the data for the article and contributed to the writing of the manuscript. E. L. Feldman provided substantial contributions to discussions of the content and contributed to the reviewing and editing of the manuscript.

Correspondence to Eva L. Feldman.

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Sims-Robinson, C., Kim, B., Rosko, A. et al. How does diabetes accelerate Alzheimer disease pathology?. Nat Rev Neurol 6, 551–559 (2010). https://doi.org/10.1038/nrneurol.2010.130

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