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.

Figure 1

Altered insulin signaling in diabetes might contribute to Alzheimer disease pathophysiology. In type 1 diabetes, insulin deficiency attenuates LTP and might lead to deficits in spatial learning and memory. In type 2 diabetes, insulin resistance leads to both Aβ plaque formation and tau hyperphosphorylation. During hyperinsulinemia, insulin and Aβ compete for insulin-degrading enzyme, leading to Aβ accumulation and plaque formation. A decrease in insulin receptor signaling leads to inhibition of Akt and dephosphorylation (activation) of GSK-3β, and results in tau hyperphosphorylation. Abbreviations: Aβ, amyloid-β; GSK-3β, glycogen synthase kinase 3β; LTP, long-term potentiation; P, phosphate.

Figure 2

Pathological mechanisms associated with diabetes might cause AD. Mitochondrial dysfunction, oxidative stress and dysregulated calcium homeostasis are all associated with diabetes and might be contributory factors to the development of AD. Glucose auto-oxidation can lead to AGE formation and, as a result, oxidative stress, which is associated with mitochondrial dysfunction. Oxidative stress combined with an increase in intracellular calcium result in a feedforward cycle of continued mitochondrial damage that can cause neuronal death and, hence contribute to AD pathology. Abbreviations: AD, Alzheimer disease; AGE, advanced glycation end product; ROS, reactive oxygen species.