Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment

Abstract

The aim of this paper is to provide a comprehensive review of the epidemiological evidence linking type 2 diabetes mellitus and its related conditions, including obesity, hyperinsulinemia, and metabolic syndrome, to Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link; however, our focus is on insulin resistance and deficiency. Studies have shown that insulin resistance and deficiency can interact with amyloid-β protein and tau protein phosphorylation, each leading to the onset and development of AD. Based on those epidemiological data and basic research, it was recently proposed that AD can be considered as "type 3 diabetes". Special attention has been paid to determining whether antidiabetic agents might be effective in treating AD. There has been much research both experimental and clinical on this topic. We mainly discuss the clinical trials on insulin, metformin, thiazolidinediones, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors in the treatment of AD. Although the results of these trials seem to be contradictory, this approach is also full of promise. It is worth mentioning that the therapeutic effects of these drugs are influenced by the apolipoprotein E (APOE)-ε4 genotype. Patients without the APOE-ε4 allele showed better treatment effects than those with this allele.

Keywords: Alzheimer’s disease; insulin; type 2 diabetes mellitus.

Figure 1

Overview of the role of insulin resistance and insulin deficiency in the pathology of Alzheimer’s disease. Abbreviations: BACE1, β-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1; GSK-3β, glycogen synthase kinase-3β; IDE, insulin-degrading enzyme; IRs, insulin receptor substrates; TNF, tumor necrosis factor; JNK, c-Jun N-terminal kinase; APP, amyloid precursor protein; Aβ, amyloid-β; IGF, insulin growth factor.

Figure 2

The underlying link between Alzheimer’s disease and type 2 diabetes mellitus. Notes: Insulin resistance reduces the degradation of Aβ by IDE, and makes the combination of insulin and insulin receptor impaired. Under normal conditions, the insulin signaling pathway can inhibit Aβ production and tau protein phosphorylation through inhibiting the translation of β-site amyloidogenic cleavage of BACE1 and its substrate APP, and inhibiting phosphorylation of GSK-3β. In addition, the insulin signaling pathway prevents abnormal intracellular accumulation of Aβ by accelerating its trafficking from the Golgi and trans-Golgi network to the plasma membrane and increasing its extracellular secretion. However, insulin resistance and deficiency make insulin signal conduction abnormal, leading to increased production of Aβ in the brain with Alzheimer’s disease. Increased Aβ monomers gather into oligomers. Aβ oligomers cause abnormal activation of the TNF-α/JNK pathway, resulting in insulin resistance. Further, insulin and IGF-1 deficiency promote Aβ accumulation by decreasing the Aβ-binding carrier proteins. Aβ oligomers can also induce oxidative damage of the mitochondria. Abbreviations: APP, amyloid precursor protein; Aβ, amyloid-β; IDE, insulin-degrading enzyme; BACE1, β-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1; GSK-3β, glycogen synthase kinase-3β; IRs, insulin receptor substrates; TNF-α, tumor necrosis factor alpha; JNK, c-Jun N-terminal kinase; IGF-1, insulin-like growth factor 1.

Figure 3

Possible mechanisms of antidiabetic drugs in the treatment of AD. Notes: The red line represents inhibition. The green line represents promotion. Abbreviations: AD, Alzheimer’s disease; DPP-4, dipeptidyl peptidase-4; TZDs, thiazolidinediones; GLP-1R, glucagon-like peptide-1 receptor.