Xiaohua Li, Dalin Song, Sean X Leng

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.