Alzheimer's disease and type 2 diabetes: multiple mechanisms contribute to interactions

Abstract

Obesity, metabolic syndrome, and type 2 diabetes (T2D) are related disorders with widespread deleterious effects throughout the body. One important target of damage is the brain. Persons with metabolic disorders are at significantly increased risk for cognitive decline and the development of vascular dementia and Alzheimer's disease. Our review of available evidence from epidemiologic, clinical, and basic research suggests that neural dysfunction from T2D-related disease results from several underlying mechanisms, including metabolic, inflammatory, vascular, and oxidative changes. The relationships between T2D and neural dysfunction are regulated by several modifiers. We emphasize 2 such modifiers, the genetic risk factor apolipoprotein E and an age-related endocrine change, low testosterone. Both factors are independent risk factors for Alzheimer's disease that may also cooperatively regulate pathologic interactions between T2D and dementia. Continued elucidation of the links between metabolic disorders and neural dysfunction promises to foster the development of effective therapeutic strategies.

Figure 1

Obesity and metabolic syndrome are precursor disorders to type 2 diabetes. All three conditions independently and interactively activate a range of metabolic, inflammatory, and oxidative changes that contribute to deleterious effects on the brain. The damaging effects of metabolic disorders are influenced by several modifying factors, including endocrine changes such as low testosterone and genetic factors such as the apolipoprotein E (Apo E) ε4 allele. In response to these damaging pathways, the brain exhibits cognitive decline and increased risk to Alzheimer’s and vascular dementias.