Adiposity, type 2 diabetes, and Alzheimer's disease

Abstract

This manuscript provides a comprehensive review of the epidemiologic evidence linking the continuum of adiposity and type 2 diabetes (T2D) with Alzheimer's disease (AD). The mechanisms relating adiposity and T2D to AD may include hyperinsulinemia, advanced products of glycosylation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of AD but the data on this association in old age is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of AD. Hyperinsulinemia is a risk factor for T2D, and numerous studies have shown a relation of T2D with higher AD risk. The implication of these associations is that a large proportion of the world population may be at increased risk of AD given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and T2D. However these associations may present a unique opportunity for prevention and treatment of AD. Several studies in the prevention and treatment of T2D are currently conducting, or have planned, cognition ancillary studies. In addition, clinical trials using insulin sensitizers in the treatment or prevention of AD are under way.

Figure 1

Mechanism linking the continuum of adiposity, insulin resistance and type 2 diabetes to the manifestation of Alzheimer's disease. Elevated adiposity leads to insulin resistance which precedes most cases of glucose intolerance and type 2 diabetes. Each of these conditions is related to specific mechanistic intermediaries, but most mechanisms are shared. For example, elevated adiposity, insulin resistance, and type 2 diabetes are all accompanied by hypertension and dyslipidemia. In addition, some of these mechanisms are bidirectional. For example, insulin resistance due to elevated adiposity results in increased inflammation which in turn increases insulin resistance. These mechanisms overlap and are highly correlated. In theory, these mechanistic intermediaries result in increased amyloid beta deposition and cerebrovascular disease. Cerebrovascular disease is thought to decrease the threshold at which amyloid deposition causes the manifestations of Alzheimer's disease, which starts with memory impairment, reaching the threshold of mild cognitive impairment, and eventually dementia.