ABSTRACT
The search for risk factors that increase the risk of Alzheimer’s disease (AD) has converged on a cluster of disorders characterized by vascular, lipid, and metabolic abnormalities, such as cardiovascular disease, hypertension, and type 2 diabetes mellitus (T2DM). A common pathophysiology uniting these diseases is derangement of insulin metabolism, characterized by the inability of insulin to efficiently promote glucose uptake into muscle (insulin resistance), with concomitant peripheral insulin elevations (hyperinsulinemia). Although much attention has been paid to the metabolic consequences of insulin resistance, peripheral hyperinsulinemia has additional deleterious effects on systems that do not habituate to increased insulin. For example, as will be discussed, peripheral hyperinsulinemia has effects on inflammation and brain insulin levels that are of special relevance to the pathogenesis of AD. There are probably several pathways leading to the final common expression of AD pathology.1 Insulin resistance and peripheral hyperinsulinemia comprise one potential pathway, and as such do not apply to all AD patients. It is, however, a pathway with relevance to a rapidly growing segment of our population. Peripheral hyperinsulinemia and insulin resistance are mutually reinforcing (each can cause or exacerbate the other) and may result from a number of causes, including genetic vulnerability and/or environmental factors such as diet and inactivity. They are also increasingly common conditions, in part due to the complexity of insulin signaling pathways, and in part due to pervasive changes in diet and physical activity occurring at an unprecedented rate in Western societies. In this chapter, we discuss mechanisms through which insulin resistance and peripheral hyperinsulinemia may induce AD pathogenesis, and the manner in which greater understanding of these mechanisms may lead to the development of novel therapeutic strategies.
