Obesity, insulin resistance, and Alzheimer's disease.

Abstract

Obesity has reached epidemic proportions in our society, affecting over one-third of US adults, with two-thirds overweight or obese (1). Trends toward overweight and obesity among younger age groups are alarming; 27.5% of men and 34.0% of women ages 20–39 are obese (1), and 11.3% of children 2–19 years of age are at or above the 97th percentile for 2000 BMI-for-age growth charts (2). The majority of overweight or obese individuals are also insulin resistant (3). The adverse health consequences of obesity and insulin resistance (IR) are well-documented, particularly with respect to cardiovascular disease and type 2 diabetes mellitus (T2DM). More recently, these conditions have also been linked to an increased risk of cognitive impairment and Alzheimer’s disease (AD) (4). AD is the most common cause of dementia, and the fifth leading cause of death in the United States among those 65 and older (5). The number of patients affected by AD in the United States is projected to increase from 5.3 million currently, to 16 million in 2050 as the population ages (5), imposing extraordinary monetary and non-monetary costs on patients, caregivers, and the healthcare system. Currently approved therapies for AD provide modest symptomatic benefits to some patients, but do not affect the underlying pathology. Identification of modifiable risk factors to delay or prevent progression to clinical dementia and functional impairment could have a dramatic impact on the prevalence and costs associated with AD. Although there is currently insufficient evidence to firmly link any modifiable risk factor with AD, substantial empirical evidence supports a role for several cardiovascular risk factors, including obesity, hypertension, dyslipidemia, diabetes, and IR (6). All of these factors have been implicated in the development and progression of AD, both individually and in aggregate (i.e., the metabolic syndrome) (7,8). A growing body of literature has demonstrated insulin dysregulation as a risk factor for both AD and its prodrome, mild cognitive impairment (4,9,10). Furthermore, IR represents a preclinical stage on the path to diabetes during which efforts at intervention are likely to have maximal effect. We focus here on the potential role of IR in the pathogenesis of AD, and discuss interventions that target IR as possible approaches to prevent or delay progression of AD.