Review
Adiposity, hyperinsulinemia, diabetes and Alzheimer's disease: An epidemiological perspective

https://doi.org/10.1016/j.ejphar.2008.02.048Get rights and content

Abstract

The objective of this manuscript is to provide a comprehensive review of the epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and diabetes with Alzheimer's disease. The mechanisms for these associations remain to be elucidated, but may include direct actions from insulin, advanced products of glycosilation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of Alzheimer's disease. The evidence relating adiposity in old age to Alzheimer's disease is conflicting. Several studies have shown that hyperinsulinemia, a consequence of higher adiposity and insulin resistance, is also related to a higher risk of Alzheimer's disease. Hyperinsulinemia is a risk factor for diabetes, and numerous studies have shown a relation of diabetes with higher Alzheimer's disease risk. Most studies fail the take into account the continuum linking these risk factors which may result in underestimation of their importance in Alzheimer's disease. The implication of these associations is that a large proportion of the world population may be at increased risk of Alzheimer's disease given the trends for increasing prevalence of overweight, obesity, hyperinsulinemia, and diabetes. However, if proven causal, these associations also present a unique opportunity for prevention and treatment of Alzheimer's disease.

Section snippets

Burden of Alzheimer's disease

Alzheimer's disease is the most common form of dementia, accounting for between 70% and over 90% of all cases (Ritchie and Lovestone, 2002), and its prevalence is expected to quadruple by the year 2047 in the United States (Brookmeyer et al., 1998). As much as 50% of the population aged 85 years and older, the fastest growing segment of the population, may have Alzheimer's disease (Evans et al., 1989). The risk factors for Alzheimer's disease can be classified as genetic and non-genetic. Three

Definition and burden of adiposity, hyperinsulinemia, and diabetes

There is a concerning epidemic of obesity, insulin resistance and diabetes in the world (Hill and Bessesen, 2003). With the aging of the population and greater longevity, the long term consequences of these conditions are serious and burdensome. Adiposity refers to the amount of adipose (fat) tissue in the body (Reaven and Laws, 1999). Some refer to adiposity as “fatness” or obesity. Adiposity is a continuum, and the normal or ideal threshold of adiposity is not clear. However, as adiposity

The continuum of adiposity, hyperinsulinemia, glucose intolerance and diabetes

Adiposity, hyperinsulinemia, glucose intolerance, and diabetes, are often treated as separate constructs, and have been separately related to the risk of Alzheimer's disease (Luchsinger and Mayeux, 2004a). However, they are related sequentially and often occur simultaneously, and understanding this relationship is fundamental in the study of the role of adiposity, insulin resistance, and diabetes in Alzheimer's disease. Keeping glucose in normal levels is achieved by the balance between the

Non-genetic risk factors for Alzheimer's disease and their relation to adiposity, hyperinsulinemia and diabetes

Among demographic characteristics, old age (Cummings, 2004), low education (Scarmeas and Stern, 2003, Scarmeas et al., 2003), and being Caribbean-Hispanic or African American (Tang et al., 2001) have been related to a higher risk of Alzheimer's disease in New York City. Weight decreases with aging and frailty (Morley, 2001), and body mass index in older age may not reflect that of middle age. In the United States, higher adiposity has been related to lower education and socioeconomic position (

Potential mechanisms linking adiposity, hyperinsulinemia and diabetes to Alzheimer's disease

Providing a comprehensive review of mechanisms linking adiposity, hyperinsulinemia, and diabetes to Alzheimer's disease is not the main goal of this article. I provide a brief mention of potential mechanisms to put in context the review of the epidemiological evidence.

Adiposity

Few studies have explored the association between adiposity and Alzheimer's disease and reveal conflicting findings. Elevated body mass index (overweight and obesity) in middle age is associated with higher dementia risk (Kivipelto et al., 2005, Whitmer et al., 2005a). Higher body mass index at ages 70, 75 and 79 years also predicts higher dementia risk (Gustafson et al., 2003). However, there have been reports of no association (Stewart et al., 2005) and of lower body mass index related to

Caveats in epidemiologic studies relating adiposity, hyperinsulinemia, and diabetes with Alzheimer's disease

As reviewed, the evidence linking diabetes and dementia is much stronger for vascular dementia than Alzheimer's disease. This begs the question of whether the findings for Alzheimer's disease are not due to misclassification of vascular dementia as Alzheimer's disease. One of the great controversies in the dementia field is whether vascular dementia can present slowly mimicking the usual presentation of Alzheimer's disease.

Another caveat is that most epidemiologic studies of cognition have

Putting it all together

One way to put the literature reviewed in perspective is to see how the continuum of adiposity, hyperinsulinemia and diabetes relates to Alzheimer's disease in the same cohort. Table 1 summarizes the findings linking the components of this continuum to Alzheimer's disease in the Washington Heights Inwood Columbia Aging Project, a longitudinal study of aging in persons 65 years and older in New York City. We found that higher body mass index has a U-shape association with Alzheimer's disease in

Implications for prevention and treatment of Alzheimer's disease

There is very strong evidence that adiposity, hyperinsulinemia, and diabetes are related to Alzheimer's disease. However, this evidence comes short of being considered as proof of causation until we understand the mechanisms and some of the caveats discussed in this review. If the relation between these conditions and Alzheimer's disease were to be causal, the public health implications are enormous. As explained before, 2/3 of the adult population of the United States is overweight or obese,

Acknowledgments

Support for this work was provided by grants from the National Institutes of Health National Institute on Aging (AG07232), by the Alzheimer's Association (IIRG-05-15053), and by the Florence and Herbert Irving Clinical Research Scholar's Award.

References (109)

  • WatsonG.S. et al.

    Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease

    Neurobiol. Aging

    (2006)
  • AcciliD.

    Lilly Lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic

    Diabetes

    (2004)
  • AllisonD.B. et al.

    Hypothesis concerning the U-shaped relation between body mass index and mortality

    Am. J. Epidemiol.

    (1997)
  • ArvanitakisZ. et al.

    Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function

    Arch. Neurol.

    (2004)
  • BaumgartnerR.N. et al.

    Human body composition and the epidemiology of chronic disease

    Obes. Res.

    (1995)
  • BrayneC. et al.

    Vascular risks and incident dementia: results from a cohort study of the very old

    Dement. Geriatr. Cogn. Disord.

    (1998)
  • BrookmeyerR. et al.

    Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset

    Am. J. Public Health

    (1998)
  • BusseA. et al.

    Mild cognitive impairment: prevalence and incidence according to different diagnostic criteria. Results of the Leipzig Longitudinal Study of the Aged (LEILA75+)

    Br. J. Psychiatry

    (2003)
  • CharlesM.A. et al.

    Risk factors for NIDDM in white population. Paris prospective study

    Diabetes

    (1991)
  • ChobanianA.V. et al.

    The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report

    JAMA

    (2003)
  • CummingsJ.L.

    Alzheimer's disease

    N. Engl. J. Med.

    (2004)
  • CurbJ.D. et al.

    Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance

    Neurology

    (1999)
  • DeFronzoR.A.

    Pharmacologic therapy for type 2 diabetes mellitus

    Ann. Intern. Med.

    (2000)
  • Diabetes Prevention Program Research Group

    Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

    N. Engl. J. Med.

    (2002)
  • EvansD.A. et al.

    Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported

    JAMA

    (1989)
  • FarrisW. et al.

    Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • FerranniniE. et al.

    Insulin: in search of a syndrome

    Diabet. Med.

    (2002)
  • FestaA. et al.

    The natural course of {beta}-cell function in nondiabetic and diabetic individuals: The Insulin Resistance Atherosclerosis Study

    Diabetes

    (2006)
  • FlegalK.M. et al.

    Prevalence and trends in obesity among US adults, 1999–2000

    JAMA

    (2002)
  • FordE.S. et al.

    Trends in waist circumference among U.S. adults

    Obes. Res.

    (2003)
  • GrundyS.M. et al.

    Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement

    Circulation

    (2005)
  • GustafsonD. et al.

    An 18-year follow-up of overweight and risk of Alzheimer disease

    Arch. Intern. Med.

    (2003)
  • HaanM.N. et al.

    The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons

    JAMA

    (1999)
  • HaffnerS.M. et al.

    Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution

    Diabetes

    (1990)
  • HaffnerS.M. et al.

    The homeostasis model in the San Antonio Heart Study

    Diabetes Care

    (1997)
  • HarrisM.I. et al.

    Higher fasting insulin but lower fasting C-peptide levels in African Americans in the US population

    Diabetes/Metab. Res. Rev.

    (2002)
  • HedleyA.A. et al.

    Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002

    JAMA

    (2004)
  • HillJ.O. et al.

    What to do about the metabolic syndrome?

    Arch. Intern. Med.

    (2003)
  • HonigL.S. et al.

    Stroke and the risk of Alzheimer disease

    Arch. Neurol.

    (2003)
  • HonigL.S. et al.

    Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center

    Neurology

    (2005)
  • KalmijnS. et al.

    Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu–Asia aging study

    Arterioscler. Thromb. Vasc. Biol.

    (2000)
  • KivipeltoM. et al.

    Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease

    Arch. Neurol.

    (2005)
  • KrajaA.T. et al.

    An evaluation of the metabolic syndrome in the HyperGEN study

    Nutr. Metab. (Lond.)

    (2005)
  • KuusistoJ. et al.

    Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study

    BMJ

    (1997)
  • LaaksoM.

    How good a marker is insulin level for insulin resistance?

    Am. J. Epidemiol.

    (1993)
  • LarsonE.B. et al.

    Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older

    Ann. Intern. Med.

    (2006)
  • LeibsonC.L. et al.

    Risk of dementia among persons with diabetes mellitus: a population-based cohort study

    Am. J. Epidemiol.

    (1997)
  • LilliojaS. et al.

    Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians

    N. Engl. J. Med.

    (1993)
  • LuchsingerJ.A.

    Diabetes

  • LuchsingerJ.A.

    A work in progress: the metabolic syndrome

    Sci. Aging Knowl. Environ.

    (2006)
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