ReviewAdiposity, hyperinsulinemia, diabetes and Alzheimer's disease: An epidemiological perspective
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)
- et al.
Diabetes Guidelines: A Summary and Comparison of the Recommendations of the American Diabetes Association, Veterans Health Administration, and American Association of Clinical Endocrinologists
Clin. Ther.
(2000) - et al.
Waist circumference and not body mass index explains obesity-related health risk
Am. J. Clin. Nutr.
(2004) - et al.
Dietary factors and Alzheimer's disease
The Lancet Neurol.
(2004) Anorexia, sarcopenia, and aging
Nutrition
(2001)- et al.
Cachexia: pathophysiology and clinical relevance
Am. J. Clin. Nutr.
(2006) - et al.
Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype
Neurobiol. Aging
(2006) - et al.
The dementias
Lancet
(2002) Insulin and cognitive function
Lancet
(2003)- et al.
Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease
Eur. J. Pharmacol.
(2004) - et al.
Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study
Am. J. Geriatr. Psychiatry
(2005)
Insulin effects on CSF norepinephrine and cognition in Alzheimer's disease
Neurobiol. Aging
Lilly Lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic
Diabetes
Hypothesis concerning the U-shaped relation between body mass index and mortality
Am. J. Epidemiol.
Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function
Arch. Neurol.
Human body composition and the epidemiology of chronic disease
Obes. Res.
Vascular risks and incident dementia: results from a cohort study of the very old
Dement. Geriatr. Cogn. Disord.
Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset
Am. J. Public Health
Mild cognitive impairment: prevalence and incidence according to different diagnostic criteria. Results of the Leipzig Longitudinal Study of the Aged (LEILA75+)
Br. J. Psychiatry
Risk factors for NIDDM in white population. Paris prospective study
Diabetes
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report
JAMA
Alzheimer's disease
N. Engl. J. Med.
Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance
Neurology
Pharmacologic therapy for type 2 diabetes mellitus
Ann. Intern. Med.
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin
N. Engl. J. Med.
Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported
JAMA
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.
Insulin: in search of a syndrome
Diabet. Med.
The natural course of {beta}-cell function in nondiabetic and diabetic individuals: The Insulin Resistance Atherosclerosis Study
Diabetes
Prevalence and trends in obesity among US adults, 1999–2000
JAMA
Trends in waist circumference among U.S. adults
Obes. Res.
Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement
Circulation
An 18-year follow-up of overweight and risk of Alzheimer disease
Arch. Intern. Med.
The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons
JAMA
Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution
Diabetes
The homeostasis model in the San Antonio Heart Study
Diabetes Care
Higher fasting insulin but lower fasting C-peptide levels in African Americans in the US population
Diabetes/Metab. Res. Rev.
Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002
JAMA
What to do about the metabolic syndrome?
Arch. Intern. Med.
Stroke and the risk of Alzheimer disease
Arch. Neurol.
Atherosclerosis and AD: analysis of data from the US National Alzheimer's Coordinating Center
Neurology
Metabolic cardiovascular syndrome and risk of dementia in Japanese-American elderly men. The Honolulu–Asia aging study
Arterioscler. Thromb. Vasc. Biol.
Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease
Arch. Neurol.
An evaluation of the metabolic syndrome in the HyperGEN study
Nutr. Metab. (Lond.)
Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study
BMJ
How good a marker is insulin level for insulin resistance?
Am. J. Epidemiol.
Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older
Ann. Intern. Med.
Risk of dementia among persons with diabetes mellitus: a population-based cohort study
Am. J. Epidemiol.
Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians
N. Engl. J. Med.
Diabetes
A work in progress: the metabolic syndrome
Sci. Aging Knowl. Environ.
Cited by (137)
Androgen deprivation therapy and risk of cognitive dysfunction in men with prostate cancer: is there a possible link?
2022, Prostate InternationalCitation Excerpt :Moreover, traditionally accepted cardiovascular risk factors (e.g., hypertension, dyslipidemia, and diabetes) appear to be associated with an increased risk of not only vascular dementia, but also AD. Numerous observational studies have shown the correlation between hypertension and diabetes with dementia; hypertension in mid-age have consistently increased the risk of all-cause dementia including AD,26,27 and patients with diabetes were found to have a doubled risk of developing vascular dementia28,29 as well as a relatively higher risk of AD compared with those without diabetes.30 These cardiovascular diseases can cause oxidative cell damage, inflammation, and insulin resistance, resulting in blood vessel dysfunction and stroke-like damage, leading to dementia.31
The dietary approaches to stop hypertension (DASH) and Mediterranean-DASH intervention for neurodegenerative delay (MIND) diets and brain aging
2021, Factors Affecting Neurological Aging: Genetics, Neurology, Behavior, and DietThe prevalence, risk factors, and clinical characteristics of insulin resistance in Chinese patients with schizophrenia
2020, Comprehensive PsychiatryLight and Shadow of Na-Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Points for Improvement Based on Our Clinical Experience
2024, International Journal of Endocrinology