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Visceral Fat & Neurotoins, Insulin Resistance & Alzheimer Disease/Dementia EDITORIAL
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Go to the head of the class to avoid vascular dementia and skip diabetes and obesity Editorial
NEUROLOGY Sept 2008;71:1046-1047
David S. Knopman, MD
From the Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN.
The authors5 make the point that high visceral adiposity might promote production of inflammatory cytokines and hormones, which themselves are neurotoxic......
Impaired acute insulin response was more strongly associated with clinical AD, while insulin resistance showed associations with both AD and vascular dementia
Three articles in this issue of Neurology address the question of risk factors for late life dementia. There is already a very large literature on this topic, but these three reports show that more precise definitions can make a difference in interpretation. The new observations create a fresh picture of vascular risk factors. One of the hypotheses that emerges is that the roots of dementia with cerebrovascular features ultimately extend back to childhood.
One study1 found an association between early childhood mental achievement testing and late life dementia. Indeed, such results have been observed before, including by the same group.2 The new findings showed that the association was limited to a late life dementia with cerebrovascular features, clinically diagnosed as vascular dementia. The association did not hold for dementia without cerebrovascular disease. How can this be? Perhaps the most plausible explanation is that childhood academic achievement is correlated with socioeconomic status. Socioeconomic status is strongly associated with stroke risk.3 Cerebrovascular risk factors that include diabetes, hypertension, and smoking are also linked to socioeconomic status,4 and are part of a pattern of general health behaviors that are driven by personal health choices such as diet, exercise, cigarette use, and use or access to medical care. Childhood mental achievement might mediate later lifestyle choices which then predispose to cerebrovascular disease, which then causes a "vascular" dementia.
The second article5 examined associations of obesity in midlife and late life dementia. There are several prior reports of the same association.6,7 The key difference in this new report is that central obesity-having large abdominal girth-was a stronger risk factor than body mass index (BMI). In fact, in the subset of subjects with normal BMI, those with central obesity had a higher risk for dementia than those without central obesity. Furthermore, controlling for diabetes did not attenuate the association. The authors speculated that central obesity-which is more closely linked to metabolic syndrome than is BMI-might have a different and more pernicious pathophysiology than simply being overweight. The authors5 make the point that high visceral adiposity might promote production of inflammatory cytokines and hormones, which themselves are neurotoxic. However, obesity is also associated with education and childhood social class8 and is strongly associated with diabetes and hypertension. One of the prior reports noted that vascular risk factors acted additively with obesity to raise the risk of dementia.7
The link between midlife diabetes and late life dementia has been observed in several longitudinal studies.9-12 The third report13 specifically examined the impact of glycemic control in midlife and late life dementia. The unique aspect of the current report was that the authors were able to separate the impact of inadequate production of insulin from insulin resistance. While both of these mechanisms result in impaired glycemic control, they have different underlying pathophysiologic bases. As the new report shows, the two mechanisms appear to have differential associations on dementia with cerebrovascular features (vascular dementia) vs clinical Alzheimer disease (AD). Impaired acute insulin response was more strongly associated with clinical AD, while insulin resistance showed associations with both AD and vascular dementia. The impact of diabetes on late life dementia might therefore flow through two routes, one that could be specific for AD pathophysiology through the interactions of insulin and beta-amyloidosis,14 and another mediated by diabetic microvascular disease. Because the pathogenesis of type 2 diabetes is convincingly tied to obesity, the risk of diabetes on late life dementia has it origins in the health-related, dietary, and exercise behaviors of early adulthood and midlife.
The three articles highlight the interplay of early life mental abilities, a particular pattern of midlife obesity, and the diversity of aberrations in midlife glycemic control. Because epidemiologic studies by themselves leave open the causal mechanisms involved in the associations, and sometimes oversimplify multifactorial processes, the proposed chain of causality should be considered simply a hypothesis. Indeed, the idea that childhood academic achievement might be linked to late life dementia might seem implausible. However, the series of associations each has an empiric basis that seem headed in one direction: 1) from unhealthy exercise habits and food preferences acquired in childhood to obesity, 2) from obesity to diabetes and metabolic syndrome, and 3) from smoking, diabetes, and obesity to an increased risk for cerebrovascular disease and vascular dementia. Going to the head of the class academically is important, but perhaps the three Rs are not the only thing to be learning when you are young. Learning healthful behaviors to avoid smoking, diabetes, and obesity are also critical to garnering an "A" for your brain in late life.
Supported in part by grants U01 AG 06786 (Mayo Alzheimer's Disease Patient Registry) and P50 AG 16574 (Mayo Alzheimer's Disease Research Center) from the National Institute on Aging.
Disclosure: D.S.K. has served on a Data Safety Monitoring Board of a clinical trial of rimonabant for Sanofi-Aventis Pharmaceuticals and is an investigator in a clinical trial sponsored by Elan Pharmaceuticals. He is an Associate Editor of Neurology.
REFERENCES
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3. Avendano M, Kawachi I, Van Lenthe F, et al. Socioeconomic status and stroke incidence in the US elderly: the role of risk factors in the EPESE study. Stroke 2006;37:1368-1373.[Abstract/Free Full Text]
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9. Curb JD, Rodriguez BL, Abbott RD, et al. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. Neurology 1999;52:971-975.[Abstract/Free Full Text]
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12. Leibson CL, Rocca WA, Hanson VA, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 1997;145:301-308.[Abstract/Free Full Text]
13. Ronnemaa E, Zethelius B, Sundelof J, et al. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology 2008;71:1065-1071.[Abstract/Free Full Text]
14. Craft S, Watson GS. Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 2004;3:169-178.[Medline]
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