Central obesity and increased risk of dementia more than three decades later
Abstract
Background: Numerous reports show that a centralized distribution of adiposity is a more dangerous risk factor for cardiovascular disease and diabetes than total body obesity. No studies have evaluated whether the same pattern exists with dementia. The objective was to evaluate the association between midlife central obesity and risk of dementia three decades later.
Methods: A longitudinal analysis was conducted of 6,583 members of Kaiser Permanente of Northern California who had their sagittal abdominal diameter (SAD) measured in 1964 to 1973. Diagnoses of dementia were from medical records an average of 36 years later, January 1, 1994, to June 16, 2006. Cox proportional hazard models adjusted for age, sex, race, education, marital status, diabetes, hypertension, hyperlipidemia, stroke, heart disease, and medical utilization were conducted.
Results: A total of 1,049 participants (15.9%) were diagnosed with dementia. Compared with those in the lowest quintile of SAD, those in the highest had nearly a threefold increased risk of dementia (hazard ratio, 2.72; 95% CI, 2.33–3.33), and this was only mildly attenuated after adding body mass index (BMI) to the model (hazard ratio, 1.92; 95% CI, 1.58–2.35). Those with high SAD (>25 cm) and normal BMI had an increased risk (hazard ratio, 1.89; 95% CI, 0.98–3.81) vs those with low SAD (<25 cm) and normal BMI (18.5–24.9 kg/m2), whereas those both obese (BMI >30 kg/m2) and with high SAD had the highest risk of dementia (HR, 3.60; 95% CI, 2.85–4.55).
Conclusions: Central obesity in midlife increases risk of dementia independent of diabetes and cardiovascular comorbidities. Fifty percent of adults have central obesity; therefore, mechanisms linking central obesity to dementia need to be unveiled.
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Published In
Neurology®
Volume 71 • Number 14 • September 30, 2008
Pages: 1057-1064
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© 2008.
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Published online: March 26, 2008
Published in print: September 30, 2008
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I read with interest the longitudinal study [1] of US patients which adds dementia to the other well known negative outcomes associated with visceral obesity. [5] I would like to add a useful caveat: waist circumference is most accurately interpreted in the context of ethnicity.
Current ATP-III criteria for metabolic syndrome define abdominal obesity as a waist circumference in men >102 cm (40 in) and in women >88 cm (35 in). [6] The International Diabetes Foundation created definitions for four different ethnic groups and may include three more groups when data become available. [7] Using ATP-III criteria, a patient of Asian origin, for example, might be misclassified as having "normal" waist circumference.
For many patients with visceral obesity, losing weight through diet control and exercise is difficult but this study provides yet another motivation to pursue these therapeutic lifestyle changes.
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Disclosure: The author reports no disclosures.
We read with interest the recent article by Whitmer et al. who provide evidence of a longitudinal link between middle-life visceral obesity and dementia risk. [1] It is now apparent that intra-abdominal fat may play a role in other health complications in addition to cardiovascular disease (CVD). Unfortunately, the underlying mechanisms are still unclear.
To explain the observations that overall adiposity is linked both to cognitive decline and CVD and that concurrent CVD is often seen in older dementia patients, we recently reviewed current physiopathologic theories. [2,3] We concluded that visceral adipose tissue (VAT) is consistently implicated in cognitive decline rather than body mass index.
In addition, women who experience changes in body composition and fat distribution after menopause transition are at an increased risk of AD. This is due to a stronger link to vascular factors (pro-inflammatory molecules) and metabolic complications (insulin resistance, dyslipidemia, hypertension). [3]
Luchsinger et al. have hypothesized that in people over 65, a short-term (5-year follow-up) prospective association seems modified by age and is different depending on the anthropometric measure. [4] However, a life course contribution to chronic diseases is recognized. [2] The study by Whitmer et al. [1] supports the previously suggested theory [2,3] particularly when multiple adjustments for concurrent VAT-related complications (diabetes, hypertension, hyperlipidemia and CVDs) are considered. In this respect, the role of VAT as endocrine organ, which is able to release a number of mediators, appears fundamental.
The confounding effect of insulin resistance should be recognized but it should also be noted that a chronic low-grade inflammation is a precondition associated with obesity duration. Reduction in VAT, particularly through physical activity, is efficacious in improving metabolic profile and inflammation. However, long-term results are difficult to maintain and protective effects are still unclear. [3] It is possible that further adjustment for physical activity would have strengthened the authors' evidence. This warrants further investigation and anthropometric data is not readily available.
Despite this study's limitations, the suggested use of available surrogates of visceral adiposity other than sagittal abdominal diameter in a neurological setting is justified. [2]
References
1. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008; (in press)
2. Cereda E, Sansone V, Meola G, Malavazos AE. Increased visceral adipose tissue rather than BMI as a risk factor for dementia. Age Ageing 2007;36:488-491.
3. Cereda E, Battezzati A, Bertoli S, Malavazos AE, Testolin G. A life-course contribution of nutrition to future cognitive decline. In: Bernhardt NE and Kasko AM editors. Nutrition for the Middle-Aged and Elderly. Hauppauge NY: Nova Science Publishers; 2008 (in press).
4. Luchsinger JA, Patel B, Tang MX, Schupf N, Mayeux R. Measures of adiposity and dementia risk in elderly persons. Arch Neurol 2007;64:392-398.
Disclosure: The authors report no disclosures.
Whitmer et al. demonstrated a significant correlation between mid-life obesity and dementia later in life and suggested that visceral adipocyte-derived factors may be neurotoxic, contributing to the slow deterioration of the CNS. [1]
However, it has been shown that some of these factors including leptin may be beneficial to neurons. Leptin is capable of reducing the brain Aß load [8], is neuroprotective and improves cognitive performance of aged rodents. [9]
Obesity is often characterized by some form of leptin resistance that may be attributable to CRP (C-reactive protein), which is elevated in obesity. [10] CRP can bind to leptin preventing its binding to the leptin receptor. Therefore, obese subjects may be deprived from leptin's beneficial action, propagating obesity and neurodegeneration.
It has also been documented that obese individuals who eventually developed AD may experience a loss in weight prior to the onset of dementia. [11] A gradual selective neuronal loss in the hippocampus, hypothalamus, or both due to the absence of centrally acting leptin may lead to disturbances in appetite.
In AD patients, leptin levels are reduced whereas blood CRP levels are normal so leptin therapy may benefit AD patients. Additional benefits may include ability to increase insulin sensitivity and alleviate insulin resistance which are common in AD.
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Disclosure: Dr. Tezapsidis is the founder of Neurotez, Inc., a private CNS biotechnology corporation (www.neurotez.com) that is pursuing leptin as a novel therapeutic for AD. Drs. Mark Smith and Wes Ashford are affiliated with Neurotez, Inc.
We thank Drs. Cereda, Farooki, and Tezapsidis for their comments on our article. [1]
We agree with Cereda et al. that obesity and central obesity confers with it a state of inflammation and this may also contribute to cognitive impairment and dementia risk. Unfortunately measures of physical activity were not available so it is unknown what effect this would have on the association between midlife central obesity status and dementia risk.
We also concur that visceral adipose tissue itself is the likely culprit in the association between central obesity and increased dementia risk. Hopefully, future studies will investigate possible actions of visceral adipocytes on the brain and effects of an altered adipokine milieu on cognitive status. [12]
Regarding comments from Farooki et al., ethnic specific anthropometric measurements are the most precise. Although there are standard ethnic specific guidelines for waist circumference in defining central obesity, there are not published ethnic specific guidelines for sagittal abdominal diameter, the anthropometric measurement used in our study. Future studies examining central obesity and disease outcomes should incorporate these guidelines.
With respect to comments from Tezapsidis concerning leptin as a possible therapeutic for patients with AD, leptin has been shown to be beneficial to neurons. However, obesity is associated with 'leptin resistance' so it is possible that obese individuals may not respond to possible neuroprotective effects of leptin. However, a recent study in non-demented elders demonstrated that higher serum leptin levels are associated with better cognitive performance independent of total body weight and total body fat. [13] More work is needed on how states of leptin resistance as induced by chronic obesity may contribute to brain aging.
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Disclosure: The authors report no disclosures.