Pound-for-Pound Protection: Does Obesity Guard Against Dementia?

In the ever-evolving saga about body weight and dementia, the plot just thickened. In fact, it put on some serious poundage. According to the largest study ever conducted on the subject, obese people in the United Kingdom carried a third lower risk of developing dementia than healthy-weight peers, while their underweight compatriots padded their risk by the same amount. The study stands against a backdrop of conflicting evidence—some previous studies linked mid-life obesity to dementia; others did not. The findings underscore the complex relationships between dementia and lifestyle factors, such as body weight. Researchers led by Stuart Pocock at the London School of Hygiene and Tropical Medicine reported their findings in the April 10 Lancet Diabetes and Endocrinology,

Before you inhale that entire tub of ice cream, know that the other health risks of obesity still outweigh the benefits of potentially dodging Alzheimer’s and similar diseases. “Even if obesity protects you from developing dementia, you may not live long enough to get the benefit,” cautioned first author Nawab Qizilbash of OXON Epidemiology, a contract research organization in Madrid. Shorter life expectancy did not explain why people with high body-mass index were spared from dementia, however, because Qizilbash and colleagues corrected for a host of potentially confounding factors including mortality.

Research conducted in the last decade paints a murky picture of the body weight/dementia dynamic. Epidemiological data from several countries indicates that obesity in middle age increases the risk of dementia later in life (see Kivipelto et al., 2005; Xu et al., 2011; Chiang et al., 2007). Typifying the “obesity paradox,” other findings suggested that while middle-age obesity raises the later risk of dementia, obesity in old age actually protects people (see Fitzpatrick et al., 2009). Others found that being underweight can precipitate dementia, while being overweight protects (see Strand et al., 2013; Stewart et al., 2005). Some studies found that the girth of the midsection, but not body mass index, elevated dementia risk (see Whitmer et al., 2008; Gustafson et al., 2009). Overall, a meta-analysis on Alzrisk indicated that being over- or underweight may be a risk factor for dementia at some point in life, but that more studies with longer follow-up times were needed.

Qizilbash and colleagues drew from the United Kingdom Clinical Practice Research Datalink. CPRD is a massive database containing health information about anyone in the country who has visited a general practitioner. They looked at the earliest available BMI measurement for nearly 2 million people who were 40 years old or older between 1992 and 2007, and retrospectively tracked the cohort for dementia diagnoses until 2013. They then compared dementia rates with those one-time baseline BMI measurements.

During an average of more than nine years of follow-up, a dementia diagnosis was made in 45,507 people, or 2.4 percent of the cohort. Compared to people who had a healthy BMI of 20-24.9, those whose BMI was lower had a 34 percent higher incidence of dementia. In contrast, dementia incidence went down as BMI rose above 25, with very obese people with a BMI over 40 having a 29 percent lower risk of developing dementia than healthy-weight people. These associations held up when the researchers adjusted the data for age, smoking, alcohol use, diabetes, previous heart attack, and the use of statins or anti-hypertensive drugs.

The correlations held up regardless of how long people were tracked after their baseline BMI measurement. In other words, underweight people had the highest risk of dementia of all BMI groups at one year or 15 years after their BMI measurement. Obese people in the study were younger, on average, at baseline than those who were underweight, but that did not explain why they were protected—the relationships between BMI and dementia held steady even when the researchers considered only people whose initial BMI measurement was taken by age 55.

To address the obvious question of whether obese people escaped dementia by dying earlier, the researchers adjusted for mortality. They found that while body weight associated with mortality (both obese and underweight people had higher death rates than healthy-weight people), adjusting for that did not dramatically alter the association with dementia. Even when taking each person who died and counting him or her as a survivor who was twice as likely to develop dementia because of some ongoing comorbidity, obese people still had a 20 percent lower risk of developing dementia than healthy-weight people.

Deborah Barnes of the University of California, San Francisco, was impressed by the study’s size and extensive controls. “This is a really interesting study that calls into question the belief that obesity in mid-life is associated with an increased risk of developing dementia later in life,” she wrote. “It still is not clear whether this is a causal relationship or whether BMI is a marker of something else—perhaps socioeconomic status or access to enough food.”

Researchers were hesitant to speculate why obesity would protect against dementia. Costantino Iadecola of Weill Cornell Medical College in New York offered that increases in adipocyte hormones such as leptin might be involved because they are thought to be neuroprotective. However, he noted that the protective effect of being overweight flattened out as BMI increased in the study, suggesting that a simple linear relationship between leptin and reduced dementia risk was unlikely.

Iadecola cautioned against over-interpretation of the results, pointing out that BMI is not a measurement of overall health, and does not explain why a person is over- or underweight. “Someone’s body weight is a result of myriad different influences that you cannot just sum up with one number,” he said. Iadecola said that, for example, the location of fat tissue in the body influences its health effects. Also, people who are underweight could have lost fat, muscle, or bone, all of which influence health outcomes differently. He added that food intake should not be interpreted as the only factor influencing weight loss or gain, as metabolic conditions can play a role. Finally, Iadecola noted that different forms of dementia are likely to be influenced by different health and cardiovascular factors, and the study did not distinguish between dementia types.

“This provocative study brings to the forefront our need to gain an understanding of how body weight is regulated in different age groups, and its cognitive impact,” he said. “We have to use this as a starting point.”

Because this study was based on a baseline measure of BMI, Qizilbash said the researchers will next consider how gaining or losing weight affects dementia. For example, dementia risk could be different for a person who has been underweight all of his or her life than another person who rapidly starts shedding pounds due to a health problem. Qizilbash said the most important finding of his study is that being underweight is a strong risk factor for dementia, even many years prior to onset. “This risk factor needs to be addressed,” he said. Regarding the obesity side of the data, Qizilbash said, “The idea that reduction in obesity will lead to a reduction in dementia is probably incorrect.”

In an accompanying commentary, Deborah Gustafson of the University of Gothenberg in Sweden struck a cautious tone. She mentioned several limitations, including the lack of specific dementia diagnoses and the wide distribution of age at which BMI was measured in the cohort. “To understand the association between BMI and late-onset dementia should sober us as to the complexity of identifying risk and protective factors for dementia,” she wrote. “The report by Qizilbash and colleagues is not the final word on this controversial topic.”—Jessica Shugart

Comments

  1. The increased dementia risk associated with underweight in midlife fits well with our own unpublished results, which have been puzzled about. Our intention has been to publish a separate paper on this, where we include BMI in early midlife, late midlife, and old age, and its association with dementia. There are few such papers and it would be interesting to see if the results are replicated.

    View all comments by Bjørn Heine Strand

  2. It is becoming more appreciated that damage to microvessels and the blood-brain barrier may kick-start Alzheimer’s disease (AD) progression. In fact, ailments affecting the neurovasculature, such as cardiovascular disease, hypertension, stroke, and diabetes, are established risk factors for AD and other neurodegenerative diseases. These vascular risk factors are more common in obese individuals. Qizilbash et al. studied almost two million individuals to determine if body mass index (BMI) alters the chance of a person developing dementia. They found that underweight individuals have a higher risk and obese people have a lower risk of developing dementia.

    So what does this mean? BMI is not the ideal anthropometric measure to use in these studies because it gives no indication of metabolic health. Unlike BMI, waist-to-hip ratio is a better indicator of the amount of visceral fat an individual has. Visceral fat around organs is negatively associated with adverse metabolic health and can go undetected by BMI. There are many obese individuals who are metabolically healthy and underweight individuals who are not. With that said, it is important to note that subcutaneous body fat can function as an energy reserve. With aging, there is a loss of appetite due to a reduction in sensory receptors and less absorption of nutrients in the gut. Senescence leads to a loss of macronutrients (energy and protein) and micronutrients (vitamins B6, B12, and folic acid). These multiple nutrient deficiencies can be the result of physiological, social, and economic factors which Qizilbash et al. did not assess. Furthermore, dietary fat determines the lipid composition of the brain. Therefore, it is possible that the data here could be parsing out individuals based on their nutrition and metabolism that could be a consequence of many factors. Future large-scale studies that determine links between metabolic health (by measuring visceral fat, ideally by DEXA scan) and dementia risk are warranted and of great importance.

    The data in the manuscript were adjusted using sophisticated statistical modeling that is difficult to follow. No raw data is shown for BMI and dementia risk. Instead, all data used to assess BMI impact on dementia risk was adjusted for age and gender. It is well established that age is the most common risk factor for AD and women are more likely to develop the disease. The authors chose to adjust their data to eliminate these effects, presumptively to have a clear picture of body weight on cognitive impairment without known confounds. However, the way in which they adjust their data for age is unusual. They account for “age at risk” but it is ambiguous what this means aside from it being a “more meaningful time point.” The authors should define what made this time point meaningful. It is possible their data would look different had they not made this adjustment.

    They next go on to modify their data for age, sex, smoking status, alcohol status, diabetes, previous myocardial infarction, statin use, and anti-hypertensive use and find the same dementia risk for BMI. When accounting for all of the above and mortality rate, Qizilbash et al. “did a sensitivity analysis to account for the hypothesis that those who died would have had double the risk of dementia if they had survived.” The authors should scientifically justify this hypothesis. Furthermore, the definition of dementia was quite broad in scope, encompassing the diagnosis of all dementia including Alzheimer’s, Lewy body disease, or Pick’s disease, and any listed on death certificates.

    Overall, these findings may give individuals the false illusion that an unhealthy lifestyle is beneficial in preventing dementia. However, this is not the case. Unfortunately, important measurements like physical activity, blood pressure, and blood lipid values were not accounted for in this study. Good nutrition and exercise are critical for proper heart and brain health. Thus, more comprehensive studies carefully examining cognition/dementia, nutrition, metabolism, physical activity and lifestyle are needed. 

    View all comments by Berislav Zlokovic

  3. In the past decade, many population-based studies have evaluated the relationship between body-mass index (BMI) and dementia. Two studies from our group have shown that obesity and even being overweight at midlife are associated with increased risk of dementia later in life (Kivipelto et al., 2005; Xu et al., 2011). In both studies, BMI was assessed in people age 40 to 60. A meta-analysis on this topic confirmed these findings (Anstey et al., 2011). However, several studies, including ours, report an association between lower BMI and prevalent dementia and a protective effect of high BMI within five years after dementia onset (Atti et al., 2008; Luchsinger and Gustafson, 2009), and low BMI and weight loss have been suggested as preclinical markers of dementia (Gustafson, 2008). Therefore, we need to pay special attention to the time windows of BMI assessment and age of dementia onset when examining their association.

    Unfortunately this issue, i.e., age at exposure, has not been properly taken into account by Qizilbash and colleagues. In their recent report they claimed that their “results contradict the hypothesis that obesity in middle age could increase the risk of dementia in old age.” BMI in Qizilbash's study was assessed in people age 40 or older (range 40 through 80-plus). Thus, age at BMI assessment included both midlife (40 to 60) and later life (60 through 80-plus). As a result, the BMI-dementia association reported in this paper reflects a mixture of midlife and later-life effects of BMI on dementia risk. In addition, other methodological limitations, such as the way the authors identified the dementia-free population and the questionable dementia ascertainment and dementia ascertainment, may affect the results.

    To better understand this paper’s contribution to the current knowledge concerning obesity and cognitive aging, it would be relevant to perform an analysis stratified by age at exposure to obesity and to estimate the extent to which cohort definition and selection bias affect the results. 

    References:

    Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1556-60. PubMed.

    Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L. Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology. 2011 May 3;76(18):1568-74. PubMed.

    Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev. 2011 May;12(5):e426-37. PubMed.

    Atti AR, Palmer K, Volpato S, Winblad B, De Ronchi D, Fratiglioni L. Late-life body mass index and dementia incidence: nine-year follow-up data from the Kungsholmen Project. J Am Geriatr Soc. 2008 Jan 1;56(1):111-6. PubMed.

    Luchsinger JA, Gustafson DR. Adiposity, type 2 diabetes, and Alzheimer's disease. J Alzheimers Dis. 2009;16(4):693-704. PubMed.

    Gustafson D. A life course of adiposity and dementia. Eur J Pharmacol. 2008 May 6;585(1):163-75. Epub 2008 Mar 4 PubMed.

    View all comments by Weili Xu

  4. You seem to have overlooked a paper published by myself and a colleague (Wotton and Goldacre, 2014) on obesity and subsequent risk of dementia. 

    This was also a very large study of people in England, although our data are from hospital episode statistics (HES) data.  We found people admitted to hospital with obesity whilst in their 30s conveyed the greatest risk of future dementia, and that this risk gradually declined with increasing age.  In people admitted to hospital with obesity in their 70s, there was no association with dementia, and for those older, the risk became reduced.

    References:

    Wotton CJ, Goldacre MJ. Age at obesity and association with subsequent dementia: record linkage study. Postgrad Med J. 2014 Oct;90(1068):547-51. Epub 2014 Aug 20 PubMed.

    View all comments by Clare Wotton

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References

Paper Citations

  1. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1556-60. PubMed.
  2. Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L. Midlife overweight and obesity increase late-life dementia risk: a population-based twin study. Neurology. 2011 May 3;76(18):1568-74. PubMed.
  3. Chiang CJ, Yip PK, Wu SC, Lu CS, Liou CW, Liu HC, Liu CK, Chu CH, Hwang CS, Sung SF, Hsu YD, Chen CC, Liu SI, Yan SH, Fong CS, Chang SF, You SL, Chen CJ. Midlife risk factors for subtypes of dementia: a nested case-control study in Taiwan. Am J Geriatr Psychiatry. 2007 Sep;15(9):762-71. PubMed.
  4. Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth WT, Luchsinger JA. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol. 2009 Mar;66(3):336-42. PubMed.
  5. Strand BH, Langballe EM, Hjellvik V, Handal M, Næss O, Knudsen GP, Refsum H, Tambs K, Nafstad P, Schirmer H, Bergem AL, Selmer R, Engedal K, Magnus P, Bjertness E, . Midlife vascular risk factors and their association with dementia deaths: results from a Norwegian prospective study followed up for 35 years. J Neurol Sci. 2013 Jan 15;324(1-2):124-30. PubMed.
  6. Stewart R, Masaki K, Xue QL, Peila R, Petrovitch H, White LR, Launer LJ. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol. 2005 Jan;62(1):55-60. PubMed.
  7. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008 Sep 30;71(14):1057-64. Epub 2008 Mar 26 PubMed.
  8. Gustafson DR, Bäckman K, Waern M, Ostling S, Guo X, Zandi P, Mielke MM, Bengtsson C, Skoog I. Adiposity indicators and dementia over 32 years in Sweden. Neurology. 2009 Nov 10;73(19):1559-66. PubMed.

External Citations

  1. Alzrisk 

Further Reading

No Available Further Reading

Primary Papers

  1. Qizilbash N, Gregson J, Johnson ME, Pearce N, Douglas I, Wing K, Evans SJ, Pocock SJ. BMI and risk of dementia in two million people over two decades: a retrospective cohort study. Lancet Diabetes Endocrinol. 2015 Jun;3(6):431-6. Epub 2015 Apr 9 PubMed.

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