BMI and dementia feast or famine for the brain

Comment BMI and dementia: feast or famine for the brain?Overweight and obesity in mid-life, measured by BMI, have been associated with a higher risk for late-onset dementias on the basis of epidemiological reports. Adipose tissue, the main contributor to overweight and obesity, lends biological plausibility to increased risk because it is the largest endocrine organ in the human body and because it increases vascular risk.1 In The Lancet Diabetes & Endocrinology, Nawab Qizilbash and colleagues2 report the largest observational study so far of the association between BMI and dementia. In their study, which is based on almost 2 million adults from a health-care dataset in the UK (the Clinical Practice Research Datalink [CPRD]), the authors report a positive association between mid-life BMI lower than 20 kg/m² and risk of dementia: people in this BMI category had a 34% higher risk (95% CI 29–38) of dementia than did those of a healthy weight. The authors refute the hypothesis that mid-life obesity is associated with dementia risk: indeed, the incidence of dementia continued to decrease for every increasing BMI category, with very obese people (BMI >40 kg/m²) having a 29% lower (95% CI 22–36%) dementia risk than those of a healthy weight. H owever, when we seek to quantitatively estimate relevant exposure effects that are associated with health outcomes, we should assess the entire body of published literature for strength, consistency, specifi city, temporality, biological plausibility, dose–response, and coherence.3The published literature about BMI and dementia is equivocal.4 Some studies report a positive association between high mid-life BMI and dementia, whereas others do not. Studies showing an association between high mid-life BMI and dementia tend to be studies of survivors—ie, those who live long enough to develop sporadic late-onset dementias that, by defi nition, occur at 65 years of age and older. To survive means to not succumb to the chronic illnesses associated with high BMI, such as cardiovascular disease. Studies that follow people continuously from mid-to-late life, with repeated follow-ups, such as the H onolulu-Asia Aging Study (HAAS)5 and the Gothenburg Birth Cohort Studies (GBCS),6 do not report an association between higher (or lower) levels of mid-life bodyweight or BMI and late-onset dementia. In H AAS and GBCS, baseline mid-life measures were not related to the development of late-onset dementia. In H AAS, the rate and degreeof bodyweight decline was associated with late-onsetdementia,5 whereas in GBCS, women who developedlate-onset dementia had a slower rate of increase inBMI to 70 years of age than did those who did notdevelop late-onset dementia.7 H owever, the rate ofdecline thereafter was similar, resulting in a lower BMIcross-sectionally in women with late-onset dementia.7Additionally, when a survivors cohort was mimickedwithin the GBCS, an association between increasedcentral obesity (not BMI) in mid-life (38–60 years) andlate-onset dementia was recorded.6 Thus, BMI trajectorythroughout the life course, baseline BMI, competingcauses of death, and adiposity measurement (total vscentral) are important considerations.Qizilbash and colleagues’ study does have severallimitations that mean the fi ndings should be interpretedwith care. First, no consistent defi nition of “mid-life”exists in the published epidemiological literature. Studiesthat recruit birth cohorts or populations with continuousage distributions use arbitrary cutpoints. Qizilbash andcolleagues’ analyses included adults, who at baselinein 1992–2007 were aged between 40 and 80 years orolder (median 55 years [IQR 45–66]). Clearly, therefore,not all baseline ages are mid-life. Thus, a mixture ofboth mid-life and late-life BMI exposures seems to exist,representing diff erent segments of the life-course BMItrajectory.Second, studies of medical record abstraction under-estimate the occurrence of late-onset dementia andare inadequate for the diagnosis of subtypes of late-onset dementia. Dementia diagnoses in the CPRD (anydementia, Alzheimer’s disease, Lewy body dementia,and Pick’s disease) are validated, as is “any dementia”,as the cause of death. H owever, details about thisvalidation are unavailable. Traditionally, studies oflate-onset dementia risk factors are smaller than thecurrent study because of the high rigour and costthat accompany ascertainment of population-baseddementias. Extensive neuropsychiatric or neurocognitiveexaminations, consensus panels com p rising neurologistsand psychiatrists, and medical record abstractionare common in dementia epi d emiology. At present,diagnoses of late-onset dementia are made according toDSM criteria, whereas Alzheimer’s disease is diagnosedLancet Diabetes Endocrinol 2015Published OnlineApril 10, 2015/10.1016/S2213-8587(15)00085-6See Online/Articles/10.1016/S2213-8587(15)00033-9CristinaPedrazzini/SciencePhotoLibraryCommentrisk and protective factors for dementia. The report by Qizilbash and colleagues is not the fi nal word on this controversial topic. Deborah GustafsonDepartment of Neurology, SUNY – Downstate Medical Center, 450 Clarkson Avenue, Box 1213 Brooklyn, New York, NY 11203, USA; and Neuropsychiatric Epidemiology Unit, University of Gothenburg, Gothenburg, Sweden deborah.gustafson@I declare no competing interests.1 Kiliaan AJ, Arnoldussen IAC, Gustafson DR. Adipokines and dementia. Lancet Neurol 2014; 13: 913–23.2Qizilbash N, Gregson J, Johnson ME, et al. BMI and risk of dementia in two million people over two decades: a retrospective cohort study.Lancet Diabetes Endocrinol 2015; published online April 10. /10.1016/S2213-8587(15)00033-9.3 Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965; 58: 295–300.4 Emerzaal TL, KIliaan AJ, Gustafson DR. 2003–2013: a decade of body mass index, Alzheimer’s disease and dementia. J Alzheimers Dis 2015; 43: 739–55.5Stewart R, Masaki K, Xue Q-L, et al. A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study. Arch Neurol 2005; 62: 55–60.6 Gustafson DR, Bäckman K, Waern M, et al. Adiposity indicators and dementia over 32 years in Sweden. Neurology 2009; 73: 1559–66.7Gustafson DR, Backman K, Joas E, et al. 37 years of body mass index and dementia: observations from the prospective population study of women in Gothenburg, Sweden. J Alzheimers Dis 2012; 28: 163–71.8Guerreiro RJ, Gustafson DR, Hardy J. The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Aging 2012; 33: 437–56.by NINDS-ADRDA criteria and vascular dementia with NINDS-AIREN criteria.Third, age of dementia diagnosis in the CPRD is unclear. From a risk factor perspective, early-onset dementias diff er from late-onset dementias. Typically, late-onset dementias do not have a strong genetic component such as genetic mutations in APP , PSEN1, or PSEN2.8 Because baseline ages in the CPRD were 40 years and older, with a median of 9·1 years of follow-up, patients with dementia who were younger than 65 years of age were included in the cohort.Finally, the median baseline BMI in the CPRD, 26·4 kg/m² (IQR 23·5–30·0), was higher than that re-corded in previous cohorts, such as GBCS and H AAS (20–24·9 kg/m²). Whether or not the observed associations between BMI and late-onset dementia will be similar over time, in view of the secular trend of increasing BMI, is unknown.Many considerations are needed in the assessment of the epidemiology of the association between BMI and late-onset dementia, as is the case for many recorded associations involving late-life disorders. To understand the association between BMI and late-onset dementia should sober us as to the complexity 1 of identifying。