Midlife adiposity predicts earlier onset of Alzheimer’s dementia, neuropathology and presymptomatic cerebral amyloid accumulation

Abstract

Understanding how midlife risk factors influence age at onset (AAO) of Alzheimer’s disease (AD) may provide clues to delay disease expression. Although midlife adiposity predicts increased incidence of AD, it is unclear whether it affects AAO and severity of Alzheimer’s neuropathology. Using a prospective population-based cohort, Baltimore Longitudinal Study of Aging (BLSA), this study aims to examine the relationships between midlife body mass index (BMI) and (1) AAO of AD (2) severity of Alzheimer’s neuropathology and (3) fibrillar brain amyloid deposition during aging. We analyzed data on 1394 cognitively normal individuals at baseline (8643 visits; average follow-up interval 13.9 years), among whom 142 participants developed incident AD. In two subsamples of BLSA, 191 participants underwent autopsy and neuropathological assessment, and 75 non-demented individuals underwent brain amyloid imaging. Midlife adiposity was derived from BMI data at 50 years of age. We find that each unit increase in midlife BMI predicts earlier onset of AD by 6.7 months (P=0.013). Higher midlife BMI was associated with greater Braak neurofibrillary but not CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuritic plaque scores at autopsy overall. Associations between midlife BMI and brain amyloid burden approached statistical significance. Thus, higher midlife BMI was also associated with greater fibrillar amyloid measured by global mean cortical distribution volume ratio (P=0.075) and within the precuneus (left, P=0.061; right, P=0.079). In conclusion, midlife overweight predicts earlier onset of AD and greater burden of Alzheimer’s neuropathology. A healthy BMI at midlife may delay the onset of AD.

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References

  1. 1

    Barnes DE, Yaffe K . The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 2011; 10: 819–828.

    Article  Google Scholar 

  2. 2

    Brookmeyer R, Johnson E, Ziegler-Graham K, Arrighi HM . Forecasting the global burden of Alzheimer's disease. Alzheimers Dement 2007; 3: 186–191.

    Article  Google Scholar 

  3. 3

    Brookmeyer R, Gray S, Kawas C . Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health 1998; 88: 1337–1342.

    CAS  Article  Google Scholar 

  4. 4

    Lourida I, Soni M, Thompson-Coon J, Purandare N, Lang IA, Ukoumunne OC et al. Mediterranean diet, cognitive function, and dementia: a systematic review. Epidemiology 2013; 24: 479–489.

    Article  Google Scholar 

  5. 5

    Radak Z, Hart N, Sarga L, Koltai E, Atalay M, Ohno H et al. Exercise plays a preventive role against Alzheimer's disease. J Alzheimers Dis 2010; 20: 777–783.

    Article  Google Scholar 

  6. 6

    Hassing LB, Dahl AK, Thorvaldsson V, Berg S, Gatz M, Pedersen NL et al. Overweight in midlife and risk of dementia: a 40-year follow-up study. Int J Obes (Lond) 2009; 33: 893–898.

    CAS  Article  Google Scholar 

  7. 7

    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; 12: e426–e437.

    CAS  Article  Google Scholar 

  8. 8

    Beydoun MA, Beydoun HA, Wang Y . Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obes Rev 2008; 9: 204–218.

    CAS  Article  Google Scholar 

  9. 9

    Beydoun MA, Lhotsky A, Wang Y, Dal Forno G, An Y, Metter EJ et al. Association of adiposity status and changes in early to mid-adulthood with incidence of Alzheimer's disease. Am J Epidemiol 2008; 168: 1179–1189.

    Article  Google Scholar 

  10. 10

    Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O'Meara ES, Longstreth WT Jr et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol 2009; 66: 336–342.

    Article  Google Scholar 

  11. 11

    Tolppanen AM, Ngandu T, Kareholt I, Laatikainen T, Rusanen M, Soininen H et al. Midlife and late-life body mass index and late-life dementia: results from a prospective population-based cohort. J Alzheimers Dis 2014; 38: 201–209.

    Article  Google Scholar 

  12. 12

    Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K . Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ 2005; 330: 1360.

    Article  Google Scholar 

  13. 13

    Ford ES, Mokdad AH . Epidemiology of obesity in the Western Hemisphere. J Clin Endocrinol Metab 2008; 93 (Suppl 1): S1–S8.

    CAS  Article  Google Scholar 

  14. 14

    Kelly T, Yang W, Chen CS, Reynolds K, He J . Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 2008; 32: 1431–1437.

    CAS  Article  Google Scholar 

  15. 15

    Wang Y, Beydoun MA, Liang L, Caballero B, Kumanyika SK . Will all Americans become overweight or obese? estimating the progression and cost of the US obesity epidemic. Obesity (Silver Spring, MD) 2008; 16: 2323–2330.

    Article  Google Scholar 

  16. 16

    Shock NW, Gruelich R, Andres R, Arenberg D, Costa PT, Lakatta E et al. Normal Human Aging. The Baltimore Longitudinal Study of Aging, US Government Printing Office: Washington, DC, USA, 1984.

  17. 17

    Ferrucci L . The Baltimore Longitudinal Study of Aging (BLSA): a 50-year-long journey and plans for the future. J Gerontol A 2008; 63: 1416–1419.

    Article  Google Scholar 

  18. 18

    Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A . Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 2000; 54: 2072–2077.

    CAS  Article  Google Scholar 

  19. 19

    American Psychiatric Association APAWGtRDSM, III Diagnostic and Statistical Manual of Mental Disorders: DSM-III-R. American Psychiatric Association: : Washington, DC, 1987.

  20. 20

    McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.

    CAS  Article  Google Scholar 

  21. 21

    Petersen RC . Mild cognitive impairment as a diagnostic entity. J Intern Med 2004; 256: 183–194.

    CAS  Article  Google Scholar 

  22. 22

    O'Brien RJ, Resnick SM, Zonderman AB, Ferrucci L, Crain BJ, Pletnikova O et al. Neuropathologic studies of the Baltimore Longitudinal Study of Aging (BLSA). J Alzheimers Dis 2009; 18: 665–675.

    Article  Google Scholar 

  23. 23

    Gamaldo A, Moghekar A, Kilada S, Resnick SM, Zonderman AB, O'Brien R . Effect of a clinical stroke on the risk of dementia in a prospective cohort. Neurology 2006; 67: 1363–1369.

    CAS  Article  Google Scholar 

  24. 24

    Troncoso JC, Zonderman AB, Resnick SM, Crain B, Pletnikova O, O'Brien RJ . Effect of infarcts on dementia in the Baltimore longitudinal study of aging. Ann Neurol 2008; 64: 168–176.

    Article  Google Scholar 

  25. 25

    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al. The Consortium to establish a registry for Alzheimer's disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991; 41: 479–486.

    CAS  Article  Google Scholar 

  26. 26

    Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.

    CAS  Article  Google Scholar 

  27. 27

    Resnick SM, Goldszal AF, Davatzikos C, Golski S, Kraut MA, Metter EJ et al. One-year age changes in MRI brain volumes in older adults. Cereb Cortex 2000; 10: 464–472.

    CAS  Article  Google Scholar 

  28. 28

    Sojkova J, Zhou Y, An Y, Kraut MA, Ferrucci L, Wong DF et al. Longitudinal patterns of beta-amyloid deposition in nondemented older adults. Arch Neurol 2011; 68: 644–649.

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Fischl B . FreeSurfer. Neuroimage 2012; 62: 774–781.

    Article  Google Scholar 

  30. 30

    McAuliffe MJ, Lalonde FM, McGarry D, Gandler W, Csaky K, Trus BL . Medical image processing, analysis and visualization in clinical research. In: Fourteenth IEEE Symposium On Computer-based Medical Systems. Washington, DC, USA 2001.

  31. 31

    Lucas BC, Bogovic JA, Carass A, Bazin PL, Prince JL, Pham DL et al. The Java Image Science Toolkit (JIST) for rapid prototyping and publishing of neuroimaging software. Neuroinformatics 2010; 8: 5–17.

    Article  Google Scholar 

  32. 32

    Ashburner J, Friston KJ . Spatial transformation of images. In: Frackowiak RSJ, Friston KJ, Frith C, Dolan R, Mazziotta JC . Human Brain Function. Academic Press: New York, NY, USA, 1997.

    Google Scholar 

  33. 33

    Jenkinson M, Bannister P, Brady M, Smith S . Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 2002; 17: 825–841.

    Article  Google Scholar 

  34. 34

    Zhou Y, Endres CJ, Brasic JR, Huang SC, Wong DF . Linear regression with spatial constraint to generate parametric images of ligand-receptor dynamic PET studies with a simplified reference tissue model. Neuroimage 2003; 18: 975–989.

    Article  Google Scholar 

  35. 35

    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP et al. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol 2004; 55: 306–319.

    CAS  Article  Google Scholar 

  36. 36

    Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH et al. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 2006; 67: 446–452.

    CAS  Article  Google Scholar 

  37. 37

    Carroll RJ . Measurement Error in Nonlinear Models : A Modern Perspective. Chapman & Hall/CRC: : London, UK, 2006.

    Google Scholar 

  38. 38

    Swindell WR . Accelerated failure time models provide a useful statistical framework for aging research. Exp Gerontol 2009; 44: 190–200.

    Article  Google Scholar 

  39. 39

    Singh B, Parsaik AK, Mielke MM, Erwin PJ, Knopman DS, Petersen RC et al. Association of mediterranean diet with mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis 2014; 39: 271–282.

    Article  Google Scholar 

  40. 40

    Carlson MC, Helms MJ, Steffens DC, Burke JR, Potter GG, Plassman BL . Midlife activity predicts risk of dementia in older male twin pairs. Alzheimers Dement 2008; 4: 324–331.

    Article  Google Scholar 

  41. 41

    Farrell SW, Finley CE, Radford NB, Haskell WL . Cardiorespiratory fitness, body mass index, and heart failure mortality in men: Cooper Center Longitudinal Study. Circ Heart Fail 2013; 6: 898–905.

    Article  Google Scholar 

  42. 42

    Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto J et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol 2005; 4: 705–711.

    Article  Google Scholar 

  43. 43

    Sabia S, Singh-Manoux A, Hagger-Johnson G, Cambois E, Brunner EJ, Kivimaki M . Influence of individual and combined healthy behaviours on successful aging. CMAJ 2012; 184: 1985–1992.

    Article  Google Scholar 

  44. 44

    Akushevich I, Kravchenko J, Ukraintseva S, Arbeev K, Kulminski A, Yashin AI . Morbidity risks among older adults with pre-existing age-related diseases. Exp Gerontol 2013; 48: 1395–1401.

    Article  Google Scholar 

  45. 45

    Gillette-Guyonnet S, Nourhashemi F, Andrieu S, de Glisezinski I, Ousset PJ, Riviere D et al. Weight loss in Alzheimer disease. Am J Clin Nutr 2000; 71: 637S–642S.

    CAS  Article  Google Scholar 

  46. 46

    Driscoll I, Beydoun MA, An Y, Davatzikos C, Ferrucci L, Zonderman AB et al. Midlife obesity and trajectories of brain volume changes in older adults. Hum Brain Mapp 2012; 33: 2204–2210.

    Article  Google Scholar 

  47. 47

    Das UN . Is obesity an inflammatory condition? Nutrition 2001; 17: 953–966.

    CAS  Article  Google Scholar 

  48. 48

    Purkayastha S, Cai D . Neuroinflammatory basis of metabolic syndrome. Mol Metab 2013; 2: 356–363.

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful to the Baltimore Longitudinal Study of Aging participants and neuroimaging staff for their dedication to these studies and the staff of the Johns Hopkins University PET facility for their assistance. This work was supported in part by research and development contract HHSN-260-2004-00012C and the Intramural Research Program, National Institute on Aging, National Institutes of Health.

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Correspondence to M Thambisetty.

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Chuang, Y., An, Y., Bilgel, M. et al. Midlife adiposity predicts earlier onset of Alzheimer’s dementia, neuropathology and presymptomatic cerebral amyloid accumulation. Mol Psychiatry 21, 910–915 (2016). https://doi.org/10.1038/mp.2015.129

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