Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population

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Abstract

The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants1,2. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia3. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.

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Fig. 1: Cumulative incidence of dementia during follow-up.

Data availability

Data from the Rotterdam Study can be made available to interested researchers upon reasonable request. Requests can be directed to data manager F. J. A. van Rooij (f.vanrooij@erasmusmc.nl). We are unable to place data in a public repository owing to legal and ethical restraints. Sharing of individual participant data was not included in the informed consent of the study, and there is potential risk of revealing participants’ identities as it is not possible to completely anonymize the data. This is of particular concern given the sensitive personal nature of much of the data collected as part of the Rotterdam Study.

References

  1. 1.

    van der Lee, S. J. et al. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: a community-based cohort study. Lancet Neurol. 17, 434–444 (2018).

  2. 2.

    Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019).

  3. 3.

    de Bruijn, R. F. et al. The potential for prevention of dementia across two decades: the prospective, population-based Rotterdam Study. BMC Med. 13, 132 (2015).

  4. 4.

    Ngandu, T. et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385, 2255–2263 (2015).

  5. 5.

    Andrieu, S. et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 16, 377–389 (2017).

  6. 6.

    Moll van Charante, E. P. et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet 388, 797–805 (2016).

  7. 7.

    Licher, S. et al. Development and validation of a dementia risk prediction model in the general population: an analysis of three longitudinal studies. Am. J. Psychiatry 176, 543–551 (2018).

  8. 8.

    Guerreiro, R., Bras, J. & Hardy, J. SnapShot: genetics of Alzheimer’s disease. Cell 155, 968–968 e961 (2013).

  9. 9.

    Solomon, A. et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention: a subgroup analysis of a randomized clinical trial. JAMA Neurol. 75, 462–470 (2018).

  10. 10.

    Baumgart, M. et al. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. Alzheimers Dement. 11, 718–726 (2015).

  11. 11.

    Livingston, G. et al. Dementia prevention, intervention, and care. Lancet 390, 2673–2734 (2017).

  12. 12.

    Peters, R. et al. Combining modifiable risk factors and risk of dementia: a systematic review and meta-analysis. BMJ Open 9, e022846 (2019).

  13. 13.

    Boyle, P. A. et al. Attributable risk of Alzheimer’s dementia attributed to age-related neuropathologies. Ann. Neurol. 85, 114–124 (2019).

  14. 14.

    Risk Reduction of Cognitive Decline and Dementia: WHO Guidelines (WHO, Geneva, 2019).

  15. 15.

    Conroy, R. M. et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur. Heart J. 24, 987–1003 (2003).

  16. 16.

    Rovio, S. et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol. 4, 705–711 (2005).

  17. 17.

    Anttila, T. et al. Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study. BMJ 329, 539 (2004).

  18. 18.

    Laitinen, M. H. et al. Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dement. Geriatr. Cogn. Disord. 22, 99–107 (2006).

  19. 19.

    Karlsson, I. K. et al. Apolipoprotein E ε4 genotype and the temporal relationship between depression and dementia. Neurobiol. Aging 36, 1751–1756 (2015).

  20. 20.

    Podewils, L. J. et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am. J. Epidemiol. 161, 639–651 (2005).

  21. 21.

    Huang, T. L. et al. Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology 65, 1409–1414 (2005).

  22. 22.

    Barberger-Gateau, P. et al. Dietary patterns and risk of dementia: the Three-City cohort study. Neurology 69, 1921–1930 (2007).

  23. 23.

    Luchsinger, J. A., Tang, M. X., Siddiqui, M., Shea, S. & Mayeux, R. Alcohol intake and risk of dementia. J. Am. Geriatr. Soc. 52, 540–546 (2004).

  24. 24.

    Merchant, C. et al. The influence of smoking on the risk of Alzheimer’s disease. Neurology 52, 1408–1412 (1999).

  25. 25.

    Ott, A. et al. Smoking and risk of dementia and Alzheimer’s disease in a population-based cohort study: the Rotterdam Study. Lancet 351, 1840–1843 (1998).

  26. 26.

    Lindsay, J. et al. Risk factors for Alzheimer’s disease: a prospective analysis from the Canadian Study of Health and Aging. Am. J. Epidemiol. 156, 445–453 (2002).

  27. 27.

    Ritchie, K. et al. Designing prevention programmes to reduce incidence of dementia: prospective cohort study of modifiable risk factors. BMJ 341, c3885 (2010).

  28. 28.

    Samieri, C. et al. Association of cardiovascular health level in older age with cognitive decline and incident dementia. JAMA 320, 657–664 (2018).

  29. 29.

    Kivipelto, M. et al. Apolipoprotein E ε4 magnifies lifestyle risks for dementia: a population-based study. J. Cell Mol. Med. 12, 2762–2771 (2008).

  30. 30.

    Khera, A. V. et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N. Engl. J. Med. 375, 2349–2358 (2016).

  31. 31.

    Rutten-Jacobs, L. C. et al. Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: cohort study of 306 473 UK Biobank participants. BMJ 363, k4168 (2018).

  32. 32.

    Voortman, T. et al. Adherence to the 2015 Dutch dietary guidelines and risk of non-communicable diseases and mortality in the Rotterdam Study. Eur. J. Epidemiol. 32, 993–1005 (2017).

  33. 33.

    Craig, C. L. et al. International physical activity questionnaire: 12-country reliability and validity. Med. Sci. Sports Exerc. 35, 1381–1395 (2003).

  34. 34.

    Chang, L. et al. Gray matter maturation and cognition in children with different APOE epsilon genotypes. Neurology 87, 585–594 (2016).

  35. 35.

    Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer’s disease. Neuron 63, 287–303 (2009).

  36. 36.

    Ornish, D. et al. Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial. Lancet 336, 129–133 (1990).

  37. 37.

    Licher, S. et al. Lifetime risk and multimorbidity of non-communicable diseases and disease-free life expectancy in the general population: a population-based cohort study. PLoS Med. 16, e1002741 (2019).

  38. 38.

    Bell, R. D. et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512–516 (2012).

  39. 39.

    McGuinness, B., Craig, D., Bullock, R. & Passmore, P. Statins for the prevention of dementia. Cochrane Database Syst. Rev., CD003160 (2016).

  40. 40.

    Ikram, M. A. et al. The Rotterdam Study: 2018 update on objectives, design and main results. Eur. J. Epidemiol. 32, 807–850 (2017).

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Acknowledgements

We acknowledge the dedication, commitment, and contributions of inhabitants, general practitioners, and pharmacists of the Ommoord district who took part in the Rotterdam Study. We acknowledge F. J. A. van Rooij as data manager, and B. C. T. Leening-Kieboom as study coordinator. We thank J. Verkroost-van Heemst for her invaluable contribution to data collection. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing and the Dutch Heart Foundation (2012T008) and the Dutch Cancer Society (NKI-20157737). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (project: ORACLE, grant agreement no.: 678543).

Author information

S.L. contributed to study conceptualization, drafting of the analysis plan, data curation, formal analysis, interpretation of results and writing of the original draft of the manuscript. S.A. contributed to interpretation of results, analysis and writing and reviewing of the manuscript. H.K.-C. contributed to interpretation of results and writing and reviewing of the manuscript. T.V. contributed to data curation, interpretation of results and writing and reviewing of the manuscript. M.J.G.L. contributed to the design of the analysis plan, interpretation of results and writing and reviewing of the manuscript. M.A.I. contributed to study conceptualization, funding acquisition, the design of the analysis plan, interpretation of results, writing and reviewing of the manuscript and supervision of the study. M.K.I. contributed to study conceptualization, the design of the analysis plan, interpretation of results, writing and reviewing of the manuscript and supervision of the study.

Correspondence to Silvan Licher or M. Kamran Ikram.

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The authors declare no competing interests.

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Peer review information: Brett Benedetti was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary Fig. 1 and Supplementary Tables 1–13

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Licher, S., Ahmad, S., Karamujić-Čomić, H. et al. Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nat Med 25, 1364–1369 (2019) doi:10.1038/s41591-019-0547-7

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