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


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.

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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 ( 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.


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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).

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Authors and Affiliations



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.

Corresponding authors

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).

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