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Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis

BMJ 2017; 359 doi: (Published 07 December 2017) Cite this as: BMJ 2017;359:j5375

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  1. Susanna C Larsson, associate professor1 2,
  2. Matthew Traylor, senior research associate2,
  3. Rainer Malik, postdoctoral fellow3,
  4. Martin Dichgans, professor3 4 5,
  5. Stephen Burgess, statistician6 7,
  6. Hugh S Markus, professor2
  7. for the CoSTREAM Consortium, on behalf of the International Genomics of Alzheimer’s Project
  1. 1Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden
  2. 2Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  3. 3Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
  4. 4Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
  5. 5German Centre for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
  6. 6MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
  7. 7Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  1. Correspondence to: S C Larsson susanna.larsson{at}
  • Accepted 8 November 2017


Objective To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer’s disease.

Design Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables.

Setting International Genomics of Alzheimer’s Project.

Participants 17 008 cases of Alzheimer’s disease and 37 154 controls.

Main outcome measures Odds ratio of Alzheimer’s per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis.

Results This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer’s. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10−6) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10−5) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer’s (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer’s and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer’s. Genetically predicted alcohol consumption, serum folate, serum vitamin B12, homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer’s disease.

Conclusion These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer’s disease.


  • Contributors: SCL analysed the data, drew the figures, and wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. For the International Genomics of Alzheimer’s Project the investigators contributed to the design and implementation of this specific study and/or provided data but did not participate in analysis or writing of the present study. See appendix 4 for further information. SCL is guarantor.

  • Funding: This study was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667375 and the Swedish Brain Foundation. HSM and MT have infrastructural support from the Cambridge University Trusts National Institute for Health Research (NIHR) Biomedical Research Centre. SB is funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 204623/Z/16/Z). HSM is supported by a NIHR senior investigator award. The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no financial relationships with any organisation that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study is based on publicly available summarised data. Individual studies within each genome-wide association study had received approval from a relevant institutional review board, and informed consent was obtained from participants or from a caregiver, legal guardian, or other proxy.

  • Data sharing: No additional data available.

  • Transparency: The lead author (SCL) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; that discrepancies from the study as planned have been explained, and that the paper conforms to transparency policy of the International Committee of Medical Journal Editors uniform requirement for manuscripts submitted to biomedical journals.

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