Plasma Caffeine Levels And Risk Of Alzheimer’s Disease And Parkinson’s Disease: Mendelian Randomization Study Part 2

\Previously published MR studies on genetically predicted coffee consumption and risk of Alzheimer's disease [16,17] and all-cause dementia [18] have found trends in the opposite direction to our findings about genetically predicted plasma caffeine levels of Alzheimer's disease. 

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This is expected because the considered genetic variants associated with slower caffeine metabolism and thus higher plasma caffeine levels are also related to lower coffee consumption [19]. 

This also makes physiological sense, as those individuals who metabolize caffeine more slowly will tend to drink less coffee to achieve the same levels of plasma caffeine. 

A previous MR study found no association between genetically predicted coffee consumption and Parkinson's disease [20], which is in line with our overall null results for genetically predicted plasma caffeine levels and this disease. 

It should be noted that the genetic instrument used in our MR study aimed to capture caffeine exposure rather than coffee consumption per se. 

Thus, our findings for genetically predicted caffeine exposure are not directly comparable to the possible effects of coffee drinking, as coffee contains other bioactive compounds that may prevent amyloid aggregation [12] and potentially reduce the risk of Alzheimer's disease.

A strength of our study is the MR design. MR studies that leverage genetic variants in genomic regions (e.g., CYP1A2) with a biological link to the metabolism of the exposure of interest (e.g., caffeine) are less likely to be affected by confounding compared to traditional observational studies. Additionally, we analyzed the association between genetically predicted plasma caffeine and Alzheimer's disease in two independent studies, and the association was consistent in both studies, albeit with non-significant results, possibly due to low power. 

The observed consistency strengthens the evidence for causality. A potential shortcoming of our work is that the results might only be generalizable to European populations. 

In addition, with only two genetic instruments and summary-level data, we could not use statistical methods to investigate possible pleiotropy biasing the MR estimates, or non-linear relationships between plasma caffeine and disease risk. 

We therefore cannot rule out a threshold effect, with a protective effect only seen, for example, with very high plasma levels of caffeine.

5. Conclusions

This MR study showed that genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer's disease. The potential role of caffeine in Alzheimer's and Parkinson's disease needs further research. 

Author Contributions: Conceptualization, S.C.L. methodology, S.C.L., B.W., and D.G.; validation, S.C.L.; formal analysis, S.C.L., and B.W.; investigation, S.C.L., B.W., and D.G.; data curation, S.C.L.; writing-original draft preparation, S.C.L.; writing-review and editing, B.W. and D.G.; visualization, S.C.L.; supervision, S.C.L., and D.G.; project administration, S.C.L.; funding acquisition, S.C.L., B.W., and D.G. 

All authors have read and agreed to the published version of the manuscript. Funding: S.C.L. was supported by research funding from the Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123). 

B.W. was funded by an Economic and Social Research Council (ESRC) South West Doctoral Training Partnership (SWDTP) 1+3 PhD Studentship Award (ES/P000630/1). 

D.G. was supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College, and a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George's, University of London.

Institutional Review Board Statement: The study was conducted by the Declaration of Helsinki, and approved by the Swedish Ethical Review Authority (No. 2019-02793).

Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement: Data generated and analyzed during the study are available from the corresponding author by request.

Acknowledgments: The authors thank the participants and investigators of the International Genomics of Alzheimer's Project, International Parkinson's Disease Genomics, FinnGen consortia, and the UK Biobank. 

The genome-wide association study analysis of UK Biobank data was conducted under UK Biobank application no. 15825. UK Biobank was established by the Wellcome Trust medical charity, the Medical Research Council, the Department of Health, the Scottish Government, and the Northwest Regional Development Agency. 

It has also received funding from the Welsh Government, the British Heart Foundation, Cancer Research UK, and Diabetes UK. UK Biobank is supported by the National Health Service (NHS). 

UK Biobank is open to bona fide researchers anywhere in the world. The graphical abstract was created with BioRender.com.

Conflicts of Interest: D.G. is employed part-time by Novo Nordisk. S.C.L. and B.W. have no conflicts of interest to disclose. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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