Abstract
Higher coffee consumption has been associated with reduced dementia risk, yet with inconsistencies across studies. CYP1A2 polymorphisms, which affects caffeine metabolism, may modulate the association between coffee and the risk of dementia and Alzheimer’s disease (AD). We included 5964 participants of the Three-City Study (mean age 74 years-old), free of dementia at baseline when they reported their daily coffee consumption, with available genome-wide genotyping and followed for dementia over a median of 9.0 (range 0.8–18.7) years. In Cox proportional-hazards models, the relationship between coffee consumption and dementia risk was modified by CYP1A2 polymorphism at rs762551 (p for interaction = 0.034). In multivariable-adjusted models, coffee intake was linearly associated with a decreased risk of dementia among carriers of the C allele only (“slower caffeine metabolizers”; HR for 1-cup increased [95% CI] 0.90 [0.83–0.97]), while in non-carriers (“faster caffeine metabolizers”), there was no significant association but a J-shaped trend toward a decrease in dementia risk up to 3 cups/day and increased risk beyond. Thus, compared to null intake, drinking ≥ 4 cups of coffee daily was associated with a reduced dementia risk in slower but not faster metabolizers (HR [95% CI] for ≥ 4 vs. 0 cup/day = 0.45 [0.25–0.80] and 1.32 [0.89–1.96], respectively). Results were similar when studying AD and another CYP1A2 candidate polymorphism (rs2472304), but no interaction was found with CYP1A2 rs2472297 or rs2470893. In this cohort, a linear association of coffee intake to lower dementia risk was apparent only among carriers of CYP1A2 polymorphisms predisposing to slower caffeine metabolism.
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Acknowledgements
The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut de Santé Publique et Développement of the Victor Segalen Bordeaux 2 University and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3 C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Regional Governments of Aquitaine and Bourgogne, Fondation de France, Ministry of Research-INSERM Programme “Cohortes et collections de données biologiques”, French National Research Agency COGINUT ANR-06-PNRA-005, the Fondation Plan Alzheimer (FCS 2009–2012), and the Caisse Nationale pour la Solidarité et l’Autonomie (CNSA).
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Catherine Helmer, Claudine Berr and Stephanie Debette contributed to the Three-City study conception, design and data collection. Statistical analyses were performed by Sophie Lefèvre-Arbogast under the supervision of Cécilia Samieri. The first draft of the manuscript was written by Sophie Lefèvre-Arbogast and Cécilia Samieri, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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The Consultative Committee for the Protection of Persons participating in Biomedical Research at Kremlin-Bicêtre University Hospital (Paris, France) approved the Three-City study protocol (CPP no 99-28, June 10, 1999).
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Lefèvre-Arbogast, S., Helmer, C., Berr, C. et al. Habitual coffee consumption and risk of dementia in older persons: modulation by CYP1A2 polymorphism. Eur J Epidemiol 39, 81–86 (2024). https://doi.org/10.1007/s10654-023-01060-x
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DOI: https://doi.org/10.1007/s10654-023-01060-x