Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance

BMC Medicine

Research Article

Wichanon Sae-jie¹  Suangsuda Supasai²  Jorgen Engmann³  Tina Shah³  Aroon Hingorani³  Pimphen Charoen⁴  Meena Kumari⁵  Amand F. Schmidt⁶  Tom R. Gaunt⁷  Andrew Wong⁸  Mika Kivimaki⁹  Jackie F. Price^1,10 

[1] Department of Mathematics, Faculty of Science, Mahidol University, 10400, Bangkok, Thailand;Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, 10400, Bangkok, Thailand;Institute of Cardiovascular Science, Faculty of Population Health, University College London, WC1E 6BT, London, UK;Institute of Cardiovascular Science, Faculty of Population Health, University College London, WC1E 6BT, London, UK;Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Ratchawithi Road, Ratchathewi, 10400, Bangkok, Thailand;Integrative Computational Bioscience (ICBS) Center, Mahidol University, Bangkok, Thailand;Institute of Cardiovascular Science, Faculty of Population Health, University College London, WC1E 6BT, London, UK;Institute for Social and Economic Research, University of Essex, Colchester, UK;Institute of Cardiovascular Science, Faculty of Population Health, University College London, WC1E 6BT, London, UK;UCL British Heart Foundation Research Accelerator, Department of Cardiology, Division Heart and Lungs, University College London, London, UK;MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, BS8 2BN, Bristol, UK;NIHR Bristol Biomedical Research Centre, University Hospitals Bristol National Health Service Foundation Trust and University of Bristol, Bristol, UK;MRC Unit Lifelong Health and Ageing at UCL, London, UK;UCL Brain Sciences, University College London, 149 Tottenham Court Road, W1T 7NF, London, UK;Usher Institute, University of Edinburgh, EH8 9AG, Edinburgh, UK;

关键词: Ketone bodies;    Cognitive performance;    Alzheimer’s disease;    Mendelian randomization;   

DOI  :  10.1186/s12916-023-03047-7

 received in 2023-04-25, accepted in 2023-08-24,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundKetone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function.MethodsIn observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer’s disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer’s Project (N = 54,162), respectively. Both strong (P < 5 × 10−8) and suggestive (P < 1 × 10−5) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism.ResultsBOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10−3). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: βIVW = 7.89 × 10−2, PIVW = 1.03 × 10−2; weighted median: βW-Median = 8.65 × 10−2, PW-Median = 9.60 × 10−3) and a protective effect on AD (βIVW =  − 0.31, odds ratio: OR = 0.74, PIVW = 3.06 × 10−2). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment.ConclusionsTriangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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