Sae-Jie, Wichanon;
Supasai, Suangsuda;
Kivimaki, Mika;
Price, Jackie F;
Wong, Andrew;
Kumari, Meena;
Engmann, Jorgen;
... UCLEB Consortium; + view all
(2023)
Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance.
BMC Medicine
, 21
(1)
, Article 340. 10.1186/s12916-023-03047-7.
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Abstract
BACKGROUND: Ketone 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. METHODS: In 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. RESULTS: BOHBUT 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. CONCLUSIONS: Triangulation 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.
| Type: | Article |
|---|---|
| Title: | Triangulating evidence from observational and Mendelian randomization studies of ketone bodies for cognitive performance |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s12916-023-03047-7 |
| Publisher version: | https://doi.org/10.1186/s12916-023-03047-7 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
| Keywords: | Alzheimer’s disease, Cognitive performance, Ketone bodies, Mendelian randomization, Humans, 3-Hydroxybutyric Acid, Alzheimer Disease, Cognition, Ketone Bodies, Ketones, Mendelian Randomization Analysis, Middle Aged |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Division of Psychiatry > Mental Health of Older People |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10176495 |
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