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

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: β_IVW = 7.89 × 10^-2, P_IVW = 1.03 × 10^-2; weighted median: β_W-Median = 8.65 × 10^-2, P_W-Median = 9.60 × 10^-3) and a protective effect on AD (β_IVW = - 0.31, odds ratio: OR = 0.74, P_IVW = 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.

Keywords: Alzheimer’s disease; Cognitive performance; Ketone bodies; Mendelian randomization.

Fig. 1

Study setting and dataset. The approach of triangulating evidence from observational and Mendelian randomization studies is used to investigate the associations between ketone bodies and cognitive functions including Alzheimer’s disease. WHII, Whitehall II study; UCLEB, University College-London School-Edinburgh-Bristol Consortium; SSGAC, Social Science Genetic Association Consortium; IGAP, International Genomics of Alzheimer’s Project; BOHBUT, 3-β-hydroxybutyrate; ACACE, acetoacetate; SNPs, single nucleotide polymorphism

Fig. 2

Observational analysis of ketone bodies 3-β-hydroxybutyrate (BOHBUT) and acetoacetate (ACACE) in relation to cognitive function. A Associations between observational BOHBUT and cognitive functions. B Associations between observational ACACE and cognitive functions. Ketone bodies (KBs) were categorized into two groups, e.g., high vs normal levels, based on the assumption that KBs could have a therapeutic benefit when the concentrations reach a certain level. The categorical cutoffs across the range of KBs were varied due to their unknown value. The full model was adjusted by age, sex, diabetes (yes/no), smoking (ever/never), alcohol consumption (heavy/other), waist-to-hip ratio, and occupational position (low/intermediate/high) across the cutoff values of BOHBUT from 0.07 to 0.52 mmol/L and ACACE from 0.02 to 0.20 mmol/L

Fig. 3

Causal estimates of 3-β-hydroxybutyrate on cognitive performance and Alzheimer’s disease from Mendelian randomization analyses. Causal estimates were calculated based on three MR methods: inverse-variance weighted (IVW), weighted median (W-Median), and weighted mode (W-Mode)