Abstract / Description of output
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 efect 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 efect 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 benefcial efect on cognitive performance. Our
fndings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive
impairment and reducing the risk of AD.
Keywords Ketone bodies, Cognitive performance, Alzheimer’s disease, Mendelian randomization
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 efect 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 efect 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 benefcial efect on cognitive performance. Our
fndings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive
impairment and reducing the risk of AD.
Keywords Ketone bodies, Cognitive performance, Alzheimer’s disease, Mendelian randomization
Original language | English |
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Article number | 340 |
Number of pages | 10 |
Journal | BMC Medicine |
Volume | 21 |
Issue number | 1 |
DOIs | |
Publication status | Published - 4 Sept 2023 |
Keywords / Materials (for Non-textual outputs)
- Ketone bodies
- Cognitive performance
- Alzheimer’s disease
- Mendelian randomization