Role of B vitamins in modulating homocysteine and metabolic pathways linked to brain atrophy: Metabolomics insights from the VITACOG trial.
Kacerova T., Yates AG., Dai J., Shepherd D., Pires E., de Jel S., Gong Q., Schiffer E., Jernerén F., Olsen T., De Jager Loots CA., Refsum H., Smith AD., McCullagh JSO., Anthony DC., Probert F.
INTRODUCTION: Elevated total homocysteine (tHcy) is a major predictor of brain atrophy, cognitive decline, and Alzheimer's disease (AD) progression. The VITACOG trial, a randomized, placebo-controlled study in mild cognitive impairment (MCI), previously showed that B vitamin supplementation lowered tHcy, slowing brain atrophy and cognitive decline; however, the underlying mechanisms remained unclear. METHODS: We used untargeted, multi-platform metabolomics, with nuclear magnetic resonance and liquid chromatography-mass spectrometry to analyze serum samples from 89 B vitamin-treated and 84 placebo-treated MCI participants over a 2 year follow-up period. RESULTS: Multivariate modeling distinguished treated from placebo groups with 91.2 ± 1.8% accuracy. B vitamin supplementation induced significant metabolic reprogramming, lowering quinolinic acid, α-ketoglutarate, α-ketobutyrate, glucose, and glutamate. DISCUSSION: These findings reveal that B vitamins influence metabolic pathways beyond tHcy reduction, particularly the tricarboxylic acid cycle and glutamine-glutamate cycling, critical for brain energy homeostasis and neurotransmission. This metabolic signature supports B vitamin supplementation as a strategy for slowing MCI progression. HIGHLIGHTS: Nuclear magnetic resonance and multi-platform liquid chromatography tandem mass spectrometry metabolomics were performed on serum samples from 89 B vitamin-treated and 84 placebo participants in the VITACOG trial. Multi-platform metabolomics revealed B vitamin-driven metabolic reprogramming, achieving 91% classification accuracy. B vitamin supplementation modulates key neuroprotective metabolic pathways. Regulation of energy metabolism and neurotransmission by B vitamins contributes to brain health in elderly individuals. B vitamins demonstrate potential as an adjunct therapy in mild cognitive impairment, potentially mitigating progression to Alzheimer's disease.