Role of B vitamins in modulating homocysteine and metabolic pathways linked to brain atrophy: Metabolomics insights from the VITACOG trial

Journal article

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.

Authors: Kacerova, T; Yates, AG; Dai, J; Shepherd, D; Pires, E

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Alzheimer's & Dementia: The Journal of the Alzheimer's Association
• Volume: 21
• Issue: 7
• Article number: e70521
• Publication date: 2025-07-19
• Acceptance date: 2025-06-26
• DOI: 10.1002/alz.70521
• EISSN: 1552-5279
• ISSN: 1552-5260
• Language: English
• Keywords: mass spectrometry; nuclear magnetic resonance; homocysteine; B vitamins; untargeted metabolomics; cognitive impairment