In 2021, the Journal of Nutrition, Health, & Aging published an analysis of 2 randomized and placebo-controlled clinical trials, which found that supplementation with B vitamins, specifically folic acid, vitamin B12, and, in one of the trials, vitamin B6, improved global cognitive functioning and slowed brain atrophy among older adults with mild cognitive impairment (MCI) who were not taking aspirin. One of these two trials is known as the VITACOG trial, and a follow-up metabolomics study was just published in Alzheimer’s & Dementia, identifying some of the pathways by which B vitamins may improve MCI.
Participants in VITACOG were an average age of approximately 77 and received 500ug cyanocobalamin, 800 ug folic acid, and 20 mg vitamin B6 once per day for 2 years. This untargeted metabolomics study used both NMR and LC‐MS to detect metabolites and found that amino acid metabolism, particularly glycine, serine, and threonine, as well as arginine biosynthesis, were among the most significantly affected pathways. Supplementation modulated central carbon metabolism as well as the kynurenine pathway, and these changes were associated with (reduced) brain atrophy. Supplementation was associated with a significant decrease in lactate levels, a possible indicator of improved mitochondrial function. B vitamin supplementation also decreased citric acid cycle intermediates, including glucose, glutamate, and quinolinic acid.
Thus, it seems that the impact of B vitamins on metabolites that are likely to influence brain aging and cognitive function is likely to extend well beyond changes to homocysteine levels, even if many of the shifts in metabolite concentrations were subtle. Also, the variability among participants in diet, microbiome composition, and serum folate levels had some predictive ability in who most responded to supplementation, suggesting possible avenues for future research.