B-vitamins for neuroprotection: narrowing the evidence gap.

A compelling and extensive epidemiological literature documents the strong association of inadequate status of folate, vitamin B₁₂, and to a lesser degree vitamin B6, with increased risk of neurodegenerative and cerebrovascular disease. Mildly elevated plasma total homocysteine, which is biochemically related to low status of these B-vitamins, is similarly associated with increased risk for these conditions. This, together with experimental data showing that experimental B-vitamin deficiency and/or hyperhomocysteinemia can cause a variety of neurological and vascular deficits in animals, has provided the evidence base and motivation for a growing number of large randomized, double-blind clinical trials aimed at determining the efficacy and safety of B-vitamin supplementation for preserving cognitive function in older adults. Despite some encouraging trials showing benefit of B-vitamins for slowing brain atrophy and cognitive decline, the majority of these studies have not demonstrated that B-vitamin supplementation has protective or therapeutic cognitive benefit. There are many possible explanations for the inconsistency between the clinical trials and for the discrepancy between their findings and the predictions of the epidemiological evidence. Among these are the possibility of inadequate hypotheses guiding the trials, design limitations of the individual trials, and inherent limitations of nutritional randomized clinical trials. Resolving these issues will be crucial for designing definitive trials and ultimately for guiding nutritional interventions for cognitive protection.