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Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals.

Clarke R1, Bennett D, Parish S, Lewington S, Skeaff M, Eussen SJ, Lewerin C, Stott DJ, Armitage J, Hankey GJ, Lonn E, Spence JD, Galan P, de Groot LC, Halsey J, Dangour AD, Collins R, Grodstein F (2014) The American Journal of Clinical Nutrition 100 (2)  657-666 American Society for Clinical Nutrition

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Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain.


The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging.


meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)-type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals).


The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: -0.054 ± 0.004 and -0.036 ± 0.001/y, respectively).

Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: -0.05, 0.06).

Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: -0.01; 95% CI: -0.03, 0.02).

Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: -0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment.


Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.


This study - which pooled the results from many different trials - reports finding no significant effect of multi-year supplementation with B vitamins on cognitive function or 'cognitive ageing'. 

By contrast, it did show B vitamin significantly reduced blood levels of homocysteine - a toxic by-product of normal metabolism, high levels of which are associated with age-related cognitive decline and dementia. 

Quite extraordinarily, this meta-analysis excluded the single most important clinical trial in this area - the VITACOG study, carried out at Oxford University.  This trial was specifically designed by leading international experts in the field to investigate the effects of supplementation with vitamins B6, B12 and folate (B9) in older adults with mild cognitive impairment, and included brain imaging as well as cognitive and clinical measures. Significant benefits were found on all measures - including striking reductions in the rate of physical brain shrinkage, as well as cognitive and clinical measures. See:

While failing to include this key trial, the authors of this meta-analysis chose to include other trials that were simply not even capable of addressing the question of whether B vitamins may prevent age-related cognitive decline and dementia (e.g. trials designed to investigate other conditions, involving younger adults and/or those with little or no cognitive impairment - in whom significant decline would not be expected during the study period in any case).

For a discussion of the serious flaws in this meta analysis from an expert in the field, explaining the negative implications of the attention it has nonetheless received, see: