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Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.

de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. (2012) Int J Geriatr Psychiatry.  27(6) 592-600 John Wiley & Sons, Ltd.

Web URL: Read more and find related articles on the pubmed website here



Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI).

Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study.


This was a double-blind, single-centre study, which included participants with MCI, aged ≥ 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y.

Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models.


The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015).

There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 µmol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). 

Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01).


In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia.


Previously published findings from this clinical trial showed that supplementation with the B vitamins B6, B12 and folate (B9) could significantly reduce physical brain shrinkage in older adults with Mild Cognitive Impairment (MCI). See:
Here, experimental measures and clinical ratings of cognitive function from the same trial are reported. These measures also showed significant benefits of these B vitamins in protecting against age-related cognitive decline.

For both the brain imaging findings and these cognitive and clinical measures, the benefits of B vitamins were greater in those patients with higher blood levels of homocysteine.  This is a toxic by-product of normal metabolism - which these B vitamins are known to help recycle and reduce - and previous studies have already shown that high homocysteine levels are associated with both cognitive decline and dementia.

Further, large-scale trials are now needed to confirm whether this simple and low-cost treatment may help to prevent the progression of age-related cognitive decline, and slow dementia.

For more details of this research, and the larger programme of which it forms a part, see:

See also: