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Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial.

Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H. (2010) PLoS One.  5(9): e12244 

Web URL: View this and related abstracts via PubMed here. Free Full Text of this paper is available online.



An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins.


To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159).


Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B(6) and B(12) in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study.

Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B(12) (0.5 mg/d) and vitamin B(6) (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.


A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% (95% CI, 0.63-0.90)in the active treatment group and 1.08% (0.94-1.22) in the placebo group (P =? 0.001).

The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P =? 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.


The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease.

Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease.



In older adults with Mild Cognitive Impairment, supplementation with Vitamins B6, B12 and folate over 2 years led to significant reductions in the rate of brain atrophy - reducing physical brain shrinkage by half the usual rate - in this pioneering clinical trial.

These B vitamins all play important roles in recycling homocysteine - a toxic by-product of normal metabolism - and high levels of homocysteine are associated with dementia, as well as with cardiovascular disease and other degenerative health conditions.

Brain volume reduces in most people with increasing age - but the rate of shrinkage is much faster in those with age-related cognitive decline and dementia.  By the age of 70, more than 1 in 6 people show Mild Cognitive Impairment, of whom more than half go on to develop dementia. 

These findings provide preliminary evidence that B vitamin supplementation may help to reduce and/or delay further brain degeneration in adults with age-related memory problems, particularly in those with high levels of homocysteine. 

Larger trials are now needed to confirm and extend these findings.

Please see the related news article here: 

For more details of this randomised, double-blind, placebo-controlled trial, see:

This trial was carried out as part of the The Oxford Project To Investigate Memory and Ageing (OPTIMA)
 - a long-running proramme of research investigating age related cognitive decline and dementia.


More findings from this study have subsequently been published - showing

1) that B vitamin supplementation also improved both cognitive and clinical outcomes, in addition to slowing the rate of physical brain shrinkage: 

2) that these effects of B vitamins depended on omega-3 status - such that B vitamin supplementation was ONLY effective for the participants with higher blood levels of long-chain omega-3 fatty acids.