Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
, 5 (9), e12244

Homocysteine-lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

Randomized Controlled Trial

Homocysteine-lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

A David Smith et al. PLoS One.


Background: 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.

Objective: 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).

Methods and findings: 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.

Results: 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.

Conclusions and significance: 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.

Trial registration: ISRCTN94410159.

Conflict of interest statement

Competing Interests: Dr. A. D. Smith is named as an inventor on two patents held by the University of Oxford on the use of folic acid to treat Alzheimer's disease (US6008221; US6127370); under the University's rules he could benefit financially if the patent is exploited. Drs. Refsum and A. D. Smith report having in the past received speaking honoraria from Recip AB, the company that donated the vitamin tablets, and from Axis-Shield, who make the equipment used to assay homocysteine. These competing interests do not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. None of the other authors have any financial disclosures.


Figure 1
Figure 1. Participant Flow in the trial.
Figure 2
Figure 2. Atrophy rate by baseline homocysteine.
Linear regression lines with 95% mean prediction intervals. R2 for placebo group (n = 83) was 0.242 (P<0.001); for the treatment group (n = 85) R2 was 0.001 (P = 0.74). The x-axis is a logarithmic scale labelled with linear values.
Figure 3
Figure 3. Atrophy rate by change in plasma total homocysteine over a two year period.
Subjects in this analysis were a subset (66 in placebo; 70 in the active treatment) who showed biochemical evidence of good compliance (see Table 3). Linear regression with 95% mean prediction intervals, adjusted for age at baseline; partial r = 0.22, P = 0.011. The x-axis is a logarithmic scale labelled with linear values.
Figure 4
Figure 4. Selected subtraction MRI scans.
The images are from the baseline scan with colour superimposed to show the brain tissue change over the following two years. Colours show expansion (red/yellow) or contraction (blue/light blue) of the brain of 0.3 to 1.0 mm, with the lightest colour indicating the biggest change. (A) Subtraction image of female participant in the placebo group, age 79 years, with baseline tHcy of 22 µmol/L, whose tHcy concentration increased by 8 µmol/L over two years. Atrophy rate was 2.50% per year. Atrophy most strongly appears here as enlargement of the ventricles. (B) Subtraction image of female participant in active treatment group, age 72 years, with baseline tHcy of 24 µmol/L at baseline, whose tHcy concentration decreased by 12 µmol/L over two years. Atrophy rate 0.46% per year. There is no clear visible pattern of atrophy.

Similar articles

See all similar articles

Cited by 148 PubMed Central articles

See all "Cited by" articles


    1. Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C. Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J Neurosci. 2003;23:3295–3301. - PMC - PubMed
    1. Fox NC, Scahill RI, Crum WR, Rossor MN. Correlation between rates of brain atrophy and cognitive decline in AD. Neurology. 1999;52:1687–1689. - PubMed
    1. Bradley KM, Bydder GM, Budge MM, Hajnal JV, White SJ, et al. Serial brain MRI at 3-6 month intervals as a surrogate marker for Alzheimer's disease. Br J Radiol. 2002;75:506–513. - PubMed
    1. Smith AD. Imaging the progression of Alzheimer pathology through the brain. Proc Natl Acad Sci U S A. 2002;99:4135–4137. - PMC - PubMed
    1. Jack CR, Jr, Shiung MM, Gunter JL, O'Brien PC, Weigand SD, et al. Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology. 2004;62:591–600. - PMC - PubMed

Publication types

MeSH terms

Associated data