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Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial
Open accessAbstract
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: Controlled-Trials.com ISRCTN94410159.
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“Finally, dietary approaches in terms of nutrition supplementation, such as combined formulation of specific active ingredients or probiotics, or nutritional guidance, such as fasting intermitting or Mediterranean diet, ameliorate both cognition and function of prodromal and mild AD patients [200,201,202].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [200]
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“While some degree of brain atrophy is common in older age, even in people who are cognitively healthy, atrophy is accelerated in people with Alzheimer's dementia.”
From 2024 Alzheimer's disease facts and figures (2024) · cites this paper as [20]
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Metadata
- Authors
- Smith, A. D., Smith, S. M., de Jager, C. A., Whitbread, P., Johnston, C., Agacinski, G., Oulhaj, A., Bradley, K. M., Jacoby, R., & Refsum, H.
- Affiliations
- University of Oxford (GB)
- University of Oslo (NO)
- Corresponding author
- Smith, A. David
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-08
- Volume
- 5
- Issue
- 9
- Pages
- e12244
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC2935890
- OpenAlex
- W2156635660
- Cited by
- 813
- References
- 49
- Citations by year
- 2026: 50 · 2025: 49 · 2024: 34 · 2023: 44 · 2022: 58 · 2021: 58 · 2020: 66 · 2019: 39 · 2018: 43 · 2017: 55 · 2016: 59 · 2015: 49 · 2014: 44 · 2013: 58 · 2012: 59
- FWCI
- 36.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Alzheimer's Research Trust
- National Institute for Health and Care Research
- University of Oxford
- Medical Research Council
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Alcoholism and Thiamine Deficiency
- Keywords
- homocysteine, B vitamins, folic acid, vitamin B6, vitamin B12, brain atrophy, mild cognitive impairment, cognitive decline, dementia prevention, older adults, plasma homocysteine, volumetric MRI, cognitive performance, adverse events
- MeSH terms
- Aged, Aged, 80 and over, Atrophy, Brain, Cognition Disorders, Female, Homocysteine, Humans, Magnetic Resonance Imaging, Male, Radiography, Vitamin B Complex, Treatment Outcome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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