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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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InfluentialSelf-citationImpaired Lysosomal Cobalamin Transport in Alzheimer's Disease
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“These results suggest a possible delay in brain atrophy due to Bvitamin supplementation and thus a possible delay in the rate of conversion of MCI to AD.(39) The other research that came out of this same VITACOG trial was one that investigated cognitive and clinical decline in participants with MCI.”
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“On the other hand, in a study of over-70-year-olds with MCI, B-vitamin supplementation was found to be associated with both lower homocysteine and a slower rate of cognitive decline [38].”
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Digit symbol substitution test score and hyperhomocysteinemia in older adults
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Siswanto, O., Smeall, K., Watson, T. D., Donnelly-Vanderloo, M., O'Connor, C., Foley, N. C., & Madill, J. (2015) · The journal of nutrition health & aging · doi:10.1007/s12603-015-0660-3 · Cited by 7
“The results of a randomized, controlled trial of homocysteine-lowering B vitamins (folic acid, B6, and B12) in subjects with mild cognitive impairment suggested that treatment with B vitamins may help reduce the rate of brain atrophy (30).”
Serum Homocysteine and Folate Levels are Associated With Late-life Dementia in a Korean Population
Song, J. H., Park, M. H., Han, C., Jo, S. A., & Ahn, K. (2010) · Osong Public Health and Research Perspectives · doi:10.1016/j.phrp.2010.12.006 · Cited by 8
“A recent clinical trial showed that the supplementation of high-dose B vitamins to MCI patients for 2 years reduced Hcy levels and had beneficial effects on brain shrinkage.(31) An interesting observation was that B vitamin treatment slowed the rate of brain atrophy and memory decline only in the group with initial Hc…”
Gupta, S., Fiertag, O., & Warner, J. P. (2009) · Advances in Psychiatric Treatment · doi:10.1192/apt.bp.107.003558 · Cited by 11
The effects of bioactive compounds on Alzheimer’s disease and mild cognitive impairment
McAnany, B., & Martirosyan, D. M. (2016) · Functional Foods in Health and Disease · doi:10.31989/ffhd.v6i6.257 · Cited by 8
“Smith AD, 2010 [26] Randomized controlled trial 271 individuals aged 70 years old or older diagnosed with MCI 0.”
BackgroundInfluentialHomocysteine Levels in Neurological Disorders
Moustafa, A. A., Hewedi, D. H., Eissa, A. M., Frydecka, D., & Misiak, B. (2015) · doi:10.1002/9781118840634.ch7 · Cited by 8
Kolanu, N. D., Ahmed, S., Kerimkulova, M. K., Stańczak, M., Vera, G. D. J. A., Shaikh, N., Addula, A. R., Cheran, M., Chilla, S. P., Lima, S. R. O. S., et al. (2024) · Cureus · doi:10.7759/cureus.53711 · Cited by 7
“Further research is imperative to refine nutritional care guidelines and optimize rehabilitation strategies in stroke care [17-19].”
BackgroundThe association of vitamin deficiency with depression risk in late-life depression: a review
Gao, Y., Song, X.-N., Wen, Z.-P., Hu, J.-Z., Du, X.-Z., Zhang, J., & Liu, S. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1551375 · Cited by 7
Hien, N. K., Bay, M. V., Vo, Q. V., Ngô, S. T., Nhan, D. T., Nam, P. C., & Quang, D. T. (2025) · RSC Advances · doi:10.1039/d5ra07368e · Cited by 7
Probiotic and Dietary Supplements Intervention in Age-Related Neurodegenerative Disorders
Salles, C. B. D. D., Prajapati, S. K., Yadav, D., Rennar, J., Marcano-Rodriguez, A., Yadav, H., & Jain, S. (2026) · Microorganisms · doi:10.3390/microorganisms14020290 · Cited by 8
“While B vitamins exert neuroprotective effects by lowering homocysteine levels, a key contributor to hippocampal degeneration and vascular dysfunction [56,88,96].”
Folates, folic acid and preconception care – a review
House, S. H., Nichols, J. A., & Rae, S. (2021) · JRSM Open · doi:10.1177/2054270420980875 · Cited by 7
Garrido-Dzib, Á. G., Chávez-Loría, G., Magallón-Zertuche, V., Ávila-Nava, A., Palacios‐González, B., & Solis, A. L. G. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230231 · Cited by 7
“Some foods have been shown to have neuroprotective properties, especially some vitamins B [72], antioxidants (vitamins E and C) [73], and polyunsaturated fatty acids (PUFA) (omega-3 s) [74], which are the nutrients for which evidence has been reported in AD patients.”
Storoschuk, K. L., Gharios, R., Potter, G. D., Galpin, A. J., House, B. T., & Wood, T. R. (2023) · Lifestyle Medicine · doi:10.1002/lim2.90 · Cited by 7
Improving Cognition in the Elderly With Nutritional Supplements
Stough, C. K. K., & Pase, M. P. (2015) · Current Directions in Psychological Science · doi:10.1177/0963721414565449 · Cited by 8
Lind, M. V., Lauritzen, L., Pedersen, O. B., Vestergaard, H., Stark, K. D., Hansen, T. F., Ross, A. B., & Kristensen, M. (2017) · Nutrition Research · doi:10.1016/j.nutres.2017.09.008 · Cited by 7
“One-carbon metabolism and especially high circulating homocysteine (Hcy) levels have been linked to a wide range of diseases such as cardiovascular disease[1], cognitive diseases[2,3], cancer[4,5], metabolic syndrome[6–8] and type 2 diabetes[9–12].”
BackgroundGiudici, K. V., Barreto, P. D. S., Guyonnet, S., Cantet, C., Zetterberg, H., Boschat, C., Hudry, J., Andrieu, S., Schmitt, J. A. J., Vellas, B. J., et al. (2023) · Journal of Aging Research and Lifestyle · doi:10.14283/jarlife.2023.7 · Cited by 7
“While ambiguous results have been found in trials supplementing single nutrients (8), other studies evaluating the combination of several nutrients have suggested that this might be a better strategy (9-13).”
ResultDomínguez‐López, I., Casas, R. M., Chiva‐Blanch, G., Martínez‐González, M. Á., Fitó, M., Ros, E., Lamuela-Raventós, R. M., & Estruch, R. (2023) · Clinical Nutrition · doi:10.1016/j.clnu.2023.10.025 · Cited by 7
Diet and Mental Health: An Up-to-Date Analysis
Casper, R. C. (2011) · World review of nutrition and dietetics · doi:10.1159/000327798 · Cited by 7
Prevention of Alzheimer’s Disease: Intervention Studies
Mangialasche, F., Xu, W., & Kivipelto, M. (2013) · InTech eBooks · doi:10.5772/55034 · Cited by 7
“A more recent RCT testing the efficacy of B vitamins (B6, B12, folate) in subjects with MCI reported beneficial effects of the supplementation, in terms of reduced rate of brain atrophy and cognitive decline, which were more evident in subjects with elevated homocysteine levels [122, 123].”
BackgroundVaskinn, A., Wilsgård, I., Holm, A., Wootton, R., & Elvevåg, B. (2013) · Journal of Telemedicine and Telecare · doi:10.1177/1357633x12473904 · Cited by 7
Allam, M., Fahmy, E. M., Sharaf, S. A. E.-A., Amer, H. M. A., Abokrysha, N. T., & ELSawy, E. E. T. (2013) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2013.06.023 · Cited by 7
Folic Acid, Selected Cancers and All-cause Mortality: A Meta-analysis
Mackerras, D., Tan, J., & Larter, C. Z. (2014) · International Food Risk Analysis Journal · doi:10.5772/58396 · Cited by 7
“…A Meta-analysis Author, Year, (Reference) (Study Name) Description Comparison (daily dosage unless otherwise stated) Data to allow calculation of Relative risks for Total cancer Site specific cancer Colorectal Adenoma Mortality Smith et al, 2010 [74] (VITACOG) 2 year trial, 271 UK patients with…”
InfluentialIntegrative health check reveals suboptimal levels in a number of vital biomarkers
Travica, N., Ried, K., Bujnowski, R., & Sali, A. (2015) · Advances in Integrative Medicine · doi:10.1016/j.aimed.2015.11.002 · Cited by 7
“When the serum level drops below 500 or 550 pg/ml the cerebrospinal fluid level can become deficient [37].”
BackgroundPourié, G., Guéant, J., & Quadros, E. V. (2022) · Vitamins and hormones · doi:10.1016/bs.vh.2022.02.002 · Cited by 7
Neuroprotection in Alzheimer’s Disease
Jain, K. K. (2011) · Humana Press eBooks · doi:10.1007/978-1-61779-049-2_8 · Cited by 7
Wahlqvist, M. L., Xiu, L., Lee, M., Chen, R. C.-Y., Chen, K. J., & Li, D. (2016) · PubMed · doi:10.6133/apjcn.112015.06 · Cited by 7
Bartley, M., Bokde, A. L. W., & O'Neill, D. (2011) · New England Journal of Medicine · doi:10.1056/nejmc1108238 · Cited by 7
Yadav, P., Nasir, F., & Sivanandam, T. M. (2024) · Neurochemistry International · doi:10.1016/j.neuint.2024.105869 · Cited by 6
Briglia, M., Allia, F., Avola, R., Signorini, C., Cardile, V., Romano, G. L., Giurdanella, G., Malaguarnera, R., Bellomo, M., & Graziano, A. C. E. (2024) · Nutrients · doi:10.3390/nu16183114 · Cited by 8
“Specifically, as for vitamins, it has been reported that the vitamins of the B group (B6 pyridoxine, B9 folic acid, and B12 cobalamin) may slow the progression of cognitive decline in patients with mild cognitive impairment [58,59] by a reduction in homocysteine levels.”
BackgroundAssociation of vitamin B12 deficiency in a dementia cohort with hippocampal atrophy on MRI
Ueno, A., Hamano, T., Nagata, M., Yamaguchi, T., Endo, Y., Enomoto, S., Kimura, H., Ikawa, M., Yamamura, O., Yamanaka, D., et al. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100265 · Cited by 6
“As previous studies including VITACOG study [ 30 , 39 ] have shown, cognitive decline and brain atrophy may be slower by vitamin B 12 supplementation [ 40 ], necessitating earlier therapeutic interventions.”
Micronutrient balance and brain function: neuropsychological, metabolic, and clinical interactions
López-Sebastiani, V. A., Quiroz, K., Salazar, M. A. D. L. C., Monje-Bolivar, F., & Samillan, V. J. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1748487 · Cited by 8
“…for homocysteine metabolism and for methylation reactions required for DNA synthesis, myelin maintenance, and the production of neurotransmitters such as serotonin, dopamine, and noradrenaline (Kennedy, 2016; Verdin, 2015; Smith et al., 2010; Ford and Almeida, 2019; El-Mezayen et al., 2022).”
InfluentialChai, G., Gong, J., Mao, Y.-M., Wu, J.-J., Bi, S.-G., Wang, F., Zhang, Y., Shen, M.-T., Lei, Z.-Y., Nie, Y., et al. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-03995-y · Cited by 7
“Prospective studies have reported links between elevated Hcy and elevated global or regional atrophy rates in individuals with mild cognitive impairment (MCI) [4, 5].”
How Statins Could Be Evaluated Successfully in Clinical Trials for Alzheimer’s Disease?
Burgos, J. S., Bénavidès, J., Douillet, P., Velasco, J., & Valdivieso, F. (2012) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317512442998 · Cited by 6
Bailey, S., & Ayling, J. E. (2013) · Journal of Chromatography A · doi:10.1016/j.chroma.2013.09.027 · Cited by 6
Tannorella, P., Stoccoro, A., Tognoni, G., Bonuccelli, U., Migliore, L., & Coppedè, F. (2016) · Europe PMC (PubMed Central) · Cited by 6
Cheema, A. K., Wiener, L. E., McNeil, R. B., Abreu, M. M., Craddock, T. J. A., FLETCHER, M. A., Helmer, D. A., Ashford, J. W., Sullivan, K. A., & Klimas, N. G. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119819 · Cited by 5
Opicapone Protects Against Hyperhomocysteinemia-Induced Increase in Blood–Brain Barrier Permeability
Wang, J., Zheng, B., Yang, S., Zheng, H., & Wang, J. (2021) · Neurotoxicity Research · doi:10.1007/s12640-021-00429-8 · Cited by 6
Heffernan, M., Doherty, L. C., Mendes, R. H., Clarke, M., Hodge, S. J., Clements, M., McAnena, L. B., Rivelsrud, M., Ward, M., Strain, J. J., et al. (2021) · Nutrition & Metabolism · doi:10.1186/s12986-021-00630-8 · Cited by 6
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
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