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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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Background2025 Alzheimer's disease facts and figures
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“◦ The importance of plasma tHcy as a marker for a subgroup was shown in a randomized trial (VITACOG) on elderly people with mild cognitive impairment: ▪ In VITACOG, a combination of B vitamins (800 μg folic acid, 500 μg B12, and 20 mg vitamin B6/d) slowed brain atrophy and cognitive decline over a 2-y period (59, 60),…”
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Otaegui-Arrazola, A., Amiano, P., Elbusto, A., Urdaneta, E., & Martínez-Lage, P. (2014) · European Journal of Nutrition · doi:10.1007/s00394-013-0561-3 · Cited by 214
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“This value corresponds to the median baseline tHcy concentration in the VITACOG cohort: previous studies showed that the beneficial effect of B vitamin treatment on global and regional brain atrophy (20, 21) and cognitive decline (28) was dependent on baseline tHcy.”
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Stefaniak, O., Dobrzyńska, M., Drzymała-Czyż, S., & Przysławski, J. (2022) · Nutrients · doi:10.3390/nu14214564 · Cited by 185
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Neuroenhancement with Vitamin B12—Underestimated Neurological Significance
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“The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins [43].”
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Almeida, O. P., Garrido, G. J., Etherton‐Beer, C., Lautenschlager, N. T., Arnolda, L., & Flicker, L. A. (2012) · European Heart Journal · doi:10.1093/eurheartj/ehr467 · Cited by 159
“High tHcy has been associated with cognitive decline and brain atrophy, and recent evidence suggests that lowering tHcy may decrease the rate of neuronal loss, possibly because apoptosis and vascular pathology are attenuated by consumption of folate and vitamin B12.(49)”
BackgroundHomocysteine: a biomarker in neurodegenerative diseases
Herrmann, W., & Obeid, R. (2011) · Clinical Chemistry and Laboratory Medicine (CCLM) · doi:10.1515/cclm.2011.084 · Cited by 149
Heart Failure-Induced Brain Injury
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“High levels of tHcy were shown to produce brain atrophy and cognitive decline through brain cell apoptosis (55), and interventions aimed at reducing the levels of tHcy were shown to delay brain atrophy (56).”
BackgroundDiagnosing Mild Cognitive Impairment (MCI) in clinical trials: a systematic review
Stephan, B. C. M., Minett, T., Pagett, E., Siervo, M., Brayne, C., & McKeith, I. G. (2013) · BMJ Open · doi:10.1136/bmjopen-2012-001909 · Cited by 154
“Smith et al10 used four items from the Cambridge Examination for Mental Disorders.28 Rapp et al22 used the Memory Functioning Questionnaire,29 which is a 64-item questionnaire assessing memory problems and the use of mnemonics.”
MethodAdvances in clinical determinants and neurological manifestations of B vitamin deficiency in adults
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Wang, Z., Zhu, W. P., Xing, Y., Jia, J., & Tang, Y. (2021) · Nutrition Reviews · doi:10.1093/nutrit/nuab057 · Cited by 147
Butler, M., Nelson, V. A., Davila, H., Ratner, E., Fink, H. A., Hemmy, L. S., McCarten, J. R., Barclay, T. R., Brasure, M., & Kane, R. L. (2018) · Annals of Internal Medicine · doi:10.7326/m17-1530 · Cited by 144
Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing
Porter, K. M., Hoey, L., Hughes, C., Ward, M., & McNulty, H. (2016) · Nutrients · doi:10.3390/nu8110725 · Cited by 150
“This effect was modulated by baseline homocysteine concentration, with the greatest impact observed in those with concentrations ≥ 13 μmol/L [196].”
BackgroundHampel, H. J., Lista, S., Teipel, S. J., Garaci, F., Nisticò, R., Blennow, K., Zetterberg, H., Bertram, L., Duyckaerts, C. J., Bakardjian, H., et al. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.11.009 · Cited by 148
Mohajeri, M. H., Troesch, B., & Weber, P. (2015) · Nutrition · doi:10.1016/j.nut.2014.06.016 · Cited by 141
Emerging roles for folate and related B-vitamins in brain health across the lifecycle
McGarel, C., Pentieva, K. D., Strain, J. J., & McNulty, H. (2014) · Proceedings of The Nutrition Society · doi:10.1017/s0029665114001554 · Cited by 143
“The effect was greatest in participants with the highest baseline homocysteine concentrations (>13 μmol/l), among whom an overall reduction of brain atrophy rate of 53 % was reported, while no effect was found in those in the bottom quartile (≤9·5 μmol/l)((65)).”
InfluentialMetabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke
Spence, J. D. (2015) · Nutrition Research · doi:10.1016/j.nutres.2015.10.003 · Cited by 141
“[30] Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al.”
BackgroundNutritional Interventions for Elderly and Considerations for the Development of Geriatric Foods
Kaur, D., Rasane, P., Singh, J., Kaur, S., Kumar, V., Mahato, D. K., Dey, A., Dhawan, K., & Kumar, S. (2019) · Current Aging Science · doi:10.2174/1874609812666190521110548 · Cited by 159
Hainsworth, A. H., Yeo, N., Weekman, E. M., & Wilcock, D. M. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.11.015 · Cited by 136
The Future of Precision Medicine in the Cure of Alzheimer’s Disease
Arafah, A., Khatoon, S., Rasool, I., Khan, A., Rather, M. A., Abujabal, K. A., Faqih, Y. A. H., Rashid, H., Rashid, S. M., Bilal Ahmad, S., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11020335 · Cited by 133
“It has been investigated in several trials if reduced homocysteine can affect brain disease and/or cognitive function by using a mixture of B vitamins [81].”
BackgroundCerebral atrophy in mild cognitive impairment: A systematic review with meta‐analysis
Tabatabaei‐Jafari, H., Shaw, M. E., & Cherbuin, N. (2015) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2015.11.002 · Cited by 128
“Indeed, initial attempts at early therapeutic interventions have reported some successes in the early phase ofMCI [1,2].”
BackgroundPrice, B. R., Wilcock, D. M., & Weekman, E. M. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00350 · Cited by 128
Dobrijević, D., Pastor, K., Nastić, N. M., Özoğul, F., Krulj, J. A., Kokić, B. M., Bartkienė, E., Rocha, J. M., & Kojić, J. S. (2023) · Molecules · doi:10.3390/molecules28124824 · Cited by 128
“Even a slightly elevated level of homocysteine in the blood could be considered a biomarker of increased risk of cardiovascular, cerebral, and peripheral vascular diseases, neurodegenerative disorders, and cognitive decline [47,48].”
Backgroundvan Wijk, N., Broersen, L. M., de Wilde, M. C., Hageman, R. J. J., Groenendijk, M., Sijben, J. W. C., & Kamphuis, P. J. G. H. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130998 · Cited by 128
“For example, supplementing humans with DHA [73], choline [74], or the combination of folic acid, vitamin B12, and B6 [75] result in increased levels in the circulation.”
Nutrition and the ageing brain: Moving towards clinical applications
Flanagan, E. C., Lamport, D. J., Brennan, L., Burnet, P. W. J., Calabrese, V., Cunnane, S. C., de Wilde, M. C., Dye, L., Farrimond, J. A., Lombardo, N. B. E., et al. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101079 · Cited by 132
“Regarding the association with homocysteine, total brain atrophy in the placebo group doubled across the levels of baseline homocysteine, whereas in the active treatment group there was no relation between homocysteine at baseline and atrophy, such that subjects within the top quartile of homocysteine levels showed a…”
Self-citationKuśmierek, K., Chwatko, G., Głowacki, R., Kubalczyk, P., & Bald, E. (2010) · Journal of Chromatography B · doi:10.1016/j.jchromb.2010.10.035 · Cited by 122
Vitamin B12, cognition, and brain MRI measures
Tangney, C., Aggarwal, N. T., Li, H., Wilson, R. S., DeCarli, C. S., Evans, D. A., & Morris, M. C. (2011) · Neurology · doi:10.1212/wnl.0b013e3182315a33 · Cited by 119
Preventing dementia? Interventional approaches in mild cognitive impairment
Lissek, V. J., & Boris Suchan, A. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2020.12.022 · Cited by 127
for the FINGER study group, Stephen, R., Liu, Y., Ngandu, T., Antikainen, R., Hulkkonen, J., Koikkalainen, J., Kemppainen, N., Lötjönen, J., Levälahti, E., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0506-z · Cited by 116
DIETARY FACTORS AND COGNITIVE DECLINE
Smith, P. J., & Blumenthal, J. A. (2015) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2015.71 · Cited by 111
“It will also be important to gain a better understanding of the mechanisms underlying the relationship between nutritional intake and cognitive outcomes from human studies: although multiple causal factors have been hypothesized, including neuroinflammatory pathways (162), reductions in CVD risk factors (121, 141), al…”
BackgroundFord, A. H., & Almeida, O. P. (2019) · Drugs & Aging · doi:10.1007/s40266-019-00649-w · Cited by 113
Grimm, M. O. W., Michaelson, D. M., & Hartmann, T. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r076331 · Cited by 114
Fekete, M., Lehoczki, A., Tarantini, S., Fazekas‐Pongor, V., Csípő, T., Csizmadia, Z., & Varga, J. T. (2023) · Nutrients · doi:10.3390/nu15245116 · Cited by 126
“Studies [119–121] have demonstrated that a high intake of these B vitamins can significantly slow cognitive decline in older adults, particularly in those with elevated homocysteine levels or mild cognitive impairment [116,122].”
Ma, F., Zhou, X., Li, Q., Zhao, J., Song, A., An, P., Du, Y. J., Xu, W., & Huang, G. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190725144629 · Cited by 109
Ma, F., Wu, T., Zhao, J., Song, A., Liu, H., Xu, W., & Huang, G. (2016) · Scientific Reports · doi:10.1038/srep37486 · Cited by 105
Walhovd, K. B., Storsve, A. B., Westlye, L. T., Drevon, C. A., & Fjell, A. M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.011 · Cited by 114
Ross, A. B., Zangger, A., & Guiraud, S. P. (2013) · Food Chemistry · doi:10.1016/j.foodchem.2013.08.122 · Cited by 103
Nutrient intake, nutritional status, and cognitive function with aging
Tucker, K. L. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13062 · Cited by 103
Mechanistic Link between Vitamin B12 and Alzheimer’s Disease
Lauer, A. A., Grimm, H. S., Apel, B., Golobrodska, N., Kruse, L., Ratanski, E., Schulten, N., Schwarze, L., Slawik, T., Sperlich, S., et al. (2022) · Biomolecules · doi:10.3390/biom12010129 · Cited by 121
“[169] 2010 RCT/2 years/intervention group (n = 85) and placebo group (n = 83) Accelerated brain atrophy in MCI patients can be slowed by treatment with B vitamins (folic acid, vitamin B6 and B12)”
BackgroundBrain foods - the role of diet in brain performance and health
Ekstrand, B., Scheers, N., Rasmussen, M. K., Young, J. F., Ross, A. B., & Landberg, R. (2020) · Nutrition Reviews · doi:10.1093/nutrit/nuaa091 · Cited by 115
Ford, T. C., Downey, L. A., Simpson, T. N., McPhee, G. M., Oliver, C., & Stough, C. K. K. (2018) · Nutrients · doi:10.3390/nu10121860 · Cited by 101
“In fact, combined vitamin B (folate, B6, and B12) supplementation has been shown to slow the rate of brain atrophy for those with mild cognitive impairment over a 24-month period, which corresponded significantly to increases in B12 and folate levels [1].”
BackgroundHomocysteine and disease: Causal associations or epiphenomenons?
Hannibal, L., & Blom, H. J. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.11.003 · Cited by 99
Cognitive reserve, cortical plasticity and resistance to Alzheimer's disease
Esiri, M. M., & Chance, S. A. (2012) · Alzheimer's Research & Therapy · doi:10.1186/alzrt105 · Cited by 95
Vitamin B12status, cognitive decline and dementia: a systematic review of prospective cohort studies
O'Leary, F., Allman-Farinelli, M., & Samman, S. (2012) · British Journal Of Nutrition · doi:10.1017/s0007114512004175 · Cited by 96
Rucklidge, J. J., Eggleston, M. J. F., Johnstone, J. M., Darling, K. A., & Frampton, C. M. (2017) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12817 · Cited by 103
“Reduction of homocysteine levels has been associated with improvements in mood (Mech & Farah, 2016) and cognitive function (Smith et al., 2010).”
BackgroundThe United Kingdom Glaucoma Treatment Study
Garway‐Heath, D. F., Lascaratos, G., Bunce, C., Crabb, D. P., Russell, R. A., & Shah, A. (2012) · Ophthalmology · doi:10.1016/j.ophtha.2012.07.028 · Cited by 97
Kwok, T. C. Y., Wu, Y., Lee, J., Lee, R., Yung, C. Y., Choi, G., Lee, V. W. Y., Harrison, J., Lam, L. C. W., & Mok, V. (2019) · Clinical Nutrition · doi:10.1016/j.clnu.2019.11.005 · Cited by 98
Vascular risk factors and Alzheimer’s disease
O'Brien, J. T., & Markus, H. S. (2014) · BMC Medicine · doi:10.1186/s12916-014-0218-y · Cited by 99
“This relationship is particularly important to determine since raised homocysteine levels were associated with increased brain volume loss on serial magnetic resonance imaging (MRI) in those with mild cognitive impairment in one study [12], and reducing homocysteine levels through folate and vitamin B12 replacement ha…”
BackgroundHodgson, N., Trivedi, M. S., Muratore, C., Li, S., & Deth, R. C. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130101 · Cited by 93
Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies
Buccellato, F. R., D’Anca, M., Tartaglia, G. M., Del Fabbro, M., Scarpini, E., & Galimberti, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813900 · Cited by 94
“…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 [200–202].”
BackgroundRomán, G. C., Páez, O. M., & Bernal, C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020319 · Cited by 94
Kellar, D., Lockhart, S. N., Aisen, P. S. S., Raman, R., Rissman, R. A., Brewer, J. B., & Craft, S. (2021) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2021.14 · Cited by 92
“Previous interventions have shown decreased rates of atrophy in patients with MCI treated with other non-insulin interventions; however, these findings were over a 2-year period (73).”
Hooshmand, B., Mangialasche, F., Kalpouzos, G., Solomon, A., Kåreholt, I., Smith, A. D., Refsum, H., Wang, R., Mühlmann, M., Ertl-Wagner, B. B., et al. (2016) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2016.0274 · Cited by 91
Self-citationMcNulty, H., Ward, M., Hoey, L., Hughes, C., & Pentieva, K. D. (2019) · Proceedings of The Nutrition Society · doi:10.1017/s0029665119000661 · Cited by 91
“Cognitive function typically declines with age, but in some cases, the decline occurs at a greater rate than expected, ranging in severity from relatively minor slips in performing activities, through to subjective cognitive decline, mild cognitive impairment (MCI) and dementia(55).”
ResultInfluential
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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