Cited by 813Folate and B Vitamins ResearchDementia and Cognitive Impairment ResearchAlcoholism and Thiamine Deficiency

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

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Smith, A. David, Smith, Stephen M., de Jager, Celeste A., Whitbread, Philippa, Johnston, Carole, Agacinski, Grzegorz, Oulhaj, Abderrahim, Bradley, Kevin M., Jacoby, Robin, Refsum, Helga·2010·PLoS ONE

DOI 10.1371/journal.pone.0012244PMC PMC2935890

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Abstract

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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Figure 1 Participant Flow in the trial.CC BY · PubMed Central

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.CC BY · PubMed Central

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.CC BY · PubMed Central

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.CC BY · PubMed Central

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Influential
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Self-citation
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Self-citation
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MethodInfluential
Influences of Vitamin B12 Supplementation on Cognition and Homocysteine in Patients with Vitamin B12 Deficiency and Cognitive Impairment
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“An abnormally high blood concentration of homocysteine is recognized as a risk factor for vascular diseases and neurodegenerative conditions (McCully, 2007; Vogel et al., 2009; Smith et al., 2010).”
Background
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Nehls, M. (2016) · Journal of Molecular Psychiatry · doi:10.1186/s40303-016-0018-8 · Cited by 41
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“Some clinical trials target the folate pathway specifically, and advocate taking high doses of B vitamins as a preventative measure against further brain atrophy (Smith et al., 2010) and cognitive decline (Jager et al.”
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“Vitamin B treatment has been shown to slow brain volume shrinkage [61], prevent atrophy of gray matter [62], and slow cognitive decline in people with mild cognitive impairment [63], an effect that was not confirmed by all studies [64].”
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“…regimen suffered significantly less brain shrinkage (atrophy) compared to those who had received a placebo, as measured by volumetric MRI scans (Smith et al. 2010) and another supporting study measured lower levels of vitamin B12 in individuals with increased chances of developing AD or…”
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“These novel findings shed new light on the mechanism of action of folate in CNS development and suggest new approaches for the prevention and treatment of neurodegenerative diseases.”
BackgroundInfluential
Cognitive impairment is associated with elevated serum homocysteine levels among older adults
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“Homocysteine is also suspected to cause cognitive impairment in aged peoples (Smith et al., 2010).”
Background
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Ford, A. H., Flicker, L. A., Alfonso, H. S., Hankey, G. J., Norman, P. E., BOCKXMEER, F. M. V., & Almeida, O. P. (2011) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.2011.242446 · Cited by 38
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“This allows researchers to identify adverse aswellasprotective factorsthat mayin ﬂ uence healthyand pathological changes in brain anatomy and function over time (see e.g. Taki et al., 2013; Thambisetty et al., 2012; Smith et al., 2010; Debette et al., 2011; den Heijer et al., 2012).”
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Farkas, M., Keskitalo, S., Smith, D. E. C., Bain, N., Semmler, A., Ineichen, B. V., Smulders, Y. M., Blom, H. J., Kulic, L., & Linnebank, M. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121378 · Cited by 36
“This may be a vicious cycle breakable by homocysteinelowering vitamins as suggested by the VITACOG trial [12].”
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“The rate of atrophy was also correlated with final cognitive test scores [12], although the trial was not powered for the cognitive outcome.”
BackgroundResultInfluential
Role of Homocysteine in Cognitive Impairement and Alzheimer’s Disease
Bhargava, S., Bhandari, A., & Choudhury, S. (2017) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-017-0646-5 · Cited by 36
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“Other possible mediators include exercise-induced alterations in insulin-like growth factor-1 [41], homocysteine [42], irisin [43], vascular endothelial-derived growth factor [44], metabolites [45], and hormonal responses, which all mediate an active interaction between muscles and the brain through muscle–organ cross…”
Background
Nutritional interventions and cognitive-related outcomes in patients with late-life cognitive disorders: A systematic review
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“Previous findings showed that B vitamin treatment was beneficial by reducing the rate of brain atrophy [5].”
BackgroundMethodResultInfluentialSelf-citation
Serum Homocysteine, Vitamin B12, Folate, and Their Association with Mild Cognitive Impairment and Subtypes of Dementia
Song, Y., Quan, M., Li, T., & Jia, J. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220410 · Cited by 36
“Several studies have found elevated Hcy level is associated with cognitive decline [22], brain atrophy [7], neuroﬁbrillary tangles [38], and white matter damage [39], which are all related to dementia.”
A nutrient‐dense, high‐fiber, fruit‐based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2‐wk trial
Mietus‐Snyder, M., Shigenaga, M. K., Suh, J. H., Shenvi, S. V., Lal, A., McHugh, T. H., Olson, D., Lilienstein, J., Krauss, R. M., Gildengoren, G. L., et al. (2012) · The FASEB Journal · doi:10.1096/fj.11-201558 · Cited by 34
“2 are not clinical cutoffs, but were chosen to reflect results from prospective studies that suggest relatively modest increases in plasma Hcy result in statistically significant increases in future risk of CVD (52, 53) and cognitive decline (54, 55).”
Background
Dietary Intake Is Associated with Occlusal Force Rather Than Number of Teeth in 80-y-Old Japanese
Inomata, C., Ikebe, K., Okubo, H., Takeshita, H., Mihara, Y., Hatta, K., Tada, S., Enoki, K., Ogawa, T., Matsuda, K., et al. (2016) · JDR Clinical & Translational Research · doi:10.1177/2380084416673963 · Cited by 34
“Folate decreases the risk of Alzheimer disease (Luchsinger et al. 2007; Smith et al. 2010).”
Background
Nutrition and brain aging: how can we move ahead?
Barberger‐Gateau, P. (2014) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2014.177 · Cited by 34
Souvenaid in the management of mild cognitive impairment: an expert consensus opinion
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“A 2010 randomized controlled trial found that vitamin B6, B12, and folic acid supplementation decreased the rate of brain atrophy, a characteristic finding in individuals with MCI who later develop Alzheimer’s disease [45].”
Background
Homocysteine, Grey Matter and Cognitive Function in Adults with Cardiovascular Disease
Ford, A. H., Garrido, G. J., Etherton‐Beer, C., Lautenschlager, N. T., Arnolda, L., Flicker, L. A., & Almeida, O. P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033345 · Cited by 32
“These findings are in contrast to data from the VITACOG trial [41,42].”
Result
A blood‐based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial
Bowman, G. L., Dodge, H. H., Guyonnet, S., Zhou, N., Donohue, J., Bichsel, A., Schmitt, J. A. J., Hooper, C., Bartfai, T., Andrieu, S., et al. (2019) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2019.11.004 · Cited by 35
“This notion has emerged in trials of homocysteine (HCy)lowering B vitamins to slow cognitive decline and reduce total brain atrophy in people with hyperhomocysteinemia and higher baseline n-3 polyunsaturated fatty acid (PUFA) in circulation [7,9].”
Background
Elevated Blood Homocysteine and Risk of Alzheimer's Dementia: An Updated Systematic Review and Meta-Analysis Based on Prospective Studies
Zuin, M., Cervellati, C., Brombo, G., Trentini, A., Roncon, L., & Zuliani, G. (2021) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2021.7 · Cited by 32
“H-Hcy has been found to be related with cognitive decline, global and regional brain atrophy (including hippocampus volumes), white matter damage, formation and/or accumulation of the major AD-neuropathological hallmarks, neurofibrillary tangles and neuritic plaques (31).”
Background
Association between intake of dairy products and short-term memory with and without adjustment for genetic and family environmental factors: A twin study
Ogata, S., Tanaka, H., Omura, K., Honda, C., & Hayakawa, K. (2015) · Clinical Nutrition · doi:10.1016/j.clnu.2015.03.023 · Cited by 34
Risk Profiles of Alzheimer Disease
Bilbul, M., & Schipper, H. M. (2011) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100012129 · Cited by 34
Parkinson's disease subtypes: Approaches and clinical implications
Deng, X., Mehta, A., Xiao, B., Chaudhuri, К. R., Tan, E., & Tan, L. C. (2024) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2024.107208 · Cited by 41
Frequency of dementia syndromes with a potentially treatable cause in geriatric in-patients: analysis of a 1-year interval
Djukic, M., Wedekind, D., Franz, A., Gremke, M., & Nau, R. (2015) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-015-0583-3 · Cited by 31
The role of nutrition on cognition and brain health in ageing: a targeted approach
Monti, J. M., Moulton, C. J., & Cohen, N. J. (2015) · Nutrition Research Reviews · doi:10.1017/s0954422415000141 · Cited by 34
“In one report, Smith et al.((112)) noted that after 2 years of supplementation, the overall brain volume of the B vitamin group (relative to the placebo group) was higher, indicating reduced atrophy as a result of B vitamin supplementation.”
Background
Using redescription mining to relate clinical and biological characteristics of cognitively impaired and Alzheimer’s disease patients
Mihelčić, M., Šimić, G., Leko, M. B., Lavrač, N., Džeroski, S., Šmuc, T., & Initiative, A. D. N. (2017) · PLoS ONE · doi:10.1371/journal.pone.0187364 · Cited by 31
“Administering of vitamin B12 is known to sometimes improve cognition when there is insufficient level of B12 in the organism [56,57].”
Disturbed Connectivity of EEG Functional Networks in Alcoholism: A Graph-Theoretic Analysis
Cao, R., Wu, Z., Li, H., Xiang, J., & Chen, J. (2014) · Bio-Medical Materials and Engineering · doi:10.3233/bme-141112 · Cited by 33
“Moreover, chronic alcohol abuse can cause malnutrition and liver dysfunction, which can result in serious diseases, such as Wernicke encephalopathy and Korsakoff syndrome [4].”
Background
Megaloblastic Anemias
Antony, A. C. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-35762-3.00039-1 · Cited by 32
Blood Flow Deficits and Cerebrovascular Changes in a Dietary Model of Hyperhomocysteinemia
Braun, D. J., Abner, E. L., Bakshi, V., Goulding, D. S., Grau, E., Lin, A., Norris, C. M., Sudduth, T. L., Webster, S. J., Wilcock, D. M., et al. (2019) · ASN NEURO · doi:10.1177/1759091419865788 · Cited by 28
“, 2018), and data from several metaanalyses of randomized controlled trials demonstrate the efficacy of B vitamin supplementation on lowering homocysteine levels (Durga et al., 2007; Smith et al., 2010; Ford & Almeida, 2012; Clarke et al., 2014).”
Dietary Interventions to Prevent or Delay Alzheimer’s Disease: What the Evidence Shows
Bartochowski, Z., Conway, J., Wallach, Y., Chakkamparambil, B., Alakkassery, S., & Grossberg, G. T. (2020) · Current Nutrition Reports · doi:10.1007/s13668-020-00333-1 · Cited by 31
Precision Medicine for Alzheimer’s Disease Prevention
Berkowitz, C. L., Mosconi, L., Scheyer, O., Rahman, A., Hristov, H., & Isaacson, R. (2018) · Healthcare · doi:10.3390/healthcare6030082 · Cited by 31
“Several trials have studied a combination of B vitamins to determine whether lowering homocysteine can impact cognitive function and/or brain pathology [55].”
Background
The Role of B-Vitamins in Nutritional Anemia
McNulty, H. (2022) · Nutrition and health · doi:10.1007/978-3-031-14521-6_13 · Cited by 30
Reversing Epigenetic Dysregulation in Neurodegenerative Diseases: Mechanistic and Therapeutic Considerations
Olawade, D. B., Rashad, I., Egbon, E., Teke, J., Ovsepian, S. V., & Boussios, S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26104929 · Cited by 37
“Smith et al. (2010) conducted a randomized, double-blind, placebo-controlled trial involving 168 elderly subjects with mild cognitive impairment [112].”
Influential
Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex
Kunisawa, K., Nakashima, N., Nagao, M., Nomura, T., Kinoshita, S., & Hiramatsu, M. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.06.004 · Cited by 29
The Evaluation of Folic Acid-Deficient or Folic Acid-Supplemented Diet in the Gestational Phase of Female Rats and in Their Adult Offspring Subjected to an Animal Model of Schizophrenia
Canever, L., Alves, C. S. V., Mastella, G. A., Damázio, L. S., Polla, J. V., Citadin, S. A., Luca, L. A. D., Barcellos, A. S., Garcez, M. L., Quevedo, J., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0493-7 · Cited by 28
Higher vitamin B12 level at Parkinson's disease diagnosis is associated with lower risk of future dementia
McCarter, S. J., Stang, C. D., Turcano, P., Mielke, M. M., Ali, F., Bower, J. H., & Savica, R. (2020) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2020.03.009 · Cited by 28
Nutrition and Cognition in Aging Adults
Coley, N., Vaurs, C., & Andrieu, S. (2015) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2015.04.008 · Cited by 29
Relationship between folate, vitamin B12, homocysteine, transaminase and mild cognitive impairment in China: a case-control study
Zhou, X., Wang, Q., An, P., Du, Y. J., Zhao, J., Song, A., & Huang, G. (2019) · International Journal of Food Sciences and Nutrition · doi:10.1080/09637486.2019.1648387 · Cited by 28
“Indeed, vitamin B supplementation can slow the rate of brain atrophy (Smith et al. 2010) and improve cognitive performance in patients with MCI (de Jager et al.”
Background
Folate and Vitamin B12-Related Biomarkers in Relation to Brain Volumes
van der Zwaluw, N. L., Brouwer-Brolsma, E. M., van de Rest, O., van Wijngaarden, J. P., Veld, P. H. I. '., Kourie, D., Swart, K. M. A., Enneman, A. W., Dijk, S. V., van der Velde, N., et al. (2016) · Nutrients · doi:10.3390/nu9010008 · Cited by 27
The Effect of Whey and Soy Protein Isolates on Cognitive Function in Older Australians with Low Vitamin B12: A Randomised Controlled Crossover Trial
Zajac, I. T., Herreen, D., Bastiaans, K., Dhillon, V. S., & Fenech, M. F. (2018) · Nutrients · doi:10.3390/nu11010019 · Cited by 27
“Prior research has proposed that interventions involving otherwise healthy participants, as used herein, require durations as long as 2-to-5 years in order to demonstrate an impact on cognitive function [42].”
Method
Specific Challenges in Geriatric Cirrhosis and Hepatic Encephalopathy
Bajaj, J. S., Gentili, A., Wade, J. B., & Godschalk, M. (2022) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2022.04.035 · Cited by 28
Biomarker characterization of clinical subtypes of Parkinson Disease
Deng, X., Saffari, S. E., Liu, N., Xiao, B., Allen, J. C., Ng, S. Y., Chia, N. S. Y., Tan, Y. J., Choi, X., Heng, D. L., et al. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00375-y · Cited by 27
Plasma homocysteine and cognitive decline in older hypertensive subjects
Narayan, S. K., Saxby, B. K., Firbank, M., O'Brien, J. T., Harrington, F., McKeith, I. G., Hansrani, M., Stansby, G. P., & Ford, G. A. (2011) · International Psychogeriatrics · doi:10.1017/s1041610211000779 · Cited by 28
CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer’s Disease and Cerebrovascular Disease
Shankle, W. R., Hara, J., Barrentine, L. W., & Curole, M. V. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160241 · Cited by 27
“The present study used doses of L-methylfolate and B12 that were respectively 10 and 4 times larger than the folate and B12 doses used in other regional brain volumetric studies of HHcy treatment with B vitamins [6, 7, 44].”
Result
Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription
Xie, Q., Li, C., Song, X., Wu, L., Jiang, Q., Qiu, Z., Cao, H., Yu, K., Wan, C., Li, J., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw1208 · Cited by 27
Relationships between dietary nutrients intake and lipid levels with functional MRI dorsolateral prefrontal cortex activation
Lau, H., Shahar, S., Mohamad, M., Rajab, N. F., Yahya, H. M., Din, N. C., & Hamid, H. A. (2018) · Clinical Interventions in Aging · doi:10.2147/cia.s183425 · Cited by 27
Effect of vitamin intake on cognitive decline in older adults: Evaluation of the evidence
Krause, D., & Roupas, P. (2015) · The journal of nutrition health & aging · doi:10.1007/s12603-015-0539-3 · Cited by 27
“The mechanism for the homocysteine lowering effect is still under investigation as Smith et al, (40) reported that the effect was likely to be from folate and vitamin B12 rather than vitamin B6, while a study from Faux et al (43) found no clear relationship between folate and vitamin B12 in modulating homocysteine lev…”
Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer’s Disease
Hudd, F., Shiel, A., Harris, M., Bowdler, P., McCann, B., Tsivos, D., Wearn, A., Knight, M., Kauppinen, R., Coulthard, E., et al. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-180879 · Cited by 26
“This is particularly relevant to AD as a study that used vitamin B supplementation over 2 years showed how accelerated brain atrophy in elderly subjects with MCI was slowed by 30%, which corresponded to a decrease of 31.7% in total homocysteine levels [68].”
Influential
Levodopa, homocysteine and Parkinson's disease: What's the problem?
Ahlskog, J. E. (2023) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2023.105357 · Cited by 31
To establish the parameters of optimal nutrition do we need to consider psychological in addition to physiological parameters?
Benton, D. (2012) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201200477 · Cited by 26
“An interesting exception is the report that in those over 70 years, with mild cognitive impairment (early signs of memory loss), the rate of brain atrophy as measured using structural MRI scans of the brain, was slowed over a period of 2 years by using B vitamins to decrease the levels of homocysteine [38].”
Background
Strategies to improve diet in older adults
Johnson, M. A. (2012) · Proceedings of The Nutrition Society · doi:10.1017/s0029665112002819 · Cited by 27
“8 mg folic acid and 20 mg vitamin B6) were associated with lower rates of brain atrophy((52)) and stabilisation of executive function relative to the placebo treatment((53)).”
Background
Assessment of brain cognitive functions in patients with vitamin B12 deficiency using resting state functional MRI: A longitudinal study
Gupta, L. K., Gupta, R. K., Gupta, P. K., Malhotra, H. S., Saha, I., & Garg, R. K. (2015) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2015.10.026 · Cited by 26
“A number of studies have described that evidence of B12 deficiency is associated with cognitive decline, WM damage and brain atrophy [11,12,28].”
Background
Cognitive Impairment and Risk Factors in Elderly People Living in Fluorosis Areas in China
Li, M., Gao, Y., Cui, J., Li, Y., Li, B., Liu, Y., Sun, J., Liu, X., Liu, H., Zhao, L., et al. (2015) · Biological Trace Element Research · doi:10.1007/s12011-015-0568-0 · Cited by 27
“Serum Hcy concentrations were increased with theexacerbation of cognitive impairment, which supported that higher serum concentrations of Hcy may be one of the risk factors for cognitive impairment as reported by a previous study [15].”
Result
Homocysteine and Cerebral Atrophy: The Epidemiology of Dementia in Singapore Study
Tan, B. W. Q., Venketasubramanian, N., Vrooman, H. A., Cheng, C., Wong, T. Y., Ikram, M. K., Chen, C., & Hilal, S. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170796 · Cited by 28
“A randomized controlled trial showed that homocysteine-lowering vitamin B12 supplementation decreased progression in global cerebral atrophy, with effects most prominent in subjects with elevated homocysteine levels [32].”
Association of serum homocysteine levels with intestinal flora and cognitive function in schizophrenia
Li, H., Li, H., Zhu, Z., Xiong, X., Huang, Y., Feng, Y., Li, Z., Wu, K., & Wu, F. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.01.045 · Cited by 26
Recent Advances in Imaging Alzheimer's Disease
Braskie, M. N., Toga, A. W., & Thompson, P. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129016 · Cited by 26
The Relationship between Associative Learning, Transfer Generalization, and Homocysteine Levels in Mild Cognitive Impairment
Moustafa, A. A., Hewedi, D. H., Eissa, A. M., Myers, C. E., & Sadek, H. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046496 · Cited by 26
“Many studies have reported that lowering homocysteine levels enhances memory and cognition in individuals with MCI and AD [20,101].”
Background
Methylenetetrahydrofolate reductase C677T variant and hyperhomocysteinemia in subarachnoid hemorrhage patients from India
Kumar, M., Goudihalli, S. R., Mukherjee, K. K., Dhandapani, S., & Sandhir, R. (2018) · Metabolic Brain Disease · doi:10.1007/s11011-018-0268-5 · Cited by 26
“MTHFR C677T polymorphism and elevated plasma Hcy levels have also been reported in coronary artery diseases (CAD) in a case control study in North Indian population (Tripathi et al. 2010).”
Preventing Alzheimer’s: Our Most Urgent Health Care Priority
Sherzai, D., & Sherzai, A. Z. (2019) · American Journal of Lifestyle Medicine · doi:10.1177/1559827619843465 · Cited by 27
Low folate predicts accelerated cognitive decline: 8-year follow-up of 3140 older adults in Ireland
O’Connor, D. M. A., Scarlett, S., Looze, C. D., O’Halloran, A. M., Laird, E. J., Molloy, A. M., Clarke, R., McGarrigle, C. A., & Kenny, R. A. (2022) · European Journal of Clinical Nutrition · doi:10.1038/s41430-021-01057-3 · Cited by 25
Dementia Prevention in Clinical Practice
Niotis, K., Akiyoshi, K., Carlton, C., & Isaacson, R. (2022) · Seminars in Neurology · doi:10.1055/s-0042-1759580 · Cited by 26
Mapping creatinine- and cystatin C-related white matter brain deficits in the elderly
Rajagopalan, P., Refsum, H., Hua, X., Toga, A. W., Jack, C. R., Weiner, M. W., & Thompson, P. M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.10.022 · Cited by 25
“, 2007) and rate of brain atrophy (Smith et al., 2010); (2) CysC with silent brain infarcts (Seliger et al.”
BackgroundSelf-citation
Assessment of functional and structural damage in brain parenchyma in patients with vitamin B12 deficiency: A longitudinal perfusion and diffusion tensor imaging study
Roy, B., Trivedi, R., Garg, R. K., Gupta, P. K., Tyagi, R., & Gupta, R. K. (2015) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2015.02.012 · Cited by 25
Diffusion tensor tractography and neuropsychological assessment in patients with vitamin B12 deficiency
Gupta, P. K., Garg, R. K., Gupta, R. K., Malhotra, H. S., Paliwal, V. K., Rathore, R. K. S., Verma, R. K., Singh, M. K., Rai, Y., & Pandey, C. M. (2013) · Neuroradiology · doi:10.1007/s00234-013-1306-y · Cited by 25
“There is much evidence that B12 deficiency is associated with brain atrophy and causes cognitive decline [32, 34].”
Background
Brain imaging and human nutrition: which measures to use in intervention studies?
Sizonenko, S. V., Babiloni, C., de Bruin, E. A., Isaacs, E., Jönsson, L. S., Kennedy, D. O., Latulippe, M. E., Mohajeri, M. H., Moreines, J., Pietrini, P., et al. (2013) · British Journal Of Nutrition · doi:10.1017/s0007114513001384 · Cited by 25
“However, this possibility has recently been weakened by a large well-controlled intervention study((84)).”
Normal Vitamin Levels and Nutritional Indices in Alzheimer’s Disease Patients with Mild Cognitive Impairment or Dementia with Normal Body Mass Indexes
Ulstein, I. D., & Bøhmer, T. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160393 · Cited by 25
“In fact, the OPTIMA group in Oxford reported that high-dose supplementation with the vitamins B6, B12, and folic acid slowed brain atrophy in persons with mild cognitive impairment (MCI) [15], particularly in those with high -3 fatty acids [16].”
Background
The Role of Malnutrition during Pregnancy and Its Effects on Brain and Skeletal Muscle Postnatal Development
Castrogiovanni, P., & Imbesi, R. (2017) · Journal of Functional Morphology and Kinesiology · doi:10.3390/jfmk2030030 · Cited by 25
“Moreover, it seems that the low concentration of maternal folate is linked to increased inattention, hyperactivity problems and emotional problems in the progeny [27], considerations that deserve further investigation.”
Background
High serum folate is associated with brain atrophy in older diabetic people with vitamin B12 deficiency
Deng, Y., Wang, D., Wang, K., & Kwok, T. C. Y. (2017) · The journal of nutrition health & aging · doi:10.1007/s12603-017-0979-z · Cited by 25
One-Carbon Metabolism Biomarkers and Cognitive Decline in the Very Old: The Newcastle 85+ Study
Mendonça, N., Granic, A., Mathers, J. C., Martin-Ruiz, C. M., Wesnes, K. A., Seal, C. J., Jagger, C., & Hill, T. R. (2017) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2017.05.008 · Cited by 25
“Physical activity, high, % (n) 38 (71) 33 (62) Education 12 y, % (n) 11 (20) 11 (20) History of cardiovascular disease, % (n) 45 (84) 57 (108) Diabetes type 1 or 2, % (n) 9 (16) 16 (31) Hypertension, % (n) 54 (100) 59 (112)”
Glycerophospholipid Supplementation as a Potential Intervention for Supporting Cerebral Structure in Older Adults
Reddan, J. M., White, D., Macpherson, H., Scholey, A. B., & Pipingas, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00049 · Cited by 29
“Supplementation with these B vitamins has been shown to lower HcY concentrations (Eussen et al., 2006; McMahon et al., 2006; Smith et al., 2010; Clarke et al., 2014; Ford and Almeida, 2014).”
BackgroundMethodInfluential
THE ALZHEIMER’S PREVENTION CLINIC AT WEILL CORNELL MEDICAL COLLEGE / NEW YORK - PRESBYTERIAN HOSPITAL: RISK STRATIFICATION AND PERSONALIZED EARLY INTERVENTION
Seifan, A., & Isaacson, R. (2015) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2015.81 · Cited by 25
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Table 4 Potential Personalized Interventions Risk Factor Individual Factor Potential Intervention Hypertension Midlife Avoid CNS-active beta blockers86; consider CCB or ARB (87) Lifestyle counseling Assess and treat sleep apnea Insulin Res…”
BackgroundInfluential
Helicobacter pylori, Vascular Risk Factors and Cognition in U.S. Older Adults
Cardenas, V. M., Boller, F., & Román, G. C. (2019) · Brain Sciences · doi:10.3390/brainsci9120370 · Cited by 24
“[31] The VITACOG trial [50] demonstrated that high-dose oral B-vitamins lowered by 53% the rate of brain atrophy in subjects with Hcy > 13.”
Background
Consideration of nutrient levels in studies of cognitive decline
Barnes, J. L., Tian, M., Edens, N. K., & Morris, M. C. (2014) · Nutrition Reviews · doi:10.1111/nure.12144 · Cited by 24
Nutrient biomarkers and vascular risk factors in subtypes of mild cognitive impairment: A cross-sectional study
Yin, Y., Fan, Y., Lin, F. R., Xu, Y., & Zhang, J. (2014) · The journal of nutrition health & aging · doi:10.1007/s12603-014-0510-8 · Cited by 23
“A single-center, randomized, double-blind controlled trial (VITACOG) of high-dose folate, VitB6, and B12 supplementation conducted in the United Kingdom (56), found that that high doses of B vitamins can be used to reduce the rate of atrophy of the brain in elderly people with MCI, but the study was not powered suffic…”
MTHFR Gene Mutations: A Potential Marker of Late-Onset Alzheimer’s Disease?
Román, G. C. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150304 · Cited by 24
Association of MTHFR, SLC19A1 Genetic Polymorphism, Serum Folate, Vitamin B12 and Hcy Status with Cognitive Functions in Chinese Adults
Cai, C., Xiao, R., Halm‐Lutterodt, N. V., Zhen, J., Huang, X., Xu, Y., Chen, S., & Yuan, L. (2016) · Nutrients · doi:10.3390/nu8100665 · Cited by 24
Magnetic Resonance Volumetry: Prediction of Subjective Memory Complaints and Mild Cognitive Impairment, and Associations with Genetic and Cardiovascular Risk Factors
Rogne, S., Vangberg, T. R., Eldevik, P., Wikran, G., Mathiesen, E. B., & Schirmer, H. (2016) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000450885 · Cited by 25
Nutrient deficiencies and depression in older adults according to sex: A cross sectional study
Park, Y., Choi‐Kwon, S., Park, K., Suh, M., & Jung, Y. (2016) · Nursing and Health Sciences · doi:10.1111/nhs.12315 · Cited by 23

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
ORCID: Smith, A. David
Smith, Stephen M.
Oulhaj, Abderrahim
Bradley, Kevin M.
Refsum, Helga
Venue: PLoS ONE
Publisher: Public Library of Science (PLoS)
Published: 2010-09-08
Volume: 5
Issue: 9
Pages: e12244
ISSN: 1932-6203 (ISSN-L)
DOI: 10.1371/journal.pone.0012244
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
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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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Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

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