Evidence-Based Nutrient Recommendations

Subclinical B12 Deficiency and Homocysteine in Vegans

Contents

Summary

If someone has little or no vitamin B12 intake for a period of years, severe deficiency can result which manifests as overt symptoms of nerve damage and anemia. It’s also possible to obtain enough B12 to ward off overt deficiency symptoms while not meeting recommendations, resulting in a subclinical deficiency.

There’s evidence that subclinical B12 deficiency increases the risk of cognitive decline, cardiovascular disease (especially stroke), early mortality, and possibly low bone mineral density.

The mechanisms for how subclinical B12 deficiency harms people haven’t been fully elucidated. A lack of B12 for optimal nerve maintenance may take a toll after many years. It’s also possible that homocysteine, which becomes elevated in subclinical B12 deficiency, can directly harm nerves and vessels.

Homocysteine also becomes elevated in folate and vitamin B6 deficiency and it’s not clear whether homocysteine is the primary cause of the damage or merely a marker for vitamin deficiencies. It could be a combination of both.

Vegans who don’t regularly supplement with B12 tend to have low B12 levels and elevated homocysteine levels. It’s important for vegans to follow B12 recommendations to prevent subclinical B12 deficiency.

Background on Homocysteine

Methionine is an essential amino acid obtained from protein in the diet. As a byproduct of metabolism, some methionine is converted to homocysteine. The body turns much of this homocysteine back into methionine with the help of vitamin B12, but if someone is B12-deficient, homocysteine levels will increase.

Normal serum homocysteine levels are from 2.2 to 13.2 µmol/l (Loehrer, 1997). Levels of homocysteine in typical Western populations are about 12 µmol/l (Homocysteine Lowering Trialists’ Collaboration, 1998). According to the European Food Safety Commission (2015), there’s no consensus on a desirable cut-off value for homocysteine, acceptable upper reference limits from 9 to 16 μmol/l have been proposed by a range of researchers, and 15 μmol/l is frequently used as an indicator of hyperhomocysteinemia in adults.

Some people have a genetic variant in folate metabolism, the MTHFR polymorphism, that might require supplementation with 5-methyl-THF though research is currently inconclusive (see the National Institutes of Health article Folate).

Many clinical trials have investigated the impact of pharmacological doses of B12, folic acid, and vitamin B6 in treating diseases associated with elevated homocysteine. To date, they haven’t shown much promise, with some exceptions noted below.

Homocysteine in Vegetarians and Vegans

In most non-vegetarians with elevated homocysteine, folate is more of a problem than is B12. Vegetarians tend to have an advantage regarding folate as many plant foods are good sources. The RDA for adults is 400 µg.

Plant Sources of Folate
Food Preparation Serving µg
Lentils cooked 1/2 cup 179
Black beans cooked 1/2 cup 128
Romaine lettuce shredded 1 1/2 cup 114
Orange juice 1 cup 109
Spinach cooked 1/2 cup 103
Refried beans canned 1/2 cup 106
Garbanzo beans
(aka chickpeas)
cooked 1/2 cup 80
Navy beans cooked 1/2 cup 82
Broccoli cooked 1 cup 78
Sunflower seeds 1/4 cup 76
Pinto beans cooked 1/2 cup 72
Kidney beans cooked 1/2 cup 63
Taken from Wardlaw GM. Perspectives in Nutrition, 4th Ed. Boston, MA: McGraw-Hill; 1999.

Since vegetarian diets are typically high in folate, elevated homocysteine levels in vegetarians are normally due to a low B12 intake.

At least 14 studies have measured the vitamin B12 and homocysteine levels in vegetarians. The findings have been consistent: when vegetarians don’t supplement their diets with B12 their homocysteine levels rise to unhealthy levels (Bissoli, 2002; Crane, 1998; Haddad, 1999; Herrmann, 2001; Herrmann, 2003; Huang, 2003; Hung, 2002; Krajcovicova-Kudlackova, 2000; Krivosikova, 2009; Mann, 1999; Mezzano, 1999; Mezzano, 2000; Obeid, 2002; Refsum, 2001). While this finding is stronger in vegans, it’s also true of lacto-ovo vegetarians.

In the 14 studies above, the average homocysteine levels of vegans were 14 to 20 µmol/l compared to about 8 to 12 µmol/l for omnivores. In contrast, a 1998 study of vegans receiving 500 µg/day of B12 for 2 months showed them to have homocysteine levels below 5 µmol/l (Crane, 1998). A 1999 study showed vegans who averaged 5.6 µg/day of B12 to have homocysteine levels of 7.9 µmol/l, slightly lower than the omnivores (Haddad, 1999).

In other words, vegans who make sure they have a reliable intake of B12 should have ideal homocysteine levels, other things being equal such as enough folate in the diet and not having a genetic variant found in 5-25% of people which increases their need for folate.

Cognition

Vitamin B12 is important for nerve function and people who become severely deficient exhibit neurological and cognitive problems. This has raised concerns that mild B12-deficiency over many years could contribute to cognitive impairment, Alzheimer’s Disease, or other forms of dementia.

The research related to these subjects is vast and inconsistent due to wide variability in methodology. Below, we review what appears to be the most relevant research for vegans.

With respect to B12, only omnivores who don’t regularly meet the Recommended Dietary Allowance for B12 appear to be at risk; vegans should meet VeganHealth’s minimum recommendations (5 µg per day for most adults) to provide the same amount of absorbed B12.

With respect to homocysteine, it’s best to keep levels below 10 µmol/l but this could be more related to folate status than B12.

B12 Status and Prospective Studies of Cognitive Decline

Zhang et al. (2020) conducted a meta-analysis of studies measuring the association between plasma levels of vitamins B12, B6, folate and cognitive function. Among 6 cross-sectional studies, higher B12 levels (OR = 0.77, 95% CI = 0.61–0.97) and folate (OR = 0.68, 95% CI = 0.51–0.90) were associated with better cognition. However, among 5 prospective studies, there was no association between higher B12 levels (OR = 1.27, 95% CI = 0.97–1.67) or intake (1.10, 95% CI = 0.85–1.42) and better cognition. Also among prospective studies, there was no association between folate concentration or intake and better cognition. This finding strongly suggests that poor B12 status in the cross-sectional studies was more likely a result, rather than a cause, of cognitive decline.

The Effects and Mechanism Investigation of Cholesterol and Oxysterol on Alzheimer’s disease (EMCOA) study from China wasn’t included in Zhang et al.’s meta-analysis above and it might be especially relevant to vegans due to the low B12-intake categories (An, 2019). The study included 2,533 people aged 50-70 years with normal cognitive functioning at baseline. After 2 years, compared to the upper two quartiles of B12 intake (2.1–3.4 and 3.4–37 µg/day) the lowest quartile of B12 intake (0–1.3 µg/day) was associated with accelerated cognitive decline across all domains, and the second quartile of B12 intake (1.3–2.1 µg/day) was associated with decline in most cognitive domains. The two lowest B12 intake quartiles were below the U.S. Recommended Dietary Allowance of 2.4 µg/day.

EMCOA conducted a subgroup case-control analysis among those diagnosed with Mild Cognitive Impairment (MCI). Among cases of MCI, they found higher homocysteine and lower folate levels, but not lower B12 intakes or B12 serum levels. They also found disturbances of B-vitamin metabolism and an imbalance of antioxidant-to-free radical ratio among cases. This suggests a larger role for folate than B12 with regard to developing MCI over the course of 2 years.

B12 Metabolites and Brain Volume

A study from the Chicago Health and Aging Project measured B12 metabolites and cognition scores in 121 older adults (Tangney, 2011). Baseline methylmalonic acid (MMA) and homocysteine levels, but not serum B12, were associated with lower total brain volume as measured by an MRI 4.6 years later. Despite the seemingly prospective nature of this study, it’s not clear that reverse causality can be ruled out since MRI measurements weren’t taken at baseline.

Randomized Controlled Trials of B-Vitamins, Cognitive Decline, and Brain Atrophy

The Cochrane Database of Systematic Reviews is a leading journal and database for systematic reviews in healthcare. They conducted a review of randomized clinical trials using B vitamins to slow cognitive decline in people diagnosed with mild cognitive impairment but without overt vitamin deficiencies (McCleery, 2018). Five trials with 879 participants qualified, though one used only folic acid. They concluded that there was probably little or no effect of B vitamins taken for 6 to 24 months on episodic memory, executive function, speed of processing, or quality of life.

The Cochrane review included the VITACOG trial, using a daily dose of folic acid (0.8 mg), B12 (500 µg), and vitamin B6 (20 mg) for 2 years and found evidence for a slower rate of brain atrophy (Douaud, 2013).

In their own meta-analysis, Smith and Refsum, two of the researchers from the VITACOG study, argue that B-vitamins are likely to provide benefit only in populations whose baseline homocysteine levels are greater than 10–11 µmol/l (Smith, 2016). Smith and Refsum hold patents to certain B-vitamin therapies (Douaud, 2013).

Research on Vegetarians and Vegans

There’s no research studying cognitive decline among vegans. For what it’s worth, there have been some studies comparing the mortality from some diseases related to cognition between vegetarians and non-vegetarians.

A 2002 study (Appleby, 2002) on British mortality found vegetarians to have a barely statistically significant, higher risk of death from mental and neurological diseases (DRR 2.21, CI 1.02–4.78). However, in the EPIC-Oxford study (Appleby, 2016), vegetarian deaths from “mental and behavioral disorders” were not statistically different from non-vegetarians (HR 1.22, CI 0.78–1.91). The risk of mortality from neurologic disease in the Adventist Health Study-2 (Orlich, 2013) was also not statistically different for vegetarians compared to non-vegetarians (HR 0.93, CI 0.67-1.29).

Summary of B12 and Cognition

It appears that B12-related cognitive impairment is limited to people who would traditionally be considered at least mildly B12-deficient or with marginal B12 intakes.

It’s prudent for vegans to make sure they’re meeting VeganHealth’s minimum B12 recommendations in order to prevent possible cognitive decline or dementia. Once discovered, cognitive decline appears not to be easily corrected.

Mortality and Cardiovascular Disease

A number of prospective studies have found an association between elevated homocysteine and early death. Studies from the USA (Bostom, 1999), Israel (Kark, 1999), and Norway (Vollset, 2001) all found a statistically significant increase in mortality in people with homocysteine levels of about 14 to 15 µmol/l.

Among prospective, observational studies, three meta-analyses found that elevated homocysteine levels were associated with an increased risk of cardiovascular disease (Homocysteine Studies Collaboration, 2002; Wald, 2002; Humphrey, 2008). Also, a reduction in stroke deaths in both the USA and Canada paralleled the fortification of foods with folic acid (Yang, 2006).

More recently, Chen et al. (2020) conducted a meta-analysis of prospective, observational studies of B-vitamin intake and the risk of stroke. While higher intakes of folate and B6 were associated with a lower risk, B12 was not. Limitations of the analysis are that most studies didn’t adjust for dietary variables such as saturated fat intake, only a small percentage of participants were likely to have had B12 deficiency, and homocysteine levels weren’t analyzed.

The Cochrane Database of Systematic Reviews conducted a meta-analysis of pharmacological doses of B-vitamins for lowering homocysteine and preventing cardiovascular disease in people with and without pre-existing cardiovascular disease. Their analysis included 15 high-quality, randomized controlled trials involving 71,422 participants lasting 1 to 7 years. They found a reduced risk of stroke (RR 0.90, CI 0.82–0.99), but no reduction in overall mortality or heart attacks (Martí-Carvajal, 2017). It’s not clear to what degree the participants in these trials had elevated homocysteine levels with some trials not reporting levels; a meta-analysis comparing the impact of lowering homocysteine only in people with levels above a particular threshold might find a stronger effect.

A 2012 randomized, placebo-controlled, crossover trial from Hong Kong studied the impact of B12 supplements on cardiovascular markers in 50 vegetarians, including 2 vegans. 35 subjects (70%) had B12 levels <150 pg/ml. After 12-week periods of 500 µg of B12 per day, blood flow improved with B12 supplementation. The positive effects more closely correlated to the correction of B12 deficiency than to lowering homocysteine (Kwok, 2012).

Adequate folate status might be more important than B12 for the primary prevention of cardiovascular events in the general population. For vegans, it’s important to follow B12 recommendations in order to maintain homocysteine levels below 10 µmol/l to minimize the risk of cardiovascular disease.

Bone Mineral Density

Vitamin B12 might also be important for bone mineral density, and two studies have linked low B12 status in vegetarians to poorer bone health. For more information, see the Vitamin B12 and Bone Mineral Density.

Bibliography

Last updated November 2021

Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. Not cited.

Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008 May 7;299(17):2027-36. Not cited.

An Y, Feng L, Zhang X, et al. Dietary intakes and biomarker patterns of folate, vitamin B6, and vitamin B12 can be associated with cognitive impairment by hypermethylation of redox-related genes NUDT15 and TXNRD1. Clin Epigenetics. 2019;11(1):139.

Antoniades C, Antonopoulos AS, Tousoulis D, Marinou K, Stefanadis C. Homocysteine and coronary atherosclerosis: from folate fortification to the recent clinical trials. Eur Heart J. 2009 Jan;30(1):6-15. Epub 2008 Nov 23. Not cited.

Appleby PN, Key TJ, Thorogood M, Burr ML, Mann J. Mortality in British vegetarians. Public Health Nutr. 2002 Feb;5(1):29-36.

Appleby PN, Crowe FL, Bradbury KE, Travis RC, Key TJ. Mortality in vegetarians and comparable nonvegetarians in the United Kingdom. Am J Clin Nutr. 2016 Jan;103(1):218-30.

Bailey RL, Jun S, Murphy L, Green R, Gahche JJ, Dwyer JT, Potischman N, McCabe GP, Miller JW. High folic acid or folate combined with low vitamin B-12 status: potential but inconsistent association with cognitive function in a nationally representative cross-sectional sample of US older adults participating in the NHANES. Am J Clin Nutr. 2020 Dec 10;112(6):1547-1557. Not cited.

Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006 Dec 13;296(22):2720-6. (Abstract) Not cited.

Bissoli L, Di Francesco V, Ballarin A, Mandragona R, Trespidi R, Brocco G, Caruso B, Bosello O, Zamboni M. Effect of vegetarian diet on homocysteine levels. Ann Nutr Metab. 2002;46(2):73-9.

Bostom, 1999. Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D’Agostino RB, Wolf PA, Jacques PF, Wilson PW. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med. 1999 May 24;159(10):1077-80.

Cecchetti L, Lettieri G, Handjaras G, et al. Brain Hemodynamic Intermediate Phenotype Links Vitamin B12 to Cognitive Profile of Healthy and Mild Cognitive Impaired Subjects. Neural Plast. 2019;2019:6874805. Not cited.

Chen L, Li Q, Fang X, Wang X, Min J, Wang F. Dietary Intake of Homocysteine Metabolism-Related B-Vitamins and the Risk of Stroke: A Dose-Response Meta-Analysis of Prospective Studies. Adv Nutr. 2020 Nov 16;11(6):1510-1528.

Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R; B-Vitamin Treatment Trialists’ Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010 Oct 11;170(18):1622-31. Not cited.

Crane MG, Register UD, Lukens RH, Gregory R Cobalamin (CBL) studies on two total vegetarian (vegan) families. Vegetarian Nutrition. 1998; 2(3):87-92.

Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8.

Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE, Refsum H, Pedersen EK, Nygard O. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA. 2008 Aug 20;300(7):795-804. Not cited.

European Food Safety Authority NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2015. Scientific Opinion on Dietary Reference Values for cobalamin (vitamin B12). EFSA Journal 2015;13(7):4150, 64 pp.

Haddad EH, Berk LS, Kettering JD, Hubbard RW, Peters WR. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr. 1999;70(suppl):586S-93S.

Herrmann W, Schorr H, Purschwitz K, Rassoul F, Richter V. Total homocysteine, vitamin b(12), and total antioxidant status in vegetarians. Clin Chem. 2001 Jun;47(6):1094-101.

Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003 Jul;78(1):131-6.

Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ. 1998 Mar 21;316(7135):894-8.

Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288(16):2015-2022.

Huang YC, Chang SJ, Chiu YT, Chang HH, Cheng CH. The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. Eur J Nutr. 2003 Apr;42(2):84-90.

Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008 Nov;83(11):1203-12.

Hung CJ, Huang PC, Lu SC, Li YH, Huang HB, Lin BF, Chang SJ, Chou HF. Plasma Homocysteine Levels in Taiwanese Vegetarians Are Higher than Those of Omnivores. J Nutr. 2002 Feb;132(2):152-158.

Kane RL, Butler M, Fink HA, Brasure M, Davila H, Desai P, Jutkowitz E, McCreedy E, Nelson VA, McCarten JR, Calvert C, Ratner E, Hemmy LS, Barclay T. Interventions to Prevent Age-Related Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer’s-Type Dementia [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2017 Mar. Not cited.

Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999 Sep 7;131(5):321-30.

Krajcovicova-Kudlackova, 2000. Krajcovicova-Kudlackova M, Blazicek P, Kopcova J, Bederova A, Babinska K. Homocysteine levels in vegetarians versus omnivores. Ann Nutr Metab. 2000;44(3):135-8.

Krivosikova Z, Krajcovicova-Kudlackova M, Spustova V, Stefikova K, Valachovicova M, Blazicek P, Nemcova T. The association between high plasma homocysteine levels and lower bone mineral density in Slovak women: the impact of vegetarian diet. Eur J Nutr. 2009 Oct 7.

Kwok T, Chook P, Qiao M, Tam L, Poon YK, Ahuja AT, Woo J, Celermajer DS, Woo KS. Vitamin B-12 supplementation improves arterial function in vegetarians with subnormal vitamin B-12 status. J Nutr Health Aging. 2012;16(6):569-73.

Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke. 2010 Jun;41(6):1205-12. Epub 2010 Apr 22. Not cited.

Loehrer FM, Schwab R, Angst CP, Haefeli WE, Fowler B. Influence of oral S-adenosylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Ther. 1997 Aug;282(2):845-50.

Loland KH, Bleie O, Blix AJ, Strand E, Ueland PM, Refsum H, Ebbing M, Nordrehaug JE, Nygard O. Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. Am J Cardiol. 2010 Jun 1;105(11):1577-84. Not cited.

Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77. Not cited.

Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD004514. Not cited.

Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, Wilson AK, Kelly FD. The effect of diet on plasma homocysteine concentrations in healthy male subjects. Eur J Clin Nutr. 1999 Nov;53(11):895-9.

Martí-Carvajal AJ, Solà I, Lathyris D, Karakitsiou DE, Simancas-Racines D. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2013 Jan 31;1:CD006612. Not cited.

Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev. 2017 Aug 17;8:CD006612.

McCaddon A, Davies G, Hudson P. Nutritionally independent B12 deficiency and Alzheimer disease. Arch Neurol. 2000 Apr;57(4):607-8. Not cited.

McCleery J, Abraham RP, Denton DA, et al. Vitamin and mineral supplementation for preventing dementia or delaying cognitive decline in people with mild cognitive impairment. Cochrane Database Syst Rev. 2018;11(11):CD011905. Published 2018 Nov 1.

Mezzano D, Munoz X, Martinez C, Cuevas A, Panes O, Aranda E, Guasch V, Strobel P, Munoz B, Rodriguez S, Pereira J, Leighton F. Vegetarians and cardiovascular risk factors: hemostasis, inflammatory markers and plasma homocysteine. Thromb Haemost. 1999 Jun;81(6):913-7.

Mezzano D, Kosiel K, Martinez C, Cuevas A, Panes O, Aranda E, Strobel P, Perez DD, Pereira J, Rozowski J, Leighton F. Cardiovascular risk factors in vegetarians. Normalization of hyperhomocysteinemia with vitamin B(12) and reduction of platelet aggregation with n-3 fatty acids. Thromb Res. 2000 Nov 1;100(3):153-60.

Nourhashemi F, Gillette-Guyonnet S, Andrieu S, Ghisolfi A, Ousset PJ, Grandjean H, Grand A, Pous J, Vellas B, Albarede JL Alzheimer disease: protective factors. Am J Clin Nutr. 2000 Feb;71(2):643S-649S. Not cited.

Obeid R, Geisel J, Schorr H, Hubner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002 Nov;69(5-6):275-9.

Orlich MJ, Singh PN, Sabaté J, Jaceldo-Siegl K, Fan J, Knutsen S, Beeson WL, Fraser GE. Vegetarian dietary patterns and mortality in Adventist Health Study 2. JAMA Intern Med. 2013 Jul 8;173(13):1230-8.

Refsum H, Yajnik CS, Gadkari M, Schneede J, Vollset SE, Orning L, Guttormsen AB, Joglekar A, Sayyad MG, Ulvik A, Ueland PM. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001 Aug;74(2):233-41.

Rieder CR, Fricke D. Vitamin B(12) and folate in relation to the development of Alzheimer’s disease. Neurology. 2001 Nov 13;57(9):1742-3. Not cited.

Saposnik G, Ray JG, Sheridan P, McQueen M, Lonn E; Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke. 2009 Apr;40(4):1365-72. Not cited.

Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010 Jun 23;303(24):2486-94. Not cited.

Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000 Feb;71(2):614S-620S. Not cited.

Selhub J, Jacques PF, Dallal G, Choumenkovitch S, Rogers G. The use of blood concentrations of vitamins and their respective functional indicators to define folate and vitamin B12 status. Food Nutr Bull. 2008 Jun;29(2 Suppl):S67-73. Review. Not cited.

Smith AD, Refsum H. Homocysteine, B Vitamins, and Cognitive Impairment. Annu Rev Nutr. 2016;36:211-239.

Soh Y, Lee DH, Won CW. Association between Vitamin B12 levels and cognitive function in the elderly Korean population. Medicine (Baltimore). 2020;99(30):e21371. Not cited.

Tangney CC, Aggarwal NT, Li H, Wilson RS, Decarli C, Evans DA, Morris MC. Vitamin B12, cognition, and brain MRI measures: A cross-sectional examination. Neurology. 2011 Sep 27;77(13):1276-82.

Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer’s disease: A systematic review. Arch Gerontol Geriatr. 2009 May-Jun;48(3):425-30.

VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. 2010 Sep;9(9):855-65. Epub 2010 Aug 3. Not cited.

Vollset SE, Refsum H, Tverdal A, Nygard O, Nordrehaug JE, Tell GS, Ueland PM. Plasma total homocysteine and cardiovascular and non cardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr. 2001 Jul;74(1):130-6.

Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002 Nov 23;325(7374):1202.

Walters MJ, Sterling J, Quinn C, Ganzer C, Osorio RS, Andrews RD, Matthews DC, Vallabhajosula S, de Leon MJ, Isaacson RS, Mosconi L. Associations of lifestyle and vascular risk factors with Alzheimer’s brain biomarker changes during middle age: a 3-year longitudinal study in the broader New York City area. BMJ Open. 2018 Nov 25;8(11):e023664.

Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y, Sun N, Liu L, Xu X. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet. 2007 Jun 2;369(9576):1876-82. Not cited.

Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H, Friedman JM. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation. 2006 Mar 14;113(10):1335-43.

Zhang C, Luo J, Yuan C, Ding D. Vitamin B12, B6, or Folate and Cognitive Function in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2020;77(2):781-794.

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