Skip to main content
SpringerLink
Log in

Effect of Vitamin B Supplementation on Cognitive Function in the Elderly: A Systematic Review and Meta-Analysis

  • Systematic Review
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Background

Vitamin B deficiency and elevated total plasma homocysteine have been associated with cognitive impairment and dementia in later life, although it is unknown if treatment with these vitamins improves cognitive outcomes.

Objectives

The objectives of this study were to examine the efficacy of treatment with vitamin B12, vitamin B6, or folic acid in slowing cognitive decline amongst older adults with and without cognitive impairment.

Methods

We summarized findings from previous systematic reviews of clinical trials and performed a new systematic review and meta-analysis of 31 English-language, randomized placebo-controlled trials of B-vitamin supplementation of individuals with and without existing cognitive impairment.

Results

Previous reviews have generally reported no effect of B vitamins on cognitive function in older adults with or without cognitive impairment at study entry, although these vitamins effectively lowered total plasma homocysteine levels in participants. Ten randomized placebo-controlled trials of 1925 participants with pre-existing cognitive impairment and 21 trials of 15,104 participants without cognitive impairment have been completed to date but these generally confirmed findings from previous reviews with the exception of two trials that showed a modest but clinically uncertain benefit for vitamins in people with elevated plasma homocysteine. B-vitamin supplementation did not show an improvement in Mini-Mental State Examination scores for individuals with (mean difference 0.16, 95% confidence interval − 0.18 to 0.51) and without (mean difference 0.04, 95% confidence interval − 0.10 to 0.18) cognitive impairment compared to placebo.

Conclusions

Raised total plasma homocysteine is associated with an increased risk of cognitive impairment and dementia, although available evidence from randomized controlled trials shows no obvious cognitive benefit of lowering homocysteine using B vitamins. Existing trials vary greatly in the type of supplementation, population sampled, study quality, and duration of treatment, thereby making it difficult to draw firm conclusions from existing data. Findings should therefore be viewed in the context of the limitations of the available data and the lack of evidence of effect should not necessarily be interpreted as evidence of no effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wu YT, Beiser AS, Breteler MMB, et al. The changing prevalence and incidence of dementia over time: current evidence. Nat Rev Neurol. 2017;13(6):327–39.

    Article  PubMed  Google Scholar 

  2. Burns A, Iliffe S. Alzheimer’s disease. BMJ. 2009;338:b158.

    Article  PubMed  Google Scholar 

  3. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care. Lancet. 2017;390(10113):2673–4.

    Article  PubMed  Google Scholar 

  4. Droller H, Dossett JA. Vitamin B12 levels in senile dementia and confusional states. Geriatrics. 1959;14(6):367–73.

    CAS  PubMed  Google Scholar 

  5. Woltman HW. Brain changes associated with pernicious anemia. Arch Intern Med. 1918;XXI(6):791–843.

    Article  Google Scholar 

  6. Goebels N, Soyka M. Dementia associated with vitamin B(12) deficiency: presentation of two cases and review of the literature. J Neuropsychiatry Clin Neurosci. 2000;12(3):389–94.

    Article  CAS  PubMed  Google Scholar 

  7. Ford AH, Flicker L, Hankey GJ, et al. Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: the health in men study. Mol Psychiatry. 2012;17(5):559–66.

    Article  CAS  PubMed  Google Scholar 

  8. Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull. 2008;29(2 Suppl.):S143–72.

    Article  PubMed  Google Scholar 

  9. Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer’s disease: a systematic review. Arch Gerontol Geriatr. 2009;48(3):425–30.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  11. Ford AH, Almeida OP. Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. J Alzheimers Dis. 2012;29(1):133–49.

    Article  CAS  PubMed  Google Scholar 

  12. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98.

    Article  CAS  PubMed  Google Scholar 

  13. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003;4:CD004514.

    Google Scholar 

  15. Malouf R, Areosa Sastre A. Vitamin B12 for cognition. Cochrane Database Syst Rev. 2003;3:CD004326.

  16. Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev. 2003;4:CD004393.

  17. 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;(4):CD004514.

  18. Wald DS, Kasturiratne A, Simmonds M. Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. Am J Med. 2010;123(6):522.e2–527.e2.

    Article  CAS  Google Scholar 

  19. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369(9557):208–16.

    Article  CAS  PubMed  Google Scholar 

  20. Clarke R, Bennett D, Parish S, et al. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr. 2014;100(2):657–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li MM, Yu JT, Wang HF, et al. Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. Curr Alzheimer Res. 2014;11(9):844–52.

    CAS  PubMed  Google Scholar 

  22. Zhang DM, Ye JX, Mu JS, Cui XP. Efficacy of vtamin B supplementation on cognition in elderly patients with cognitive-related diseases. J Geriatr Psychiatry Neurol. 2017;30(1):50–9.

    Article  PubMed  Google Scholar 

  23. Enderami A, Zarghami M, Darvishi-Khezri H. The effects and potential mechanisms of folic acid on cognitive function: a comprehensive review. Neurol Sci. 2018. https://doi.org/10.1007/s10072-018-3473-4 (Epub ahead of print).

  24. Hankey GJ, Ford AH, Yi Q, et al. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke. 2013;44(8):2232–9.

    Article  CAS  PubMed  Google Scholar 

  25. Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Clarke R, Harrison G, Richards S. Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia. J Intern Med. 2003;254(1):67–75.

    Article  CAS  PubMed  Google Scholar 

  27. Connelly PJ, Prentice NP, Cousland G, Bonham J. A randomised double-blind placebo-controlled trial of folic acid supplementation of cholinesterase inhibitors in Alzheimer’s disease. Int J Geriatr Psychiatry. 2008;23(2):155–60.

    Article  PubMed  Google Scholar 

  28. Kwok T, Lee J, Law CB, et al. A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clin Nutr. 2011;30(3):297–302.

    Article  CAS  PubMed  Google Scholar 

  29. Sommer BR, Hoff AL, Costa M. Folic acid supplementation in dementia: a preliminary report. J Geriatr Psychiatry Neurol. 2003;16(3):156–9.

    Article  PubMed  Google Scholar 

  30. Fioravanti M, Ferrario E, Massaia M, et al. Low folate levels in the cognitive decline of elderly patients and the efficacy of folate as a treatment for improving memory deficits. Arch Gerontol Geriatr. 1998;26(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  31. de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2012;27(6):592–600.

    Article  PubMed  Google Scholar 

  32. Ting SKS, Earnest A, Li H, et al. B vitamins and cognition in subjects with small vessel disease: a substudy of VITATOPS, a randomized, placebo-controlled trial. J Neurol Sci. 2017;379:124–6.

    Article  CAS  PubMed  Google Scholar 

  33. van Uffelen JG, Chinapaw MJ, van Mechelen W, Hopman-Rock M. Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. Br J Sports Med. 2008;42(5):344–51.

    Article  PubMed  Google Scholar 

  34. Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 2002;132(6):1345–56.

    Article  CAS  PubMed  Google Scholar 

  35. Cheng D, Kong H, Pang W, et al. B vitamin supplementation improves cognitive function in the middle aged and elderly with hyperhomocysteinemia. Nutr Neurosci. 2016;19(10):461–6.

    Article  CAS  PubMed  Google Scholar 

  36. Deijen JB, van der Beek EJ, Orlebeke JF, van den Berg H. Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacology. 1992;109(4):489–96.

    Article  CAS  PubMed  Google Scholar 

  37. Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84(2):361–70.

    Article  CAS  PubMed  Google Scholar 

  38. Ford AH, Flicker L, Alfonso H, et al. Vitamins B(12), B(6), and folic acid for cognition in older men. Neurology. 2010;75(17):1540–7.

    Article  CAS  PubMed  Google Scholar 

  39. Hvas AM, Juul S, Lauritzen L, Nexo E, Ellegaard J. No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord. 2004;81(3):269–73.

    Article  CAS  PubMed  Google Scholar 

  40. Kang JH, Cook N, Manson J, et al. A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr. 2008;88(6):1602–10.

    Article  CAS  PubMed  Google Scholar 

  41. Lewerin C, Matousek M, Steen G, et al. Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr. 2005;81(5):1155–62.

    Article  CAS  PubMed  Google Scholar 

  42. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354(26):2764–72.

    Article  CAS  PubMed  Google Scholar 

  43. Pathansali R, Mangoni AA, Creagh-Brown B, et al. Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects. Arch Gerontol Geriatr. 2006;43(1):127–37.

    Article  CAS  PubMed  Google Scholar 

  44. Walker JG, Batterham PJ, Mackinnon AJ, et al. Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms: the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr. 2012;95(1):194–203.

    Article  CAS  PubMed  Google Scholar 

  45. Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, et al. Cognitive function after supplementation with B vitamins and long-chain omega-3 fatty acids: ancillary findings from the SU.FOL.OM3 randomized trial. Am J Clin Nutr. 2011;94(1):278–86.

  46. Brady CB, Gaziano JM, Cxypoliski RA, et al. Homocysteine lowering and cognition in CKD: the Veterans Affairs homocysteine study. Am J Kidney Dis. 2009;54(3):440–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dangour AD, Allen E, Clarke R, et al. Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial. Am J Clin Nutr. 2015;102(3):639–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kwok T, Lee J, Ma RC, et al. A randomized placebo controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with borderline low serum vitamin B12. Clin Nutr. 2017;36(6):1509–15.

    Article  CAS  PubMed  Google Scholar 

  49. Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006;354(15):1567–77.

    Article  CAS  PubMed  Google Scholar 

  50. Seal EC, Metz J, Flicker L, Melny J. A randomized, double-blind, placebo-controlled study of oral vitamin B12 supplementation in older patients with subnormal or borderline serum vitamin B12 concentrations. J Am Geriatr Soc. 2002;50(1):146–51.

    Article  PubMed  Google Scholar 

  51. Stott DJ, MacIntosh G, Lowe GD, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr. 2005;82(6):1320–6.

    Article  CAS  PubMed  Google Scholar 

  52. Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group, Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, et al. 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;303(24):2486–94.

  53. Garcia A, Pulman K, Zanibbi K, et al. Cobalamin reduces homocysteine in older adults on folic acid-fortified diet: a pilot, double-blind, randomized, placebo-controlled trial. J Am Geriatr Soc. 2004;52(8):1410–2.

    Article  PubMed  Google Scholar 

  54. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Smith AD, Refsum H, Bottiglieri T, et al. Homocysteine and dementia: an international consensus statement. J Alzheimers Dis. 2018;62(2):561–70.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Group VTS. 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;9(9):855–65.

    Article  CAS  Google Scholar 

  58. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett. 2006;580(13):2994–3005.

    Article  CAS  PubMed  Google Scholar 

  59. Vafai SB, Stock JB. Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer’s disease. FEBS Lett. 2002;518(1–3):1–4.

    Article  CAS  PubMed  Google Scholar 

  60. Sai X, Kawamura Y, Kokame K, et al. Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J Biol Chem. 2002;277(15):12915–20.

    Article  CAS  PubMed  Google Scholar 

  61. Xu D, Neville R, Finkel T. Homocysteine accelerates endothelial cell senescence. FEBS Lett. 2000;470(1):20–4.

    Article  CAS  PubMed  Google Scholar 

  62. Orentreich N, Matias JR, DeFelice A, Zimmerman JA. Low methionine ingestion by rats extends life span. J Nutr. 1993;123(2):269–74.

    CAS  PubMed  Google Scholar 

  63. Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr. 2016;36:211–39.

    Article  CAS  PubMed  Google Scholar 

  64. Ho RC, Cheung MW, Fu E, et al. Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. Am J Geriatr Psychiatry. 2011;19(7):607–17.

    Article  PubMed  Google Scholar 

  65. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10(1):111–3.

    Article  CAS  PubMed  Google Scholar 

  66. Ford AH, Flicker L, Alfonso H, et al. Plasma homocysteine and MTHFRC677T polymorphism as risk factors for incident dementia. J Neurol Neurosurg Psychiatry. 2012;83(1):70–5.

    Article  PubMed  Google Scholar 

  67. Hu Q, Teng W, Li J, Hao F, Wang N. Homocysteine and Alzheimer’s disease: evidence for a causal link from Mendelian randomization. J Alzheimers Dis. 2016;52(2):747–56.

    Article  CAS  PubMed  Google Scholar 

  68. Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet. 2011;378(9791):584–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Western Australian Centre for Health and Ageing, Medical School (M577), University of Western Australia, 35 Stirling Highway, Perth, WA, 6009, Australia

    Andrew H. Ford & Osvaldo P. Almeida

Authors
  1. Andrew H. Ford
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Osvaldo P. Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew H. Ford.

Ethics declarations

Funding

No sources of funding were received for the preparation of this article.

Conflict of interest

Andrew H. Ford and Osvaldo P. Almeida have no conflicts that are directly relevant to the content of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ford, A.H., Almeida, O.P. Effect of Vitamin B Supplementation on Cognitive Function in the Elderly: A Systematic Review and Meta-Analysis. Drugs Aging 36, 419–434 (2019). https://doi.org/10.1007/s40266-019-00649-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-019-00649-w

Search

Navigation