Skip to main content

Emerging roles for folate and related B-vitamins in brain health across the lifecycle

  • C. McGarel (a1), K. Pentieva (a1), J. J. Strain (a1) and H. McNulty (a1)

Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy and extending into later life. A growing body of evidence suggests that folate and the metabolically related B-vitamins are essential for brain health across all age groups, owing to their specific roles in C1 metabolism and particularly in the production of S-adenosylmethionine, a universal methyl donor essential for the production of neurotransmitters. Emerging, though not entirely consistent, evidence suggests that maternal folate status throughout pregnancy may influence neurodevelopment and behaviour of the offspring. Furthermore optimal B-vitamin status is associated with better cognitive health in ageing. Of note, a recent clinical trial provided evidence that supplementation with folic acid and related B-vitamins over a 2-year-period reduced global and regional brain atrophy, as measured by MRI scan in older adults. In terms of potential mechanisms, the effects of these B-vitamins on cognitive health may be independent or may be mediated by nutrient–nutrient and/or relevant gene–nutrient interactions. Furthermore, a new area of research suggests that the in utero environment influences health in later life. Folate, an important cofactor in C1 metabolism, is indirectly involved in DNA methylation, which in turn is considered to be one of the epigenetic mechanisms that may underlie fetal programming and brain development. The present review will explore the evidence that supports a role for folate and the related B-vitamins in brain health across the lifecycle, and potential mechanisms to explain such effects.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Emerging roles for folate and related B-vitamins in brain health across the lifecycle
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Emerging roles for folate and related B-vitamins in brain health across the lifecycle
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Emerging roles for folate and related B-vitamins in brain health across the lifecycle
      Available formats
Corresponding author
* Corresponding author: Dr Kristina Pentieva, email
Hide All
1. Georgieff MK (2007) Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 85, 614S620S.
2. Anjos T, Altmäe S, Emmett P et al. (2013) Nutrition and neurodevelopment in children: focus on NUTRIMENTHE project. Eur J Nutr 52, 18251842.
3. Dominguez-Salas P, Cox SE, Prentice AM et al. (2012) Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc 71, 154165.
4. van de Rest O, van Hooijdonk LWA, Doets E et al. (2012) B Vitamins and n-3 fatty acids for brain development and function: review of human studies. Ann Nutr Metab 60, 272292.
5. Schaevitz L, Berger-Sweeney J & Ricceri L (2014) One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders. Neurosci. Biobehav Rev (Epublication ahead of print version)
6. Ford AH, Flicker L, Hankey GJ et al. (2012) Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: the health in men study. Mol Psychiatry 17, 559566.
7. McNulty B, Pentieva K, Marshall B et al. (2011) Women's compliance with current folic acid recommendations and achievement of optimal status for preventing neural tube defects. Hum Reprod 26, 15301536.
8. McNulty H, McPartlin JM, Weir DG et al. (1993) Folate catabolism is increased during pregnancy in rats. J Nutr 123, 10891093.
9. Czeizel AE & Dudás I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327, 18321835.
10. MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131137.
11. Centers for Disease Control Prevention (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morb Mortal Wkly Rep 41, 18.
12. Department of Health (1992) Folic acid and the prevention of neural tube defects. Report from an expert advisory group No.1. London: Department of Health.
13. Reynolds E (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol 5, 949960.
14. Gross RL, Newberne PM & Reid JVO (1974) Adverse effects on infant development associated with maternal folic acid deficiency. Nutr Rep Intern 10, 241248.
15. Julvez J, Fortuny J, Mendez M et al. (2009) Maternal use of folic acid supplements during pregnancy and four-year-old neurodevelopment in a population-based birth cohort. Paediatr Perinat Epidemiol 23, 199206.
16. Veena SR, Krishnaveni GV, Srinivasan K et al. (2010) Higher maternal plasma folate but not Vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10-year-old children in South India. J Nutr 140, 10141022.
17. Roth C, Magnus P, Schjølberg S et al. (2011) Folic acid supplements in pregnancy and severe language delay in children. J Am Med Assoc 306, 15661573.
18. Chatzi L, Papadopoulou E, Koutra K et al. (2012) Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: the mother-child cohort ‘Rhea’ study in Crete, Greece. Public Health Nutr 15, 17281736.
19. Villamor E, Rifas-Shiman SL, Gillman MW et al. (2012) Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr Perinat Epidemiol 26, 328335.
20. Isaacs EB (2013) Neuroimaging, a new tool for investigating the effects of early diet on cognitive and brain development. Front Hum Neurosci 7, 445.
21. Thompson RA & Nelson CA (2001) Developmental science and the media. Early brain development. Am Psychol 56, 515.
22. Pentieva K, McGarel C, McNulty B et al. (2012) Effect of folic acid supplementation during pregnancy on growth and cognitive development of the offspring: a pilot follow-up investigation of children of FASSTT study participants. Proc Nutr Soc 71, E139.
23. Whitley JR, O'Dell BL & Hogan AG (1951) Effect of diet in maze learning in second generation rats; folic acid deficiency. J Nutr 45, 153160.
24. Craciunescu CN, Brown EC, Mar MH et al. (2004) Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr 134, 162166.
25. Blaise SA, Nédélec E, Schroeder H et al. (2007) Gestational Vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats. Am J Pathol 170, 667679.
26. Wilcken B, Bamforth F, Li Z et al. (2003) Geographical and ethnic variation of the 677C>T allele of 5, 10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide. J Med Genet 40, 619625.
27. Pilsner JR, Hu H, Wright RO et al. (2010) Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City. Am J Clin Nutr 92, 226234.
28. del Río Garcia C, Torres- Sanchez L, Chen J et al. (2009) Maternal MTHFR 677C>T genotype and dietary intake of folate and vitamin B(12): their impact on child neurodevelopment. Nutr Neurosci 12, 1320.
29. Dobó M & Czeizel AE (1998) Long-term somatic and mental development of children after periconceptional multivitamin supplementation. Eur J Pediatr 157, 719723.
30. Tamura T, Goldenberg RL, Chapman VR et al. (2005) Folate status of mothers during pregnancy and mental and psychomotor development of their children at five years of age. Pediatrics 116, 703708.
31. Roza SJ, van Batenburg-Eddes T, Steegers EAP et al. (2010) Maternal folic acid supplement use in early pregnancy and child behavioural problems: the Generation R Study. Br J Nutr 103, 445452.
32. Schlotz W, Jones A, Phillips DIW et al. (2010) Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring. J Child Psychol Psychiatry 51, 594602.
33. Steenweg-de Graaff J, Roza SJ, Steegers EAP et al. (2012) Maternal folate status in early pregnancy and child emotional and behavioral problems: the Generation R Study. Am J Clin Nutr 95, 14131421.
34. Strand TA, Taneja S, Ueland PM et al. (2013) Cobalamin and folate status predicts mental development scores in North Indian children 12–18 mo of age. Am J Clin Nutr 97, 310317.
35. Nilsson TK, Yngve A, Bottiger AK et al. (2011) High folate intake is related to better academic achievement in Swedish adolescents. Pediatrics 128, E358E365.
36. Nguyen CT, Gracely EJ & Lee BK (2013) Serum folate but not Vitamin B-12 concentrations are positively associated with cognitive test scores in children aged 6–16 years. J Nutr 143, 500504.
37. Graham JE, Rockwood K, Beattie BL et al. (1997) Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet 349, 17931796.
38. McNulty H & Scott JM (2008) Intake and status of folate and related B-vitamins: considerations and challenges in achieving optimal status. Br J Nutr 99, S48S54.
39. Alzheimer's Society UK (2013) Statistics; available at
40. Kivipelto M, Ngandu T, Laatikainen et al. (2006) Risk score for the predicition of dementia risk in 20 years among middle-aged people: a longitudinal, population-based study. Lancet Neurol 5, 735741.
41. Smith AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 29, 2 Suppl, S143S172.
42. Ravaglia G, Forti P, Maioli F et al. (2003) Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr 77, 668673.
43. Ford AH, Flicker L, Singh U et al. (2013) Homocysteine, depression and cognitive function in older adults. J Affect Disord 151, 646651.
44. Allam M, Fahmy E, Elatti SA et al. (2013) Associations between total plasma homocysteine level and cognitive functions in elderly Egyptian subjects. J Neurol Sci 322, 8691.
45. Seshadri S, Beiser A, Selhub J et al. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346, 476483.
46. Miller JW, Green R, Ramos MI et al. (2003) Homocysteine and cognitive function in the Sacramento Area Latino Study on Ageing. Am J Clin Nutr 78, 441447.
47. Ramos MI, Allen LH, Mungas DM et al. (2005) Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 82, 13461352.
48. Campbell AK, Jagust WJ, Mungas DM et al. (2005) Low erythrocyte folate, but not plasma B-12 or homocysteine, is associated with dementia in elderly Latinos. J Nutr Health Aging 9, 3943.
49. de Lau LML, Refsum H, Smith AD et al. (2007) Plasma folate concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr 86, 728734.
50. Duthie SJ, Whalley LJ, Collins AR et al. (2002) Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 75, 908913.
51. Kado DM, Karlamangla AS, Huang MH et al. (2005) Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of successful aging. Am J Med 118, 161167.
52. Nurk E, Refsum H, Tell Gs et al. (2005) Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 58, 847857.
53. Haan MN, Miller JW, Aiello AE et al. (2007) Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr 85, 511517.
54. Hooshmand B, Solomon A, Kåreholt I et al. (2012) Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 271, 204212.
55. Riggs KM, Spiro A III, Tucker K et al. (1996) Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 63, 306314.
56. Moorthy D, Peter I, Scott TM et al. (2012) Status of Vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. J Nutr 142, 15541560.
57. Morris MS, Jacques PF, Rosenberg IH et al. (2007) Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85, 193200.
58. Moore EM, Ames D, Mander AG et al. (2014) Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. J Alzheimers Dis 39, 661668.
59. Doets EL, Ueland PM, Tell GS et al. (2014) Interactions between plasma concentrations of folate and markers of vitamin B12 status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study. Br J Nutr 111, 10851095.
60. McMahon JA, Green TJ, Skeaff CM et al. (2006) A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354, 27642772.
61. Durga J, van Boxtel MPJ, Schouten EG et al. (2007) Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 369, 208216.
62. Aisen PS, Schneider LS, Sano M et al. (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. J Am Med Assoc 300, 17741783.
63. de Jager CA, Oulhaj A, Jacoby R et al. (2012) Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 27, 592600.
64. Walker JG, Batterham PJ, Mackinnon AJ et al. (2012) 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 95, 194203.
65. Smith AD, Smith SM, de Jager CA et al. (2010) Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE 5, e12244.
66. Douaud G, Refsum H, de Jager CA et al. (2013) Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci USA 110, 95239528.
67. Lewerin C, Matousek M, Steen G et al. (2005) 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 81, 11551162.
68. Pathansali R, Mangoni AA, Creagh-Brown B et al. (2006) Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects. Arch Gerontol Geriatr 43, 127137.
69. Eussen SJ, de Groot LC, Joosten LW et al. (2006) Effect of oral vitamin B12 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 84, 361370.
70. Kwok T, Lee J, Law CB et al. (2011) A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clin Nutr 30, 297302.
71. de Jager CA (2014) Critical levels of brain atrophy associated with homocysteine and cognitive decline. Neurobiol Aging 35, Suppl. 2, S35S39.
72. Russo VEA, Martienssen RA & Riggs AD (1996) Epigenetic Mechanisms of Gene Regulation. Cold Springs Harbor, New York: Cold Springs Harbor Laboratory Press.
73. Waterland RA & Jirtle RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23, 52935300.
74. Cropley JE, Suter CM, Beckman KB et al. (2006) Germ-line epigenetic modifications of the murine Avy allele by nutritional supplementation. Proc Natl Acad Sci USA 103, 1730817312.
75. Cho CE, Sánchez-Hernández D, Reza-López SA et al. (2013) High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 8, 710719.
76. Roseboom TJ, Painter RC, van Abeelen AFM et al. (2011) Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas 70, 141145.
77. Heijmans BT, Tobi EW, Stein AD et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105, 1704617049.
78. Steegers-Theunissen RP, Obermann-Borst SA, Kremer D et al. (2009) Periconceptional maternal folic acid use of 400 μg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS ONE 4, 15.
79. Haggarty P, Hoad G, Campbell DM et al. (2013) Folate in pregnancy and imprinted gene and repeat element methylation in the offspring. Am J Clin Nutr 97, 9499.
80. Ivanoca E & Kelsey G (2011) Imprinted genes and hypothalamic function. J Mol Endocrinol 47, R67R74.
81. Keverne B (2009) Monoallelic gene expression and mammalian evolution. BioEssays 31, 13181326.
82. den Heijer T, Vermeer SE, Clarke R et al. (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126, 170175.
83. Clarke R, Smith AD, Jobst KA et al. (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55, 14491455.
84. di Salvo ML, Contestabile R & Safo MK (2011) Vitamin B6 salvage enzymes: mechanism, structure and regulation. Biochim Biophys Acta 1814, 15971608.
85. Clarke M, Ward M, Strain JJ et al. (2014) B-vitamins and bone health and disease: the current evidence. Proc Nutr Soc 73, 330339.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Proceedings of the Nutrition Society
  • ISSN: 0029-6651
  • EISSN: 1475-2719
  • URL: /core/journals/proceedings-of-the-nutrition-society
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 66
Total number of PDF views: 476 *
Loading metrics...

Abstract views

Total abstract views: 710 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 19th November 2017. This data will be updated every 24 hours.