Skip to main content


Log in

Effects of folic acid supplementation on cognitive function and Aβ-related biomarkers in mild cognitive impairment: a randomized controlled trial

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript



Observational studies have frequently reported that low blood folate concentrations are associated with poor cognitive performance. Our previous studies have shown the potential beneficial effect on the metabolite levels of methionine cycle and peripheral blood inflammatory cytokines from 6- and 12-month folic acid supplementation on cognitive function in mild cognitive impairment (MCI). This study aims to continue exploring the effect of 24-month folic acid supplementation on cognitive function and pathological mechanism in MCI.


180 individuals with MCI were identified and randomly divided into intervention (folic acid 400 µg/day, n = 90) and convention (n = 90) groups. Cognitive function (WAIS-RC) and blood Aβ-related biomarkers were measured at baseline and at 6, 12, 18, and 24 months. Data were analyzed using generalized estimating equation. This trial has been registered with Trial Number: ChiCTR-TRC-13003227.


During the follow-up, scores of full scale IQ, verbal IQ, and subdomains of Information and Digit Span were significantly higher in the intervention group than those in the convention group (P < 0.05). In the intervention group, blood homocysteine, S-adenosylhomocysteine (SAH), Aβ-42, and the expression of APP-mRNA were decreased (P < 0.05), while S-adenosylmethionine (SAM), SAM/SAH ratio, and the expression of DNA methyltransferase mRNA were increased (P < 0.05).


Folic acid supplementation appears to improve cognitive function and reduce blood levels of Aβ-related biomarkers in MCI. Larger-scale double-blind placebo-controlled randomized trials of longer duration are needed.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others





Alzheimer’s disease


Amyloid precursor protein


Central nervous system


Confidence intervals


Generalized estimating equation






Mild cognitive impairment


Performance IQ








Verbal IQ


  1. Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B (2001) Current concepts in mild cognitive impairment. Arch Neurol 58:1985–1992

    Article  CAS  Google Scholar 

  2. Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST (2001) Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:1133–1142

    Article  CAS  PubMed  Google Scholar 

  3. Korczyn AD (2016) Parkinson’s and Alzheimer’s diseases: focus on mild cognitive impairment. Parkinsonism Relat Disord 22:S159–S161

    Article  PubMed  Google Scholar 

  4. Gillette-Guyonnet S, Secher M, Vellas B (2013) Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol 75:738–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Smith AD, Refsum H (2016) Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 36:211–239

    Article  CAS  PubMed  Google Scholar 

  6. Michelakos T, Kousoulis AA, Katsiardanis K, Dessypris N, Anastasiou A, Katsiardani KP, Petridou ET (2013) Serum folate and B12 levels in association with cognitive impairment among seniors: results from the VELESTINO study in Greece and meta-analysis. J Aging Health 25:589–616

    Article  Google Scholar 

  7. Clarke R, Bennett D, Parish S, Lewington S, Skeaff M, Eussen SJ, Lonn E (2014) 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 100:657–666

    Article  CAS  Google Scholar 

  8. Li MM, Yu JT, Wang HF, Jiang T, Wang J, Meng XF, Tan L (2014) Efficacy of vitamins B supplementation on mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. Curr Alzheimer Res 11:844–852

    Article  CAS  PubMed  Google Scholar 

  9. Fuso A, Seminara L, Cavallaro RA, D’Anselmi F, Scarpa S (2005) S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 28:195–204

  10. Gonda TA, Kim YI, Salas MC, Gamble MV, Shibata W, Muthupalani S, Sohn KJ, Abrams JA, Fox JG, Wang TC, Tycko B (2012) Folic acid increases global DNA methylation and reduces inflammation to prevent Helicobacter-associated gastric cancer in mice. Gastroenterology 142:824–833

    Article  CAS  Google Scholar 

  11. Sinclair KD, Allegrucci C, Singh R, Gardner DS, Sebastian S, Bispham J, Thurston A, Huntley JF, Rees WD, Maloney CA, Lea RG, Craigon J, McEvoy TG, Young LE (2007) DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci 104:19351–19356

    Article  Google Scholar 

  12. Ma F, Wu T, Zhao J, Han F, Marseglia A, Liu H, Huang G (2016) Effects of 6-month folic acid supplementation on cognitive function and blood biomarkers in mild cognitive impairment: a randomized controlled trial in China. J Gerontol Ser A Biol Sci Med Sci 71:1376–1383

    Article  CAS  Google Scholar 

  13. Ma F, Wu T, Zhao J, Song A, Liu H, Xu W, Huang G (2016) Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI. Sci Rep 6:37486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Salminena A, Haapasalo A, Kauppinen A, Kaarniranta K, Soininen H, Hiltunen M (2015) Impaired mitochondrial energy metabolism in Alzheimer’s disease: impact on pathogenesis via disturbed epigenetic regulation of chromatin landscape. Prog Neurobiol 131: 1–20

    Article  CAS  Google Scholar 

  15. Leszek J, Sochocka M, Gąsiorowski K (2012) Vascular factors and epigenetic modifications in the pathogenesis of Alzheimer’s disease. J Neurol Sci 323:25–32

    Article  CAS  PubMed  Google Scholar 

  16. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang h, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX, Hao L, Gunter E, Correa A (1999) Prevention of neural-tube defects with folic acid in China. N Engl J Med 341:1485–1490

    Article  CAS  PubMed  Google Scholar 

  17. David SW, Anuradhani K, Mark S (2010) Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. Am J Med 123:522–527

    Article  CAS  Google Scholar 

  18. Maike W, Mirja H, Anke F, Uwe T, Andreas H (2005) Cognitive performance in relation to vitamin status in healthy elderly German women—the effect of 6-month multivitamin supplementation. Prev Med 41:253–259

    Article  Google Scholar 

  19. Kohout FJ, Berkman LF, Evans DA, Cornoni-Huntley J (1993) Two shorter forms of the CES-D depression symptoms index. J Aging Health 52:179–193

    Article  Google Scholar 

  20. Rose GA, Blackburn H, Gillum RF, Prineas RJ (1982) Cardiovascular survey methods, vol 58. World Health Organization, Geneva, pp 162–165

    Google Scholar 

  21. Gu D, Reynolds K, Wu X, Chen J, Duan X, Muntner P, Huang G, Reynolds RF, Su S, Whelton PK, He J, InterASIA Collaborative Group (2014) The International Collaborative Study of Cardiovascular Disease in ASIA. Prevalence, awareness, treatment, and control of hypertension in China. Hypertension 40:920–927

    Article  CAS  Google Scholar 

  22. Gong Y (1983) Revision of Wechsler’s adult intelligence scale in China. Acta Psychol Sin 15(3):121–129

    Google Scholar 

  23. Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, Seeman TE (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 118:161–167

    Article  CAS  PubMed  Google Scholar 

  24. Nurk E, Refsum H, Tell GS, Engedal K, Vollset SE, Ueland PM, Nygaard HA, Smith AD (2005) Plasm total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 58:847–857

    Article  CAS  PubMed  Google Scholar 

  25. Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A III (2005) High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr 82:627–635

    Article  CAS  PubMed  Google Scholar 

  26. Smith AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 29:S143–S172

    Article  PubMed  Google Scholar 

  27. Bryan J, Calvaresi E, Hughes D (2002) 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 132:1345–1356

    Article  CAS  PubMed  Google Scholar 

  28. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, Verhoef P (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 369:208–216

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  30. Fioravanti M, Ferrario E, Massaia M, Cappa G, Rivolta G, Grossi E, Buckley AE (1998) 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 26:1–13

    Article  CAS  PubMed  Google Scholar 

  31. den Heijer T, Vermeer SE, Clarke R, Oudkerk M, Koudstaal PJ, Hofman A, Breteler MM (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126:170–175

    Article  Google Scholar 

  32. Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31

    Article  CAS  Google Scholar 

  33. Li W, Liu H, Yu M, Zhang X, Zhang M, Wilson JX, Huang G (2015) Folic acid administration inhibits amyloid β-peptide accumulation in APP/PS1 transgenic mice. J Nutr Biochem 26:883–891

    Article  CAS  PubMed  Google Scholar 

  34. Dronse J, Fliessbach K, Bischof GN, von Reutern B, Faber J, Hammes J (2017) In vivo patterns of tau pathology, amyloid-β burden, and neuronal dysfunction in clinical variants of Alzheimer’s disease. J Alzheimers Dis 55:465–471

    Article  CAS  Google Scholar 

  35. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM (2002) Brain to plasm amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer’s disease. Science 295:2264–2267

    Article  CAS  PubMed  Google Scholar 

  36. Mehta PD, Pirtilla T, Mehta SP, Sersen EA, Aisen PS, Wisniewski HM (2000) Plasm and cerebrospinal fluid levels of amyloid beta proteins 1–40 and 1–42 in Alzheimer disease. Arch Neurol 57: 100–105

    Article  CAS  PubMed  Google Scholar 

  37. Teunissen CE, de Vente J, Steinbusch HWM, De Bruijn C (2002) Biochemical markers related to Alzheimer’s dementia in serum and cerebrospinal fluid. Neurobiol Aging 23:485–508

    Article  CAS  PubMed  Google Scholar 

  38. Bush AI, Whyte S, Thomas LD, Williamson TG, Van Tiggelen CJ, Currie J, Small DH, Moir RD, Li QX, Rumble B (1992) An abnormality of plasm amyloid protein precursor in Alzheimer’s disease. Ann Neurol 32:57–65

    Article  CAS  PubMed  Google Scholar 

  39. Martins RN, Muir J, Brooks WS, Creasey H, Montgomery P, Sellers P, Broe GA (1993) Plasm amyloid precursor is decreased in Alzheimer’s disease. Neuroreport 4:757–759

    Article  CAS  PubMed  Google Scholar 

  40. Mayeux R, Honig LS, Tang MX, Manly J, Stern Y, Schupf N, Mehta PD (2003) Plasm Aβ40 and Aβ42 and Alzheimer’s disease: relation to age, mortality, and risk. Neurology 61:1185–1190

    Article  CAS  PubMed  Google Scholar 

  41. Seppälä TT, Herukka S-K, Hänninen T, Tervo S, Hallikainen M, Soininen H, Pirttilä T (2010) Plasm Aβ42 and Aβ40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study. J Neurol Neurosurg Psychiatry 81:1123–1127

    Article  PubMed  PubMed Central  Google Scholar 

  42. Reynolds EH (2002) Folic acid, ageing, depression, and dementia. Br Med J 324:1512

    Article  CAS  Google Scholar 

  43. Duncan TM, Reed MC, Nijhout HF (2013) A population model of folate-mediated one-carbon metabolism. Nutrients 5:2457–2474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Smith DEC, Smulders YM, Blom HJ, Popp J, Jessen F, Semmler A, Farkas M, Linnebank M (2012) Determinants of the essential one-carbon metabolism metabolites, homocysteine, S-adenosylmethionine, S-adenosylhomocysteine and folate, in cerebrospinal fluid. Clin Chem Lab Med 50:1641–1647

    Article  CAS  PubMed  Google Scholar 

  45. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science (Washington DC) 293:1068–1070

    Article  CAS  Google Scholar 

  46. Greger V, Passarge E, Hopping W, Messmer E, Horsthemke B (1989) Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet 83:155–158

    Article  CAS  PubMed  Google Scholar 

Download references


The authors thank all of the subjects for their participation. This study was also supported by grants from Tianjin Science and Technology Support Program (Grant Number 15ZCZDSY01040), the National Natural Science Foundation of China (Grant Number 81130053), and Tianjin 13th five plan and TMU talent project (No. 2016KJ0304).

Author information

Authors and Affiliations



The authors’ responsibilities were as follows: G. Huang and F. Ma—study design; Q. Li, J. Zhao, and A. Song—field survey; X. Zhou, W. Li, and H. Liu—data analysis; F. Ma and W. Xu: writing the paper.

Corresponding author

Correspondence to Guowei Huang.

Ethics declarations

Conflict of interest

No potential conflicts of interest relevant to this article were reported.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, F., Li, Q., Zhou, X. et al. Effects of folic acid supplementation on cognitive function and Aβ-related biomarkers in mild cognitive impairment: a randomized controlled trial. Eur J Nutr 58, 345–356 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: