Top

European Journal of Nutrition

Published in:

01-02-2019 | Original Contribution

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

Authors: Fei Ma, Qing Li, Xuan Zhou, Jiangang Zhao, Aili Song, Wen Li, Huan Liu, Weili Xu, Guowei Huang

Published in: European Journal of Nutrition | Issue 1/2019

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusion

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.

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 58:1985–1992CrossRef

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 56:1133–1142CrossRefPubMed

Korczyn AD (2016) Parkinson’s and Alzheimer’s diseases: focus on mild cognitive impairment. Parkinsonism Relat Disord 22:S159–S161CrossRefPubMed

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

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

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 25:589–616CrossRef

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 100:657–666CrossRef

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 11:844–852CrossRefPubMed

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 142:824–833CrossRef

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 104:19351–19356CrossRef

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 71:1376–1383CrossRef

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 6:37486CrossRefPubMedPubMedCentral

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: 1–20CrossRef

15.

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

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 341:1485–1490CrossRefPubMed

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 123:522–527CrossRef

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 41:253–259CrossRef

19.

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

20.

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

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 40:920–927CrossRef

22.

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

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 118:161–167CrossRefPubMed

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 58:847–857CrossRefPubMed

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 82:627–635CrossRefPubMed

26.

Smith AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 29:S143–S172CrossRefPubMed

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 132:1345–1356CrossRefPubMed

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 369:208–216CrossRefPubMed

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 27:592–600CrossRefPubMed

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 26:1–13CrossRefPubMed

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 126:170–175CrossRef

32.

Selkoe DJ (1999) Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399:A23–A31CrossRef

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 26:883–891CrossRefPubMed

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 55:465–471CrossRef

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 295:2264–2267CrossRefPubMed

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: 100–105CrossRefPubMed

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 23:485–508CrossRefPubMed

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 32:57–65CrossRefPubMed

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 4:757–759CrossRefPubMed

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 61:1185–1190CrossRefPubMed

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 81:1123–1127CrossRefPubMedPubMedCentral

42.

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

43.

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

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 50:1641–1647CrossRefPubMed

45.

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

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 83:155–158CrossRefPubMed

Title: Effects of folic acid supplementation on cognitive function and Aβ-related biomarkers in mild cognitive impairment: a randomized controlled trial
Authors: Fei Ma
Qing Li
Xuan Zhou
Jiangang Zhao
Aili Song
Wen Li
Huan Liu
Weili Xu
Guowei Huang
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nutrition / Issue 1/2019
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI: https://doi.org/10.1007/s00394-017-1598-5

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2019

FTO rs9939609 A allele influences anthropometric outcome in response to dietary intervention, but not in response to physical exercise program

Modelling of adequate and safe vitamin D intake in Danish women using different fortification and supplementation scenarios to inform fortification policies

Is vitamin D deficiency a public health concern for low middle income countries? A systematic literature review

The effects of bovine colostrum supplementation on in vivo immunity following prolonged exercise: a randomised controlled trial

The impact of probiotic supplementation during pregnancy on DNA methylation of obesity-related genes in mothers and their children

Network meta-analysis reaches nutrition research

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page