Skip to main content

Advertisement

Log in

Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial

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

Abstract

Purpose

This study aimed to assess the effects of folic acid (FA) combined with a docosahexaenoic acid (DHA) intervention on the cognitive function and inflammatory cytokines in elderly subjects with mild cognitive impairment (MCI).

Methods

This randomized, double-blind, placebo-controlled trial recruited 240 individuals with MCI in Tianjin, China, and randomly allocated into 4 groups: FA + DHA (FA 800 μg/d + DHA 800 mg/d), FA (FA 800 μg/d), DHA (DHA 800 mg/d), and placebo. Cognitive function, serum folate and homocysteine (Hcy), plasma DHA and inflammatory cytokines levels were measured at baseline and 6 months.

Results

Daily oral FA, DHA and their combined use for 6 months significantly improved the full-scale intelligence quotient (FSIQ) and some subtests of Wechsler Adult Intelligence Scale compared to the placebo. The increases of FSIQ, arithmetic, picture completion scores in the FA group and picture completion, block design scores in the DHA group were significantly less than that in the FA combined DHA group (P < 0.05). Meanwhile, daily oral FA, DHA and their combined use for 6 months significantly decreased plasma inflammatory cytokines compared to the placebo. The changes of interleukin-1β levels in the FA group and interleukin-6 levels in the DHA group were significantly less than that in the FA + DHA group (P < 0.05).

Conclusions

Daily oral FA, DHA and their combined use for 6 months can significantly improve cognitive function and decrease plasma inflammatory cytokines in MCI individuals. The combination of FA and DHA was more beneficial than each individual nutrient on their own.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AD:

Alzheimer disease

ANOVA:

Analysis of variance

APA:

American Psychiatric Association

DHA:

Docosahexaenoic acid

DSM-5:

Diagnostic and Statistical Manual of Mental Disorders fifth edition

EM:

Expectation–maximization

FA:

Folic acid

FFQ:

Food frequency questionnaire

FSIQ:

Full-scale intelligence quotient

Hcy:

Homocysteine

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-10:

Interleukin-10

ITT:

Intention-to-treat

MCI:

Mild cognitive impairment

MCP-1:

Monocyte chemotactic protein-1

MMSE:

Mini-Mental State Examination

PUFA:

Polyunsaturated fatty acid

RCTs:

Randomized controlled trials

SD:

Standard deviations

TNF-α:

Tumor necrosis factor-α

WAIS-RC:

Wechsler Adult Intelligence Scale-Revised

References

  1. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, de Leon M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B (2006) Mild cognitive impairment. Lancet 367(9518):1262–1270. https://doi.org/10.1016/s0140-6736(06)68542-5

    Article  Google Scholar 

  2. Manly JJ, Tang MX, Schupf N, Stern Y, Vonsattel JP, Mayeux R (2008) Frequency and course of mild cognitive impairment in a multiethnic community. Ann Neurol 63(4):494–506. https://doi.org/10.1002/ana.21326

    Article  PubMed  PubMed Central  Google Scholar 

  3. Volkert D, Chourdakis M, Faxen-Irving G, Fruhwald T, Landi F, Suominen MH, Vandewoude M, Wirth R, Schneider SM (2015) ESPEN guidelines on nutrition in dementia. Clin Nutr 34(6):1052–1073. https://doi.org/10.1016/j.clnu.2015.09.004

    Article  PubMed  Google Scholar 

  4. Mann J, Trus well AS (2002) Essentials of human nutrition, 2nd edn. Oxford University Press, Oxford

    Google Scholar 

  5. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX, Correa A (1999) Prevention of neural-tube defects with folic acid in China. N Engl J Med 341(20):1485–1490. https://doi.org/10.1056/nejm199911113412001

    Article  CAS  PubMed  Google Scholar 

  6. McNulty B, McNulty H, Marshall B, Ward M, Molloy AM, Scott JM, Dornan J, Pentieva K (2013) Impact of continuing folic acid after the first trimester of pregnancy: findings of a randomized trial of Folic Acid Supplementation in the Second and Third Trimesters. Am J Clin Nutr 98(1):92–98. https://doi.org/10.3945/ajcn.112.057489

    Article  CAS  PubMed  Google Scholar 

  7. Yang B, Liu Y, Li Y, Fan S, Zhi X, Lu X, Wang D, Zheng Q, Wang Y, Wang Y, Sun G (2013) Geographical distribution of MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in China: findings from 15357 adults of Han nationality. PLoS ONE 8(3):e57917. https://doi.org/10.1371/journal.pone.0057917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Araujo JR, Martel F, Borges N, Araujo JM, Keating E (2015) Folates and aging: Role in mild cognitive impairment, dementia and depression. Ageing Res Rev 22:9–19. https://doi.org/10.1016/j.arr.2015.04.005

    Article  CAS  PubMed  Google Scholar 

  9. Su HM (2010) Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem 21(5):364–373. https://doi.org/10.1016/j.jnutbio.2009.11.003

    Article  CAS  PubMed  Google Scholar 

  10. Cardoso C, Afonso C, Bandarra NM (2016) Dietary DHA and health: cognitive function ageing. Nutr Res Rev 29(2):281–294. https://doi.org/10.1017/s0954422416000184

    Article  CAS  PubMed  Google Scholar 

  11. Ma F, Li Q, Zhou X, Zhao J, Song A, Li W, Liu H, Xu W, Huang G (2019) Effects of folic acid supplementation on cognitive function and Abeta-related biomarkers in mild cognitive impairment: a randomized controlled trial. Eur J Nutr 58(1):345–356. https://doi.org/10.1007/s00394-017-1598-5

    Article  CAS  PubMed  Google Scholar 

  12. Zhang YP, Lou Y, Hu J, Miao R, Ma F (2018) DHA supplementation improves cognitive function via enhancing Abeta-mediated autophagy in Chinese elderly with mild cognitive impairment: a randomised placebo-controlled trial. J Neurol Neurosurg Psychiatry 89(4):382–388. https://doi.org/10.1136/jnnp-2017-316176

    Article  PubMed  Google Scholar 

  13. Khot V, Kale A, Joshi A, Chavan-Gautam P, Joshi S (2014) Expression of genes encoding enzymes involved in the one carbon cycle in rat placenta is determined by maternal micronutrients (folic acid, vitamin B12) and omega-3 fatty acids. Biomed Res Int 2014:613078. https://doi.org/10.1155/2014/613078

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kulkarni A, Dangat K, Kale A, Sable P, Chavan-Gautam P, Joshi S (2011) Effects of altered maternal folic acid, vitamin B12 and docosahexaenoic acid on placental global DNA methylation patterns in Wistar rats. PLoS ONE 6(3):e17706. https://doi.org/10.1371/journal.pone.0017706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dawson SL, Bowe SJ, Crowe TC (2016) A combination of omega-3 fatty acids, folic acid and B-group vitamins is superior at lowering homocysteine than omega-3 alone: a meta-analysis. Nutr Res 36(6):499–508. https://doi.org/10.1016/j.nutres.2016.03.010

    Article  CAS  PubMed  Google Scholar 

  16. Calsolaro V, Edison P (2016) Neuroinflammation in Alzheimer's disease: current evidence and future directions. Alzheimers Dement 12(6):719–732. https://doi.org/10.1016/j.jalz.2016.02.010

    Article  PubMed  Google Scholar 

  17. Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, Mitic L, Miller ZA, Rabinovici GD, Miller BL, Kao AW, Kosik KS, Kramer JH (2016) MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer’s disease dementia phenotypes. Alzheimers Dement (Amst) 3:91–97. https://doi.org/10.1016/j.dadm.2016.05.004

    Article  Google Scholar 

  18. Serini S, Bizzarro A, Piccioni E, Fasano E, Rossi C, Lauria A, Cittadini AR, Masullo C, Calviello G (2012) EPA and DHA differentially affect in vitro inflammatory cytokine release by peripheral blood mononuclear cells from Alzheimer's patients. Curr Alzheimer Res 9(8):913–923

    Article  CAS  Google Scholar 

  19. 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. https://doi.org/10.1038/srep37486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Enderami A, Zarghami M, Darvishi-Khezri H (2018) The effects and potential mechanisms of folic acid on cognitive function: a comprehensive review. Neurol Sci 39(10):1667–1675. https://doi.org/10.1007/s10072-018-3473-4

    Article  PubMed  Google Scholar 

  21. Devassy JG, Leng S, Gabbs M, Monirujjaman M, Aukema HM (2016) Omega-3 polyunsaturated fatty acids and oxylipins in neuroinflammation and management of Alzheimer disease. Adv Nutr 7(5):905–916. https://doi.org/10.3945/an.116.012187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 A Biol Sci Med Sci 71(10):1376–1383. https://doi.org/10.1093/gerona/glv183

    Article  CAS  PubMed  Google Scholar 

  23. Bo Y, Zhang X, Wang Y, You J, Cui H, Zhu Y, Pang W, Liu W, Jiang Y, Lu Q (2017) The n-3 polyunsaturated fatty acids supplementation improved the cognitive function in the chinese elderly with mild cognitive impairment: a double-blind randomized controlled trial. Nutrients. https://doi.org/10.3390/nu9010054

    Article  PubMed  PubMed Central  Google Scholar 

  24. Petersen RC (2004) Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3):183–194. https://doi.org/10.1111/j.1365-2796.2004.01388.x

    Article  CAS  PubMed  Google Scholar 

  25. Gong Y (2002) Revision of wechsler’s adult intelligence scale in China. Acta Psychologica Sinica 3:18

    Google Scholar 

  26. Gong YX, Dai XY (1984) The usage of the Chinese version of the Wechsler Adult Intelligence Scale (WAIS-RC)-short form. J Hunan Med Univ 9:393–400

    Google Scholar 

  27. Zhang YP, Miao R, Li Q, Wu T, Ma F (2017) Effects of DHA supplementation on hippocampal volume and cognitive function in older adults with mild cognitive impairment: a 12-month randomized, double-blind. Placebo-Controlled Trial J Alzheimers Dis 55(2):497–507. https://doi.org/10.3233/jad-160439

    Article  CAS  PubMed  Google Scholar 

  28. Danthiir V, Hosking DE, Nettelbeck T, Vincent AD, Wilson C, O'Callaghan N, Calvaresi E, Clifton P, Wittert GA (2018) An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults. Am J Clin Nutr 107(5):754–762. https://doi.org/10.1093/ajcn/nqx077

    Article  PubMed  Google Scholar 

  29. Canhada S, Castro K, Perry IS, Luft VC (2018) Omega-3 fatty acids' supplementation in Alzheimer's disease: a systematic review. Nutr Neurosci 21(8):529–538. https://doi.org/10.1080/1028415x.2017.1321813

    Article  CAS  PubMed  Google Scholar 

  30. Dayon L, Guiraud SP, Corthesy J, Da Silva L, Migliavacca E, Tautvydaite D, Oikonomidi A, Moullet B, Henry H, Metairon S, Marquis J, Descombes P, Collino S, Martin FJ, Montoliu I, Kussmann M, Wojcik J, Bowman GL, Popp J (2017) One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: homocysteine and beyond. Alzheimers Res Ther 9(1):43. https://doi.org/10.1186/s13195-017-0270-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Oulhaj A, Jerneren F, Refsum H, Smith AD, de Jager CA (2016) Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in mild cognitive impairment. J Alzheimers Dis 50(2):547–557. https://doi.org/10.3233/jad-150777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jerneren F, Cederholm T, Refsum H, Smith AD, Turner C, Palmblad J, Eriksdotter M, Hjorth E, Faxen-Irving G, Wahlund LO, Schultzberg M, Basun H, Freund-Levi Y (2019) Homocysteine status modifies the treatment effect of omega-3 fatty acids on cognition in a randomized clinical trial in mild to moderate Alzheimer's disease: the OmegAD study. J Alzheimers Dis 69(1):189–197. https://doi.org/10.3233/jad-181148

    Article  CAS  PubMed  Google Scholar 

  33. van Wijk N, Watkins CJ, Hageman RJ, Sijben JC, Kamphuis PG, Wurtman RJ, Broersen LM (2012) Combined dietary folate, vitamin B-12, and vitamin B-6 intake influences plasma docosahexaenoic acid concentration in rats. Nutr Metab (Lond) 9(1):49. https://doi.org/10.1186/1743-7075-9-49

    Article  CAS  Google Scholar 

  34. Da Mesquita S, Ferreira AC, Sousa JC, Correia-Neves M, Sousa N, Marques F (2016) Insights on the pathophysiology of Alzheimer's disease: the crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci Biobehav Rev 68:547–562. https://doi.org/10.1016/j.neubiorev.2016.06.014

    Article  CAS  PubMed  Google Scholar 

  35. Gezen-Ak D, Dursun E, Hanagasi H, Bilgic B, Lohman E, Araz OS, Atasoy IL, Alaylioglu M, Onal B, Gurvit H, Yilmazer S (2013) BDNF, TNFalpha, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer's disease or mild cognitive impairment. J Alzheimers Dis 37(1):185–195. https://doi.org/10.3233/jad-130497

    Article  CAS  PubMed  Google Scholar 

  36. Dursun E, Gezen-Ak D, Hanagasi H, Bilgic B, Lohmann E, Ertan S, Atasoy IL, Alaylioglu M, Araz OS, Onal B, Gunduz A, Apaydin H, Kiziltan G, Ulutin T, Gurvit H, Yilmazer S (2015) The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer's disease, mild cognitive impairment or Parkinson's disease. J Neuroimmunol 283:50–57. https://doi.org/10.1016/j.jneuroim.2015.04.014

    Article  CAS  PubMed  Google Scholar 

  37. Zhou Q, Zhang Z, Wang P, Zhang B, Chen C, Zhang C, Su Y (2019) EPA+DHA, but not ALA, improved lipids and inflammation status in hypercholesterolemic adults: a randomized, double-blind, placebo-controlled trial. Mol Nutr Food Res 63(10):e1801157. https://doi.org/10.1002/mnfr.201801157

    Article  CAS  PubMed  Google Scholar 

  38. Rodriguez-Cruz M, Cruz-Guzman ODR, Almeida-Becerril T, Solis-Serna AD, Atilano-Miguel S, Sanchez-Gonzalez JR, Barbosa-Cortes L, Ruiz-Cruz ED, Huicochea JC, Cardenas-Conejo A, Escobar-Cedillo RE, Yam-Ontiveros CA, Ricardez-Marcial EF (2018) Potential therapeutic impact of omega-3 long chain-polyunsaturated fatty acids on inflammation markers in Duchenne muscular dystrophy: a double-blind, controlled randomized trial. Clin Nutr 37(6):1840–1851. https://doi.org/10.1016/j.clnu.2017.09.011

    Article  CAS  PubMed  Google Scholar 

  39. Stanhewicz AE, Kenney WL (2017) Role of folic acid in nitric oxide bioavailability and vascular endothelial function. Nutr Rev 75(1):61–70. https://doi.org/10.1093/nutrit/nuw053

    Article  PubMed  Google Scholar 

  40. Zgheel F, Perrier S, Remila L, Houngue U, Mazzucotelli JP, Morel O, Auger C, Schini-Kerth VB (2019) EPA:DHA 6:1 is a superior omega-3 PUFAs formulation attenuating platelets-induced contractile responses in porcine coronary and human internal mammary artery by targeting the serotonin pathway via an increased endothelial formation of nitric oxide. Eur J Pharmacol 853:41–48. https://doi.org/10.1016/j.ejphar.2019.03.022

    Article  CAS  PubMed  Google Scholar 

  41. Parlak H, Ozkan A, Dilmac S, Tanriover G, Ozsoy O, Agar A (2018) Neuronal nitric oxide synthase phosphorylation induced by docosahexaenoic acid protects dopaminergic neurons in an experimental model of Parkinson's disease. Folia Histochem Cytobiol 56(1):27–37. https://doi.org/10.5603/FHC.a2018.0005

    Article  CAS  PubMed  Google Scholar 

  42. Philippu A (2016) Nitric oxide: a universal modulator of brain function. Curr Med Chem 23(24):2643–2652

    Article  CAS  Google Scholar 

  43. Li L, Liu Z, Jiang YY, Shen WX, Peng YP, Qiu YH (2019) Acetylcholine suppresses microglial inflammatory response via alpha7nAChR to protect hippocampal neurons. J Integr Neurosci 18(1):51–56. https://doi.org/10.31083/j.jin.2019.01.114

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all of the subjects of their participation.

Funding

Supported by Nutritional science research foundation from BY-HEALTH (No. TY0151102) and National Natural Science Foundation of China (No. 81730091). The intervention used in the study was produced by BY-HEALTH.

Author information

Authors and Affiliations

Authors

Contributions

The author’s responsibilities were as follows: GH, HL, FM and YD designed the research (project conception, development of overall research plan, and study oversight); ML, YG, DB, JW and XW conducted the research (conduct of the experiment and data collection); ML, WL and YC analyzed the data or performed the statistical analysis; ML, WL, FM, HL and GH wrote the manuscript; and GH had primary responsibility for the final content. ML and WL contributed equally to the work. All authors have read and approved the final version.

Corresponding authors

Correspondence to Huan Liu or Guowei Huang.

Ethics declarations

Conflict of interest

None of the authors have conflicts of interest to declare.

Ethical approval

This study adheres to the principles of the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Tianjin Medical University, China.

Patient consent

Obtained.

Provenance and peer review

Not commissioned; externally peer reviewed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, M., Li, W., Gao, Y. et al. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial. Eur J Nutr 60, 1795–1808 (2021). https://doi.org/10.1007/s00394-020-02373-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-020-02373-3

Keywords

Navigation