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

Eur J Nutr. 2019 Feb;58(1):345-356. doi: 10.1007/s00394-017-1598-5. Epub 2017 Dec 18.


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.

Keywords: Cognitive function; DNA methyltransferase; Folate; Mild cognitive impairment; Randomized controlled trial; β-Amyloid.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Amyloidogenic Proteins / blood
  • Amyloidogenic Proteins / drug effects
  • Biomarkers / blood
  • Cluster Analysis
  • Cognition / drug effects
  • Cognitive Dysfunction / blood*
  • Cognitive Dysfunction / drug therapy*
  • DNA Methylation / drug effects
  • Dietary Supplements*
  • Female
  • Folic Acid / pharmacology*
  • Follow-Up Studies
  • Humans
  • Male


  • Amyloidogenic Proteins
  • Biomarkers
  • Folic Acid