Effects of Folic Acid Combined with DHA Supplementation on Cognitive Function and Amyloid-β-Related Biomarkers in Older Adults with Mild Cognitive Impairment by a Randomized, Double Blind, Placebo-Controlled Trial

J Alzheimers Dis. 2021;81(1):155-167. doi: 10.3233/JAD-200997.


Background: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed.

Objective: To explore the effects of 6-month folic acid + DHA on cognitive function in patients with MCI.

Methods: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients aged > 60 years into four regimen groups randomly: folic acid (0.8 mg/day) + DHA (800 mg/day), folic acid (0.8 mg/day), DHA (800 mg/day), and placebo, for 6 months. Cognitive function and blood amyloid-β peptide (Aβ) biomarker levels were measured at baseline and 6 months. Cognitive function was also measured at 12 months.

Results: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acid + DHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acid + DHA increased blood folate (folic acid + DHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (-6.51, -10.57 to -2.45) compared to placebo. DHA lower the Aβ40 levels (-40.57, -79.79 to -1.35) compared to placebo (p < 0.05), and folic acid + DHA reduced the Aβ42 (-95.59, -150.76 to -40.43) and Aβ40 levels (-45.75, -84.67 to -6.84) more than DHA (p < 0.05).

Conclusion: Folic acid and DHA improve cognitive function and reduce blood Aβ production in MCI patients. Combination therapy may be more beneficial in reducing blood Aβ-related biomarkers.

Keywords: Amyloid-β peptide-related biomarkers; docosahexaenoic acid; folic acid; mild cognitive impairment; randomized double-blind placebo-controlled trial.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyloid beta-Peptides / blood
  • Amyloid beta-Protein Precursor / blood
  • Biomarkers / blood
  • Cognition / drug effects*
  • Cognitive Dysfunction / blood
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / psychology
  • Docosahexaenoic Acids / pharmacology*
  • Docosahexaenoic Acids / therapeutic use
  • Double-Blind Method
  • Female
  • Folic Acid / pharmacology*
  • Folic Acid / therapeutic use
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Peptide Fragments / blood


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Biomarkers
  • Peptide Fragments
  • Docosahexaenoic Acids
  • Folic Acid