Current issues of ACP Journal Club are published in Annals of Internal Medicine


Daily folic acid supplementation for 3 years improved cognitive function in older persons


ACP J Club. 2007 May-Jun;146:71. doi:10.7326/ACPJC-2007-146-3-071

Clinical Impact Ratings

Mental Health: 5 stars

GIM/FP/GP: 5 stars

Genetics: 5 stars

Geriatrics: 6 stars

Neurology: 5 stars

Source Citation

Durga J, van Boxtel MP, Schouten EG,et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369:208-16. [PubMed ID: 17240287]



In older persons, does daily folic acid supplementation for 3 years improve cognitive function?


Design: Randomized placebo-controlled trial (Folic Acid and Carotid Intima-media Thickness [FACIT] trial).

Allocation: Concealed.*

Blinding: Blinded {clinicians, participants, data collectors, outcome assessors, data safety and monitoring committee, manuscript writers, and data analysts/statisticians}†.*

Follow-up period: 3 years.

Setting: Gelderland province, the Netherlands.

Participants: 818 men and postmenopausal women 50 to 70 years of age (mean age 60 y, 72% men) recruited from municipal and blood bank registries who reported ≥ 80% compliance during a 6-week placebo run-in period. 51 participants had 1 household member who was also enrolled and received the same treatment. Exclusion criteria included plasma total homocysteine level at screening < 13 µmol/L or > 26 µmol/L if possibly caused by serum vitamin B12 level < 200 pmol/L, renal or thyroid disease, or use of drugs that affect folate metabolism; intestinal disease; and use of vitamin B supplements or drugs that affect atherosclerotic progression.

Intervention: Folic acid, 800 µg/d (n = 405), or matching placebo (n = 413).

Outcomes: 3-year change in performance for 5 tests of cognitive function (memory, sensory-motor speed, complex speed, information-processing speed, and word fluency) and global cognitive function (mean of the 5 domains).

Patient follow-up: 98% (intention-to-treat analysis).

Main results

At 3 years, the folic acid group improved more than the placebo group for global cognitive function and memory and declined less for information-processing speed (Table). Groups did not differ for change in sensory-motor speed, complex speed, and word fluency (Table).


Daily folic acid supplementation for 3 years improved some aspects of cognitive function in older persons.

*See Glossary.

†Information provided by author.

Sources of funding: Netherlands Organisation for Health Research and Development.

For correspondence: Dr. J. Durga, Nestlé Research Centre, Lausanne, Switzerland. E-mail

Table. Daily folic acid vs placebo for cognitive function in older persons at 3 years‡

Outcomes Mean change from baseline§ Difference in change between groups (95% CI)
Folic acid Placebo
Global cognitive function 0.07 0.02 0.05 (0.004 to 0.10)
Memory 0.48 0.35 0.13 (0.03 to 0.23)
Sensory-motor speed −0.04 −0.11 0.06 (−0.001 to 0.13)
Complex speed −0.03 −0.06 0.04 (−0.05 to 0.12)
Information-processing speed −0.07 −0.16 0.09 (0.02 to 0.16)
Word fluency −0.002 0.07 −0.07 (−0.19 to 0.05)

‡CI defined in Glossary.
§Mean Z scores.


Despite suggestive epidemiologic associations, trials of supplementation with folate, vitamin B12, or both to reduce homocysteine levels have shown little effect on cognitive performance in older persons (1, 2). In the FACIT trial by Durga and colleagues, participants 50 to 70 years of age with elevated homocysteine levels were randomized to treatment with folate or placebo for a longer time than in previous studies. Those in the folate group showed better results for speed of information processing and memory. Several factors, including the small effect size and strict inclusion criteria, limit the clinical relevance and generalizability of results.

That some participants were functionally deficient in folate was shown by the decline in homocysteine levels following folate supplementation. Post hoc subgroup analyses showed that the effects of folate were greater in participants who had vitamin B12 levels < 250 pmol/L. These levels are often associated with occult vitamin B12 deficiency, and consequently, high homocysteine levels. Without measuring the level of methylmalonic acid, it is unclear whether this subgroup was also functionally deficient in vitamin B12.

The results of the FACIT trial may not apply to persons in the United States and Canada, where food is fortified with folic acid. 27% of all participants screened for this trial had homocysteine levels ≥ 13 µmol/L. For U.S. women of similar age, 13.2 µmol/L is the 95th percentile of homocysteine levels, whereas 10.74 µmol/L is the 75th percentile and 14.99 µmol/L is the 95th percentile for men (3). The results of the FACIT trial require replication with further elucidation of the populations who might benefit from folic acid supplementation.

Michael Bogaisky MD, MPH
Rosanne M. Leipzig, MD, PhD
Mount Sinai School of Medicine
New York, New York, USA


1. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003;(4):CD004514. [PubMed ID: 14584018]

2. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354:2764-72. [PubMed ID: 16807413]

3. Ganji V, Kafai MR. Population reference values for plasma total homocysteine concentrations in US adults after the fortification of cereals with folic acid. Am J Clin Nutr. 2006;84:989-94. [PubMed ID: 17093148]