Elsevier

The Lancet

Volume 369, Issue 9557, 20–26 January 2007, Pages 208-216
The Lancet

Articles
Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial

https://doi.org/10.1016/S0140-6736(07)60109-3Get rights and content

Summary

Background

Low folate and raised homocysteine concentrations in blood are associated with poor cognitive performance in the general population. As part of the FACIT trial to assess the effect of folic acid on markers of atherosclerosis in men and women aged 50–70 years with raised plasma total homocysteine and normal serum vitamin B12 at screening, we report here the findings for the secondary endpoint: the effect of folic acid supplementation on cognitive performance.

Methods

Our randomised, double blind, placebo controlled study took place between November, 1999, and December, 2004, in the Netherlands. We randomly assigned 818 participants 800 μg daily oral folic acid or placebo for 3 years. The effect on cognitive performance was measured as the difference between the two groups in the 3-year change in performance for memory, sensorimotor speed, complex speed, information processing speed, and word fluency. Analysis was by intention-to-treat. This trial is registered with clinicaltrials.gov with trial number NCT00110604.

Findings

Serum folate concentrations increased by 576% (95% CI 539 to 614) and plasma total homocysteine concentrations decreased by 26% (24 to 28) in participants taking folic acid compared with those taking placebo. The 3-year change in memory (difference in Z scores 0·132, 95% CI 0·032 to 0·233), information processing speed (0·087, 0·016 to 0·158) and sensorimotor speed (0·064, −0·001 to 0·129) were significantly better in the folic acid group than in the placebo group.

Interpretation

Folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.

Introduction

Cognitive function declines with ageing, especially cognitive domains related to memory and information processing speed.1 Changes in cognitive performance, especially memory function, have been linked to risk of dementia in old age.2, 3 Modifiable risk factors for age-related cognitive decline have been identified, but their causality has not yet been established.4 Poor folate status is one such suspected risk factor.5, 6

A longitudinal study,7 undertaken in the USA when folic acid fortification of foods was routine, showed greater cognitive decline in people with a high folic acid intake than in those with low intakes. A systematic review of supplementation with folic acid alone or in combination with other B vitamins showed that no beneficial effect on cognitive performance was conferred.8 Many of the trials have used small study populations, supplemented for a short duration, or used tests such as the Mini-Mental State Examination,9 which are unable to detect subtle changes in cognitive function (table 1).10, 11, 12, 13, 14, 15, 16, 17, 18, 19

We investigated whether 800 μg daily oral folic acid supplementation for 3 years improved cognitive performance compared with placebo in older adults. Cognitive performance was assessed with tests that probe cognitive domains that decline in the ageing process.

Section snippets

Participants

Participants were men and post-menopausal women aged 50–70 years, from the Gelderland region in the Netherlands who participated in the Folic Acid and Carotid Intima-media Thickness (FACIT) trial (unpublished), a study investigating the effect of folic acid supplementation on atherosclerotic progression. Additional outcomes of the trial were age-related decline in cognitive function and hearing. Here we present data for the effect of folic acid on the cognitive performance aspect of the study.

Results

Patients were randomised between November, 1999, and April, 2001, and the study was undertaken from September, 2000, to December, 2004. The figure shows the trial profile. Five participants allocated folic acid treatment reported adverse events: forgetfulness, sun allergies, weight gain, tinnitus, and dark urine. Adverse effects reported in the placebo group (n=7) were muscle aches, headaches, weight gain, queasiness, bitter taste in mouth, and skin irritations. The participant with headache

Discussion

In 818 older adults, daily oral folic acid supplementation for 3 years beneficially affected global cognitive function, and specifically memory, and information processing: functions that are sensitive to ageing.1 The decline in memory seen with ageing is generally preceded, and might be affected, by a decline in speed functions.32 Nonetheless, folic acid supplementation might beneficially affect both memory and speed simultaneously, since high concentrations of homocysteine have been

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