January 19, 2007 — A randomized, placebo-controlled trial has shown daily folic acid significantly improves cognitive performance in older adults — specifically as it relates to memory and information processing.

The study, which included 818 subjects aged 50 to 70 years who were folate deficient, showed that those who took 800 µg daily of oral folic acid for 3 years had significantly better memory and information processing speed than subjects in the placebo group.

Furthermore, serum folate concentrations increased by 576% and plasma total homocysteine concentrations decreased by 26% in participants taking folic acid compared with those taking placebo.

"We have shown that 3-year folic acid supplementation improves performance on tests that measure information-processing speed and memory, domains that are known to decline with age, in older adults with raised total homocysteine concentrations," the authors write.

Led by Jane Durga, PhD, of the Wageningen University, the Netherlands, the study is published in the January 20 issue of The Lancet.

Secondary Outcome

Study subjects were men and women from the Netherlands who were participating in the Folic Acid and Carotid Intima-media Thickness (FACIT) trial, which investigated the effect of folic acid supplementation on atherosclerotic progression.

However, this article reports on one of the study's secondary outcomes — the effect of folic acid supplementation on cognitive performance.

The trial took place between November 1999 and December 2004 in the Netherlands. A total of 818 patients were randomly assigned to receive 800 µg of daily oral folic acid or placebo for 3 years.

Patients with high concentrations of plasma total homocysteine were selected for the study based on the likelihood they would benefit from the homocysteine-lowering effects of folic acid to reduce vascular disease risk. As a result, individuals with total plasma homocysteine levels of less than 13 µmol/L or greater than 26 µmol/L were excluded from the trial.

Baseline assessment of cognitive function included 5 separate tests, which measured 5 cognitive domains — memory, sensorimotor speed, complex speed, information processing speed, and word fluency. In addition, patients also underwent the Mini-Mental State Examination (MMSE) to screen for possible dementia.

Genotype and educational level were established at the beginning of the trial. Plasma total homocysteine serum folate, vitamin B ₁₂ concentrations, and information about medical status and drug use were recorded annually, and all other measurements were taken at the beginning and end of the study.

Slower Rate of Decline

The authors report participants in both groups were well matched with similar baseline scores.

At the end of the study, the effect of folic acid on cognitive performance was measured as the difference in cognitive performance between the folic acid and placebo groups.

Among individuals in the placebo group sensorimotor speed, information-processing speed, and complex speed declined significantly. In contrast, those in the folic acid group experienced a much slower rate of decline.

Furthermore, the 3-year change in cognitive function was significantly better in the folic acid group in terms of information-processing speed. However, folic acid had no effect on complex speed or word fluency.

"The effect of folic acid might be restricted to basic aspects of speed and information processing, rather than high order information processing. Word fluency was not affected by folic acid supplementation, perhaps not surprisingly because encyclopedic memory is a component of crystallized intelligence that stays relatively intact as one grows older," the authors write.

Folate Intake Too Low

In an accompanying editorial, Martha Clare Morris, ScD and Christine C Tangney, PhD, both of Rush University Medical Center in Chicago, Illinois, point out, many populations may have folate intakes, similar to those of individuals in the study, that may be suboptimal for physiological functioning.

In part, they note, this is due to a lack of knowledge regarding optimum levels of dietary folate.

To make more informed dietary recommendations, the medical community needs more randomized trials, like the FACIT study.

"In particular, future trials should specify inclusion and exclusion criteria that target individuals at various stages of nutrient balance. They should also include comprehensive monitoring of biochemical concentrations of folate and folate metabolites in addition to monitoring of system function, such as cognitive function," the editorialists write.

Lancet. 2007;369:208-216.

Clinical Context

Study Highlights

• Participants were adults aged 50 to 70 years from one region in the Netherlands recruited by blood bank and municipal registries.
• Excluded were adults with homocysteine levels less than 13 µmol/L or more than 26 µmol/L; those with renal, intestinal, or thyroid disease; or those who used vitamin B supplements or drugs that affected atherosclerosis.
• 80% compliance during a 6-week run-in period was required.
• Primary outcome was atherosclerotic progression.
• Secondary outcomes were cognitive decline and hearing.
• Patients were randomized to either placebo or 800 µg daily of folic acid for 3 years.
• Capsules and diaries were returned every 12 weeks.
• Cognitive function was assessed in 5 domains from the Mastricht Aging Study: memory, sensorimotor speed, complex speed, information processing speed, and word fluency.
• An MMSE for dementia (defined as score < 24) was performed at baseline.
• Serum folate, erythrocyte folate, vitamin B₁₂, plasma total homocysteine, creatinine, and lipid levels were measured.
• Of 819 patients randomized, 406 were assigned folic acid and 413 placebo, and the intent-to-treat population was 405 and 413, respectively.
• Mean age was 60 years, 40% had high level of education, mean body mass index was 26.5 kg/m², 20% were current smokers, 3% had diabetes, and mean systolic blood pressure was 133 and diastolic blood pressure was 77 mm Hg.
• 99% of capsules were reportedly consumed.
• In both groups, plasma homocysteine levels were slightly lower at baseline than at screening.
• After 3 years, folic acid concentrations increased by 576% and plasma total homocysteine levels by 26% in the folic acid vs the placebo group.
• Baseline scores for cognitive function were similar at baseline.
• During 3 years, sensorimotor speed, information speed, and complex speed declined significantly in the placebo group, and the rate of decline was lower in the folic acid group.
• The 3-year change in cognitive function was significantly better in the folic acid group.
• Decline in global cognitive function (defined as the average of the 5 domain scores) improved significantly in the folic acid vs the placebo group.
• Performance on the MMSE was not affected by folic acid supplementation.
• Memory, processing speed, and sensorimotor speed improved significantly (P < .05) in the folic acid group when participants lost to follow-up and those with baseline dementia were excluded from analysis.
• 3 years of treatment with folic acid conferred on individuals resulted in the performance of someone 4.7 years younger for memory, 1.7 years younger for sensorimotor speed, 2.1 years younger for information processing speed, and 1.5 years younger for global cognitive function.
• Those with baseline homocysteine levels higher than the population mean of 12.9 µmol/L showed greater improvement in information speed vs those with lower homocysteine levels at baseline.
• Outcomes in the other 4 domains were not affected by baseline homocysteine levels.

Pearls for Practice

• Three years supplementation with 800 µg of folic acid daily in adults aged 50 to 70 years is associated with increase in serum folic acid and decrease in plasma homocysteine levels.
• Three years supplementation with 800 µg of folic acid daily in adults aged 50 to 70 years is associated with significantly less decline in global cognitive function, memory, information processing and sensorimotor speed, but not MMSE score.

CME Test