Cognitive Function Boosted by Folic Acid Supplements

WAGENINGEN, The Netherlands, Jan. 19 -- Folic acid supplementation appears to improve cognitive function, particularly memory, among older adults with poor folate status, Dutch researchers said.

Three years of daily 800 ?g folic acid orally bestowed on patients the equivalent of a 4.7- to 6.9 years of younger memory, reported Jane Durga, Ph.D., of Wageningen University here, and colleagues, in the Jan. 20 issue of The Lancet.

These results follow on the heels of an observational study in New York that found a weak link between higher folate levels and a lowered risk of Alzheimer's disease in older Americans.

However, Dr. Durga and colleagues said it is unclear whether the cognitive benefits they found would yield a similar end result.

"Whereas some have argued that cognitive decline is the beginning of a continuum leading to dementia," they wrote, "others have argued that the cause of age-related cognitive decline differs from that of dementia and that age-related cognitive decline is not an early state of mild cognitive impairment or dementia."

They added, "Although folic acid improved performance on tests of memory, including delayed recall, additional research is needed to determine whether folic acid supplementation can reduce the risk of mild cognitive impairment or Alzheimer's disease."

Their study encompassed a secondary endpoint analysis of the Folic Acid and Carotid Intimamedia Thickness (FACIT) trial, which is looking at folic acid's effect on atherosclerosis in men and women ages 50 to 70.

The study evaluated persons with elevated plasma total homocysteine (13 ?mol/L or more) who could be expected to benefit from homocysteine-lowering folic acid. All 818 participants also had normal serum vitamin B12 at baseline.

Selecting individuals with high homocysteine (in the absence of other potentially accountable factors) focused the study on those with inadequate folate status, according to an accompanying editorial by Martha Clare Morris, Sc.D., and Christine C. Tangney, Ph.D., both of the Rush Institute for Healthy Aging in Chicago.

Participants were randomly assigned to three years of double-blind treatment with placebo or 800 ?g/day folic acid, which the authors said "is regarded as a low dose for a clinical trial." Treatment was effective with serum folate concentrations increasing by 576% and plasma homocysteine falling by 26% for the folic acid group compared with placebo.

At baseline, both groups had similar scores on a battery of cognitive tests for memory, sensorimotor speed, complex speed, information processing speed, and word fluency.

Three years later, the results were significantly different comparing the folic acid versus placebo groups. The findings were (mean Z score difference):

• A significantly better mean change in global cognitive function (0.050, 95% CI 0.004 to 0.096, P=0.033).
• A significant comparative improvement in memory (0.132, 95% confidence interval 0.032 to 0.233, P=0.010).
• A significant difference in information processing speed (0.087, 95% CI 0.016 to 0.158, P= 0.016),
• A significantly better sensorimotor speed for the folic acid than the placebo group (0.064, 95% CI -0.001 to 0.129, P=0055).
• Similar information processing speeds between groups (0.037, 95% CI -0.049 to 0.122, P=0.40).
• No significant difference in word fluency between groups (-0.070, 95% CI -0.188 to 0.048, P=0.245).

On the basis of these findings, the researchers said, folic acid appeared to affect age-related aspects of cognitive function.

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

Folic acid conferred the mental performance of a younger person for the older adults, even after adjusting for sex and education. These findings were:

• 4.7 years younger for memory overall (95% CI 1.1 to 8.3).
• 6.9 years younger for delayed-recall memory (95% CI 2.1 to 11.8).
• 1.7 years younger for sensorimotor speed (95% CI -0.04 to 3.4).
• 2.1 years younger for information processing speed (95% CI 0.4-3.7).
• 1.5 years younger for global cognitive function (95% CI 0.1 to 2.8).

Performance on the Mini-Mental State Examination used to screen for possible dementia (less than 24 points) were not affected by folic acid treatment (P=0.63). Mean scores were similar between groups at 29 points after three years for both.

The results were not modified by initial folate status, MTHFR C677T genotype, dyslipidemia, or self-reported vascular disease. Compliance was high, there was no difference between groups in the proportion of patients who discontinued treatment or were lost to follow-up (P=0.25), and only five patients in the folic acid group reported adverse events (forgetfulness, sun allergies, weight gain, tinnitus, and dark urine).

The researchers said the magnitude of effect seen in the trial would likely not be as great in populations, such as that in the United States, where homocysteine concentrations are lower overall.

"Dietary intakes of folate in the trial participants were far lower than the U.S. recommended dietary allowance (RDA) of 400 ?g a day, and also lower than the RDA for The Netherlands (300 ?g a day)," wrote Dr. Morris and Dr. Tangney in their commentary. "After the introduction of fortification, fewer than 1% of the U.S. population had an inadequate serum folate status."

The results need to be confirmed by other investigators and repeated in other populations, such as those with mild cognitive impairment and dementia, the researchers concluded.