In this long-term, randomized placebo-controlled trial of 2009 older women at high risk of cognitive decline due to existing cardiovascular disease or risk factors, use of a dietary supplement of combined vitamin B6, folic acid and vitamin B12, did not confer cognitive benefits. However, a suggestive pattern of reduced risk of cognitive decline with supplementation was observed among women with low dietary intake of B vitamins at baseline.
There have been multiple randomized trials that have examined folic acid, vitamin B6
, and vitamin B12
, separately or in combination, in relation to cognitive function or dementia, in a variety of older populations.(7
) Because of the heterogeneity in the doses (e.g. range 0.4 – 15 mg / day of folic acid), combinations, duration of study (range 5 weeks – 3 years), sample size (range 7 – 3097), proportion of the study population with elevated homocysteine, and characteristics of the study population (e.g. restricted to those with cognitive impairment / dementia or restricted to those with vascular disease) it is difficult to derive a firm conclusion;(31
) however, the collective results are not convincing for beneficial effects of B vitamin supplementation on cognitive health.(32
A post-hoc power analysis, based on the mean change in cognitive function actually observed in the placebo group, and its standard deviation, showed that there was at least 80% power to detect mean differences in cognitive decline between the treatment and placebo groups which were equivalent to the mean difference in cognitive decline observed between participants who were 3.5 years apart in age. That is, we had adequate power to detect an effect of B vitamin treatment that was equivalent to delaying cognitive aging by 3.5 years in these subjects, which is a fairly modest effect. Thus, the null results could not be largely attributed to a lack of statistical power.
This present study is unique in that it provides data from a large study sample (n=2009) of older women at elevated risk due to vascular disease or risk factors, with the longest duration of treatment (6.6 years) of B vitamins to date. There have only been two other studies(7
) of participants with vascular disease, and these both included a relatively short period (1 – 2 years) of treatment. Both studies administered 2.5 mg of folic acid in various combinations with vitamin B6
and like the present study, reported no effect of B vitamin supplementation on cognitive function. These null results for cognitive decline are consistent with the results from randomized trials that have also found no benefits of B vitamin supplementation in the secondary prevention of cardiovascular disease. (7
Although additional supplementation with B vitamins might not confer any cognitive benefits for older populations that are generally well-nourished, our data is consistent with the possibility that supplementation of B vitamins may be beneficial in the small segment of the population who still have low dietary intakes of folate, vitamin B6
and vitamin B12
. Durga et al (27
) also found that older persons with elevated homocysteine and low folate intake (mean intake was < 200 μg / day) given folic acid supplementation (0.8 mg / day), showed slower decline over 3 years in global cognitive functioning, memory and information processing. Nevertheless, these subgroup analysis results need to be interpreted with caution and need to be further confirmed in similarly large studies of long duration.
WAFACS began in April 1998, 3 months after the mandated grain folic acid fortification, which has led to generally increased background dietary intakes of folic acid;(39
) further, our cognitive assessments began 1.2 years after randomization. At the end of the study, we evaluated plasma levels of folate and homocysteine among a sample of 150 participants on B vitamins and 150 on placebo to assess whether there were still substantial differences in folate status between the two groups.(13
) Those with high plasma folate levels ≥ 25 ng / mL (or 56.7 nmol / L) comprised 16.7% of the participants assigned to placebo and 85.3% of the participants assigned to B vitamins. However, the difference in plasma homocysteine levels between the groups was modest: the median was 11.8 μmol/L in the placebo group and 9.8 μmol/L in the treated group, for an average difference of 2.0 μmol/L (or 17%), which may have been insufficient for major cognitive benefits in this generally well-nourished population. It is possible, however, that among those with low dietary intakes of B vitamins at baseline, the differences in homocysteine levels between the active and placebo groups may have been larger; this could be one explanation for the apparent cognitive benefits we observed of vitamin B supplementation in this subgroup.
Other limitations of this study should be considered. Cognitive testing began a mean 1.2 years after randomization; thus we were unable to evaluate change in cognitive performance from randomization. It is possible that vitamin B supplementation may have conferred some very early cognitive changes, and if so, we would have missed such changes when we compared performance after our first cognitive assessment 1.2 years subsequent to randomization. We believe that such an early effect, though possible, is not highly biologically plausible. Moreover, since we observed no absolute differences in cognitive function 1.2 years after treatment initiation and since it is likely that cognitive function was equally distributed in the two groups at randomization (indeed, the distribution of numerous risk factors for cognitive impairment was comparable across treatment groups at randomization), then it seems unlikely that we could have missed any meaningful changes in cognitive from randomization to our initial cognitive testing. Another limitation was non-compliance which may bias associations towards the null; however, compliance rates were generally high and similar in the treatment and placebo groups.
In conclusion, in this large-scale, long-term randomized placebo-controlled trial of B vitamin supplementation and cognitive decline, no cognitive benefits were observed among women at high risk of cardiovascular disease. However, we observed a general pattern of cognitive benefits with supplementation among the subset of women with low dietary intake of the B vitamins at baseline; this finding may have been due to chance but warrants further study. Although preventing deficiency of essential vitamins such as folate, vitamin B6 and vitamin B12 remains an important health concern for older persons, additional supplementation with B vitamins is unlikely to provide cognitive benefits for those who are generally well-nourished. Alternative strategies for maintaining cognitive health in high-risk older individuals need to be investigated.