The American Journal of Medicine
Volume 123, Issue 6 , Pages 522-527.e2, June 2010

Effect of Folic Acid, with or without Other B Vitamins, on Cognitive Decline: Meta-Analysis of Randomized Trials

Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, London, UK

Article Outline

Abstract 

Purpose

We aimed to quantify the effect of folic acid supplementation on the prevention of cognitive decline.

Methods

We conducted a meta-analysis of 9 placebo-controlled randomized trials (2835 participants, median duration 6 months) of folic acid, with or without other B vitamins, on cognitive function. Standardized mean differences in cognitive function test scores were calculated between folic acid and placebo-treated groups.

Results

The standardized mean difference in cognitive function test scores was 0.01 (95% confidence interval [95% CI], −0.08 to 0.10), or an increase of 1% (95% CI, −8% to 10%) of 1 standard deviation. The results were similar within each of the 4 categories of cognitive function (memory, speed, language, and executive function); standardized mean differences were 0.01 (95% CI, −0.08 to 0.09), −0.01 (95% CI, −0.10 to 0.13), −0.05 (95% CI, −0.15 to 0.04), and 0.03 (95% CI, −0.13 to 0.19), respectively.

Conclusion

Randomized trials show no effect of folic acid, with or without other B vitamins, on cognitive function within 3 years of the start of treatment. Trials of longer duration, recording the incidence of dementia, as well as cognitive decline, are needed.

Keywords: B vitamins, Cognitive function, Folic acid, Randomized trial

 

Cognitive function declines with age, and the rate of decline is associated with the risk of developing dementia.1, 2, 3, 4 Serum homocysteine is associated with both cognitive decline and dementia, but it is not known whether the associations are causal.5, 6, 7, 8, 9, 10 Resolving the uncertainty is of practical importance because folic acid supplementation lowers serum homocysteine and is therefore a possible means of helping to prevent dementia or age-related cognitive decline.

Clinical Significance

 


•The synthesis of data from randomized trials indicates no effect of folic acid on the prevention of age-related cognitive decline within 3 years of the start of treatment.

•The lack of effect is consistent across different elements of cognitive function: memory, language, processing speed, and decision making.

•Trials have generally been of short duration (about 6 months). Long-term trials recording the incidence of dementia and cognitive function are needed.

There are no randomized trials of lowering serum homocysteine on the incidence of dementia. Randomized trials of folic acid in the prevention of cognitive decline have been carried out, but the results are not conclusive.11, 12, 13, 14 It is difficult to interpret the results of these trials because of the wide variety of tests used to assess cognitive function, with more than 40 different tests across multiple elements of cognitive function, including memory, language, information processing, and decision making.15 Consequently, there has been no quantitative summary estimate of the effect of treatment. This prompted us to carry out a meta-analysis that takes account of the different cognitive function tests used and provides such an estimate.

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Materials and Methods 

We sought randomized placebo-controlled trials of folic acid (with or without other vitamins or minerals) on tests of cognitive function, using MEDLINE (English language: 1950 to May 2009) and PsychINFO (1967 to 2009). Search terms were [“memory,” “cognitive function,” “cognitive performance,” “cognitive decline,” “cognitive impairment,” “memory impairment,” or “dementia”] and [“folic acid,” “folate,” “B vitamin”]. We included only trials with at least 20 participants, 45 years of age or older, without evidence of dementia at the outset that compared folic acid, with or without other B vitamins, against placebo and that reported the results of 1 or more cognitive function tests on all participants before and after intervention in both the folic acid and placebo groups. The primary search generated 677 articles, which was reduced to 142 after screening the title, to 34 after inspection of the abstracts, and to 9 after examining the full articles,11, 12, 13, 14, 16, 17, 18, 19, 20 including a hand search of citations in the reports of published trials and reviews. Results from each report were abstracted separately by 2 investigators, and the differences were discussed and resolved.

Statistical Methods 

We calculated the average difference between the folic acid and placebo groups in the change in cognitive function test scores over the course of the trial, for each cognitive function test used in each trial. Because the tests used in the trials had different scoring systems with different distributions of results, we expressed the result of each test as a standardized mean difference. This was the difference between the folic acid and placebo groups in the change in cognitive function test score during the trial divided by the average standard deviation across the folic acid and placebo groups. We allowed for correlation between pre- and post-intervention measurements using a correlation coefficient (r) of 0.6 for all tests in all trials based on results from the one trial that reported this.14 The standardized mean differences from all tests within each trial were combined in a random-effects model21 to obtain summary estimates of effect in each trial. We assumed that results from tests within each trial were highly correlated, which meant that trials undertaking many cognitive function tests were not given undue weight in the meta-analysis. The overall results from each trial were then combined using a random-effects model to obtain a pooled summary estimate of effect across all trials.

Because more than 40 tests of cognitive function were used, with most tests being assessed in only 1 or 2 trials, it was not practical to combine results for specific tests. Instead, each cognitive function test was classified into 1 of 4 categories that examine different elements of cognitive function: memory (the ability to learn and remember), speed (the ability to process and respond to information), language (the ability to understand and communicate), and executive function (the ability to plan, prioritize, and make decisions). Appendix A describes each of the 45 cognitive function tests used and shows their classification into the respective clinical categories. Separate random-effects meta-analyses were conducted of the standardized mean differences from the cognitive function tests within each category.

Heterogeneity across studies was assessed using the chi-square test and the I2 statistic.22 Subgroup analyses were conducted on folic acid dose (≥0.8 mg vs <0.8 mg), treatment used (folic acid alone vs folic acid with other B vitamins), trial duration (≥24 months vs <24 months), and mean age in trial (<75 years vs ≥75 years). Meta-regressions of the trial-level estimates of the effect of folic acid supplementation on cognitive decline against folic acid dose, trial duration, and mean age also were performed.

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Results 

Table 1 shows the details of the 9 randomized trials involving 2835 participants (52% male; mean age range 60-83 years) included in the meta-analysis. The daily dose of folic acid varied from 0.2 to 15 mg, and the duration of supplementation ranged from 1.2 to 36 months. Folic acid was combined with other B vitamins (B6, B2, or B12) in 4 trials, with multiple vitamins in 1 trial and used alone in 4 trials.

Table 1. Summary of Randomized Controlled Trials of Folic Acid on Cognitive Function
Study, First AuthorLocationNo. of ParticipantsMean Age of Participants (y)No. of Cognitive Tests UsedFolic Acid Dose (mg)Duration of Treatment (mo)Other Vitamins Included
Fioravanti11Italy30806152None
Bryan16Australia21174190.751None
Lewerin17Sweden1957690.84B6, B12
Pathansali18UK2473451None
Stott19UK1857312.512B2, B6, B12
Eussen12The Netherlands19583180.46B12
McMahon13New Zealand276747124B6, B12
Durga14The Netherlands8186050.836None
McNeill20UK9107220.212Multivitamin pill

Figure 1 shows the summary standardized mean differences in cognitive function tests used in each trial and the summary effect for all trials combined. The summary standardized mean difference in cognitive function test score was 0.01 (95% confidence interval [95% CI], −0.08 to 0.10), that is, 1% (95% CI, −8% to 10%) of 1 standard deviation, indicating no material effect of folic acid supplementation on cognitive function. The standardized mean difference for cognitive function tests within each of the 4 cognitive function categories (memory, speed, language, and executive function) also showed no effect (Figure 2); the summary standardized mean differences were 0.01 (95% CI, −0.08 to 0.09), 0.01 (95% CI, −0.10 to 0.13), −0.05 (95% CI, −0.15 to 0.04), and 0.03 (95% CI, −0.13 to 0.19), respectively.

  • View full-size image.
  • Figure 1. 

    Standardized mean differences in cognitive function test scores (and 95% confidence intervals) between folic acid, with or without other B vitamins, and placebo groups for all tests within each randomized trial and pooled effect across all trials. CI=confidence interval; SMD=standardized mean difference.

  • View full-size image.
  • Figure 2. 

    Standardized mean differences in cognitive function test scores (and 95% confidence intervals) between folic acid, with or without other B vitamins, and placebo groups according to category of cognitive function (each square represents 1 scored task within a cognitive function test for a randomized trial).

There was no evidence of heterogeneity across the trials (I2=0, P=.56). Meta-regression analyses of the trial-level results against the folic acid dose (P=.23), trial duration (P=.83), and mean age of participants (P=.55) showed no statistically significant associations.

Figure 3 shows the results according to the age of participant, treatment used, folic acid dose, and trial duration. There was no indication of a differential effect between specific subgroups (P values .97, .20, .88, and .94, respectively). The results were not associated with year of publication (ie, more and less recently published trials did not differ). A standard statistical test for publication bias (regression asymmetry test) gave no indication that significant publication bias affected the results (P=.95).23

  • View full-size image.
  • Figure 3. 

    Standardized mean differences and 95% confidence intervals in subgroups of randomized trials according to mean age of participants, treatment received, folic acid dose, and duration of treatment. CI=confidence interval; SMD=standardized mean difference.

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Discussion 

The results showed no effect of folic acid in the prevention of cognitive decline among individuals without preexisting dementia. The pooled standardized mean difference in cognitive function test scores was 0.01 (95% CI, −0.08 to 0.10) after a median treatment of 6 months; an increase of 1% of a standard deviation of a cognitive function test score, with confidence intervals excluding an improvement or a deterioration greater than 10% of 1 standard deviation.

Previous systematic reviews of randomized trials did not combine the results of cognitive function tests within or across studies.15, 24 Such reviews were therefore largely descriptive and lacked the power to provide a summary effect of treatment, leaving uncertainty over the effect of folic acid, with or without other B vitamins on overall cognition or according to specific cognitive functions (memory, speed, language, and executive function). A strength of our analysis was the inclusion of data from 5 additional trials since the last review on the subject24 and the application of a simple method to provide a quantitative summary of the effect of treatment on cognitive function—the standardized mean difference in cognitive function test scores before and after treatment. This is a unitless measure of effect that indicates the direction and magnitude of change in the test score as a function of its standard deviation and allows the results of different tests from different trials to be standardized and combined. Our results showed no overall effect of treatment on global cognitive performance or according to category of cognitive function. The analysis also allowed the quantitative assessment of treatment effect according to age, dose, and whether folic acid was used alone or in combination with other B vitamins. There was no indication of a beneficial effect in any subgroup.

A possible limitation of combining tests in this way is if there were a differential effect of treatment on a specific element of cognitive function (eg, language) that might be missed by combining all tests within and across studies, but the data indicate that this was not the case. The results were similar regardless of the category of cognitive function that was tested. Another limitation might arise if tests were misclassified (eg, if a test of speed was, in fact, a test of executive function). Reclassifying 3 tests (the Stroop Test, Trail Making Test, and Letter Digit Coding Test) that examine multiple functions (speed and executive function) from one category to the other resulted in no material change to the results according to specified cognitive function; the result for speed changed from 0.01 (95% CI, −0.10 to 0.13) to 0.03 (95% CI, −0.11 to 0.16), and the result for executive function changed from 0.03 (95% CI, −0.13 to 0.19) to −0.02 (95% CI, −0.14 to 0.09).

Most of the trials in the analysis were of short duration. Seven of the 9 trials lasted 12 months or less (median duration 6 months),11, 12, 16, 17, 18, 19, 20 which may be too short a time for any neuroprotective effect of folic acid, if there were one, to be observed. This limited the extent to which meta-regression or subgroup analysis could be used to examine an effect of treatment duration on cognitive performance. The 2 studies with treatment duration longer than 12 months had point estimates that were directionally opposite (one trial with a mean duration on treatment of 36 months concluded a beneficial effect of treatment on cognitive decline (0.06; 95% CI, −0.11 to 0.23),14 whereas another trial lasting 24 months suggested a deterioration in cognitive function (95% CI, −0.09; −0.33 to 0.16).13 Neither trial was conclusive, leaving open the question of whether long-term treatment with folic acid is beneficial.

Autopsy studies show an association between low serum folate and neocortical atrophy in the brains of individuals who died of Alzheimer's disease,25 but whether folic acid supplementation will lead to a reduced incidence of Alzheimer's disease is uncertain. Tests of cognitive function are a surrogate end point and may not reliably identify those who will progress to Alzheimer's disease, vascular dementia,26, 27, 28 or mild cognitive impairment, an intermediate state between normal cognition and dementia.29 Tests of memory are regarded as more sensitive than tests of other cognitive functions for distinguishing between individuals with and without cognitive impairment and more specific for predicting progression to Alzheimer's disease.30, 31 One trial concluded a preventive effect of folic acid on cognitive decline on the basis of improvement in memory testing and speed (3 other tests showed no effect).14 To the extent that we could examine the effect of folic acid affecting memory alone or speed alone (the meta-analysis included 30 tests of memory across 7 different trials and 14 tests of speed across 6 trials), there seemed to be no benefit of treatment compared with placebo. The positive effects in this trial may have been due to chance.

Our results are based on studies of individuals without dementia at the outset and are therefore clinically relevant to the primary prevention of cognitive decline. Although we cannot apply our findings to patients with preexisting disease, evidence from 2 trials of B vitamins in patients with dementia also indicate no benefit of treatment. In one trial of 128 patients given folic acid and B12 or placebo, there was no change in cognitive function after 12 weeks of treatment,32 and in another trial, involving 340 patients with Alzheimer's disease, there was no effect of B vitamins (folic acid, B6 and B12 combined) in slowing cognitive decline after 18 months of treatment.33

Although the trials included in this meta-analysis showed no benefit of folic acid in reducing cognitive decline, nor did they report any evidence of harm. This is relevant because of suggestions that folic acid may increase the risk of recurrence of colorectal adenomas or breast cancer,34, 35 claims that are not supported by the randomized trials considered in this article or detailed analyses of trials of folic acid in the prevention of colorectal adenomas36, 37 or cardiovascular disease that also reported cancer outcomes.38 Folic acid may have other health benefits, such as the treatment of folate deficiency anemia or the prevention of stroke,39 so although folic acid, on present evidence, cannot be recommended for the prevention of cognitive decline, clinicians can confidently use folic acid supplementation for other health reasons without expectation that this would cause harm.

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Conclusions 

There is no clinical evidence that folic acid treatment for up to 3 years prevents age-related cognitive decline. Longer-term randomized trials of folic acid are needed. These trials need to be large and include dementia as an outcome, as well as the assessment of cognitive decline.

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Appendix 

Appendix A. Cognitive Function Tests Used in the Clinical Trials
DomainCognitive Function TestDescription of Tasks in Cognitive Function TestStudy Using Test
MemoryDigit span forwardRepeat sets of sequentially increasing numbers of digits.
Lewerin 2005

McNeill 2007

Eussen 2006

Digit span backwardRepeat, in reverse order sets of sequentially increasing numbers of digits.
Bryan 2002

Lewerin 2005

Eussen 2006

Letter number sequencing (WAIS-III)Repeat numbers and letters in numeric and alphabetical order from a random sequence that is read out.Bryan 2002
Rey Auditory Verbal Learning Test
Immediate recall of 15 nouns that are read out.

Recall the first 15 nouns immediately after a second list of 15 different nouns are read out and after 20 min.

Identify the 30 nouns from a list of 50 nouns and recall which list each noun was in.


Bryan 2002

McMahon 2006

Digit Symbol Coding (WAIS-III)Immediate recall of symbol-digit pairs from Digit Symbol Coding Test.Bryan 2002
Activity RecallName or describe 13 cognitive tasks the participant has recently completed.Bryan 2002
Visual reproductionReproduction of 4 drawings.Lewerin 2005
Thurstone's picture memory testIdentify 28 images, embedded within 4 pictures.Lewerin 2005
Figure of Rey, immediate recallDraw a standard figure of shapes and lines (complex figure of Rey) immediately after copying it.Eussen 2006
Figure of Rey, delayed recallDraw the complex figure of Rey 30 min after copying it.Eussen 2006
Paragraph recall (Wechsler Memory Scales)Immediate verbal recall of a standard paragraph length passage of text.McMahon 2006
Word Learning testRead and memorize 15 monosyllabic words with immediate and delayed (20 min) recall.
Durga 2007

Eussen 2006

Randt Memory Test (Composite of 7 tests)
Provide accurate personal and general information.

Repeat sequentially increasing sets of numbers forward and backward.

Recall 5 words that are read out immediately after, 3 min later, and 24 h later.

Recall 6 word pairs that are read out immediately after, 3 min later, and 24 h later.

Recall 20 prime words from a paragraph that is read out immediately after, 3 min later, and 24 h later.

Recognize 7 previously shown drawings of objects from a series of 15 drawings.

Recall the titles of the preceding test modules performed.

Fioravanti 1997
Continuous attention testRespond when 2 consecutive patterns in a series are the same.Pathansali 2005
Scanning memory setsRecall whether a given number was part of a displayed series.Pathansali 2005
SpeedBoxes testDraw the missing side of 100 boxes (maximum number completed in 30 sec).Bryan 2002
Digit symbol codingCode digit sequences using a key of symbols representing each digit (maximum number coded in 120 sec and time taken to complete).
Bryan 2002

Lewerin 2005

Symbol search (WAIS-III)Identify pairs of symbols from 2 columns of symbols (number identified correctly in 60 sec).Bryan, et al. 2002
Trail making test A⁎Join up a random pattern of circles, each containing a number (1-25) in numeric order (time taken to complete the task).
Eussen 2006

McMahon 2006

Trail making test B⁎Join up a random pattern of circles, each containing a number (1-13) or letter (A-L) in alternate numeric and alphabetical order (time taken to complete the task).McMahon 2006
Identical formsMatch a specified complex shape with one of the same from within a group of 5 different shapes (maximum number completed in 240 sec).Lewerin 2005
Letter-digit coding test⁎Code digit sequences using a key of letters representing each digit in 90 sec.
Stott 2005

Durga 2007

Pathansali 2005

Finger tapping testPress a button as many times as possible within 30 sec.Eussen 2006
Motor planning test 2 and 3Press 1 of 3 buttons as quickly as possible (computerized test).Eussen 2006
Concept Shifting TestCross off 16 circles containing numbers and letters in numeric and alphabetical order (time taken to complete).Durga 2007
4 choice reaction testTouch a circle matching the displayed circle as quickly as possible.
LanguageVocabularyDefine 15 words.Bryan 2002
Spot-the-wordIdentify a word in 60 word and non-word pairs.Bryan 2002
SynonymsSelect a synonym for a given word from 5 words.Lewerin 2005
Controlled oral word association testGenerate words beginning with 3 given letters.McMahon 2006
Category word fluency testGenerate words from 3 specified categories (eg, animals, fruits) within 60 sec.McMahon 2006
Verbal/Word Fluency test (Animal)Name as many animals as possible.
Durga 2007

Eussen 2006

Verbal/Word Fluency test (Letter)Generate words beginning with 3 given letters each within 1 min.McNeill 2007
Executive FunctionSelf-ordered pointing taskIdentify each of 16 different visual patterns from a printed page of random patterns.Bryan 2002
Uses of Common ObjectsName as many different uses of a specified common object in two 90-second trials.Bryan 2002
Trail making test A⁎Join up a random pattern of circles, each containing a number (1-25) in numeric order (time taken to complete the task).Bryan 2002
Trail making test B⁎Join up a random pattern of circles, each containing a number (1-13) or letter (A-L) in alternate numeric and alphabetical order (time taken to complete the task).
Bryan 2002

Eussen 2006

Initial Letter fluencyGenerate as many words as possible from an initial letter within 60 sec.Bryan 2002
Excluded Letter FluencyGenerate as many words as possible not containing a specified letter in 60 sec.Bryan 2002
Block designCreate a pattern using blocks that have white, red, or both white and red sides.Lewerin 2005
Figure classificationClassify sets of figures into 2 groups on the basis of similarity.Lewerin 2005
Figure of Rey, copyCopy the complex figure of Rey (a standard design of shapes and lines) from an example.Eussen 2006
Similarities (WAIS)Describe the similarities between 5 pairs of nouns.Eussen 2006
Raven's Progressive MatricesIdentify the missing segment that fits into a larger pattern.
McMahon 2006

Eussen 2006

Stroop (color–word) Test⁎
First subset: Read the color name given in black ink.

Second subset: Name the colored blocks.

Third subset: Name the color of the ink rather than the word.


Bryan 2002

Durga 2007

Eussen 2006

WAIS = Wechsler Adult Intelligence Scale.

⁎Same test used to assess both speed and executive function.

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 Funding: None.

 Conflict of Interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript.

 Authorship: All authors had access to the data and played a role in writing this manuscript.

PII: S0002-9343(10)00131-2

doi:10.1016/j.amjmed.2010.01.017

The American Journal of Medicine
Volume 123, Issue 6 , Pages 522-527.e2, June 2010

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