Health Professionals:

Research on Folic Acid

Low folate status has been associated with mild cognitive impairment (Quadri et al. 2004), vascular dementia (Quadri et al. 2004, Malaguarnera et al. 2004), and Alzheimer's disease (Malaguarnera et al. 2004, Postiglione et al. 2001, Renvall et al. 1989). Elevated homocysteine concentrations also have been observed in patients with vascular dementia or Alzheimer's disease (Malaguarnera et al. 2004).

In a longitudinal study conducted in Sweden, 370 non-demented persons were followed for 3 years. Those with low serum folate concentrations and good cognition at baseline were greater than 3 times more likely to develop Alzheimer's disease during the follow-up period (Wang et al. 2001).

A longitudinal study of the Framingham cohort reported a relative risk of dementia and Alzheimer's disease of 1.4 and 1.8, respectively, for each 1 standard deviation increase in serum homocysteine at baseline compared to follow-up (Seshadri et al. 2002). A longitudinal study of over 670 elderly subjects without dementia at baseline reported that those in the highest quartile of homocysteine had a slightly higher risk for Alzheimer's, although this result was not statistically significant (Luchsinger et al. 2004).

In 2008, a multicenter, randomized, double-blind controlled clinical trial of high-dose folic acid, vitamin B6, and vitamin B12 supplementation in individuals with mild to moderate Alzheimer’s Disease and normal folic acid, B12, and homocysteine concentrations found that the vitamin supplement taken for 18 months was effective in reducing homocysteine levels, but there was no beneficial effect on the rate of change in the Alzheimer Disease Assessment Scale score. The results of this study also indicated that a higher quantity of adverse events involving depression were observed in the group treated with vitamin supplements (Aisen et. al 2008).

A cross-sectional analysis of over 1,100 older adults reported that those with higher homocysteine concentrations were more likely to score lower on tests for various cognitive skills compared to those with lower homocysteine concentrations (Schafer et al. 2005).

In a 2007 randomized, double blind, placebo controlled study, researchers assigned 818 subjects in the Netherlands a daily dose of 800 micrograms folic acid or placebo for 3 years. Serum folate concentrations increased by 576% and plasma total homocysteine concentrations decreased by 26% in subjects taking folic acid compared to those taking a placebo. The effect on cognitive performance, especially memory, information processing speed, and sensorimotor speed, was significantly better in the folic acid group than in the placebo, indicating that folic acid supplementation could help improve domains of cognitive function that decline with age (Durga et al 2007).

A 2010 meta-analysis of 9 placebo-controlled randomized trials studied the effects of folic acid, with or without B vitamins, on cognitive function for a mean duration of 6 months. The results indicated that for each of the four categories of cognitive function (memory, speed, language, and executive function) the results were similar in those taking folic acid and those taking a placebo, concluding that folic acid supplementation had no effect on cognitive function. The authors indicate that studies of longer duration may be needed (Wald et al 2010).

A 17 cross-sectional, case control, and prospective cohort studies were evaluated as part of a systematic review and meta-analysis examining the relationship between homocysteine concentration and the risk of developing dementia/cognitive decline, specifically Alzheimer’s dementia and vascular dementia.  The findings from this study revealed that individuals with Alzheimer’s or vascular dementia had higher homocysteine concentrations compared to controls. For the vascular dementia group, folate levels were considered to be a significant moderator for vascular dementia compared to the control group. Despite these results, the researchers pointed out that the causal relationship between high homocysteine concentrations and the risk of dementia is not yet supported and more research is needed (Ho et al. 2011).

Similarly, a meta-analysis of 8 cohort studies examined the relationship between serum homocysteine and dementia, and also reported a significant association between elevated homocysteine concentrations and the incidence of dementia. However, the researchers cautioned that a cause and effect relationship between homocysteine concentrations and dementia could not be supported. Analysis of the risk reduction benefit of supplementation with folic acid and vitamin B12 revealed an estimate of 22% risk reduction for a 3 µmol/L decrease in serum homocysteine (Wald et al. 2011).

A secondary analysis of the Vitamins to Prevent Stroke (VITATOPS) trial investigated whether B vitamin supplementation would reduce homocysteine and new cognitive impairment among men and women with a previous stroke or transient ischemic attack (Hankey et al. 2013). Patients (n= 8,164) were randomized to receive a placebo or B vitamins (2 milligrams folic acid, 25 milligrams vitamin B6, and 500 micrograms vitamin B12) daily for a median follow up of 3.4 years. At follow up, those taking B vitamins had significantly lower homocysteine compared to placebo; however, there were no differences in scores on the Mini-Mental State Examination or measures of cognitive impairment or cognitive decline between the groups. 

A 2014 systematic review and meta-analysis evaluated the effects of B vitamin supplementation on mild cognitive impairment and Alzheimer’s disease (Li et al. 2014). Five trials were included in the meta-analysis. Supplementation with B vitamins in subjects with mild cognitive impairment was associated with moderate beneficial effects on memory, but no significant effect on general cognitive function, executive function, or attention. Additionally, in subjects with Alzheimer’s disease there were no significant benefits of supplementation on scores from the Alzheimer’s Disease Assessment Scale or Mini Mental State Examination. The researchers concluded that folic acid alone or in combination with other B vitamins was not beneficial in slowing cognitive decline.

A 2015 meta-analysis was performed using 68 studies to examine associations between homocysteine, folic acid, vitamin B12, and Alzheimer’s disease (Shen and Ji 2015). The results of this analysis revealed that Alzheimer’s patients had significantly higher homocysteine, lower folic acid, and lower vitamin B12 concentrations compared to controls and that low folic acid and high homocysteine concentrations may be risk factors for Alzheimer’s disease.

A systematic review and meta-analysis of 111 studies reported a significant and positive association between increased plasma homocysteine and cognitive decline (Setien-Suero et al. 2016). This association was seen in the general population as well as in individuals with cognitive dysfunction.

Supplementation with B vitamins or other nutrients does not appear to provide benefits once cognitive impairment appears.
Folate has been widely studied with regard to its association with depressive disorders. Several cross-sectional studies have associated markers of depression with low folate status (Rosche et al. 2003, Ramos et al. 2004, Morris et al. 2003).

Elevated blood homocysteine concentrations were associated with an almost 2-fold increased risk for depression in two cohort studies (Bjelland et al. 2003, Tiemeier et al. 2002). A prospective study indicated that Finnish men with folate intakes below the median had 2.5 to 3 times the risk for a diagnosis of depression during a 13-year follow up period compared to men with folate intakes above the median (Tolmunen et al. 2004).

Results from a meta-analysis examining 11 studies looking at the association between depression and folate showed a significant relationship between folate status and depression. The authors concluded that low folate status was associated with depression (Gilbody et al. 2007).

In 2008 a cross-sectional study, systematic review, and meta-analysis aimed to determine if total homocysteine is causally related to depression later in life. In a large community sample, a 15 item depression scale and self-reported past or current treatment of depression was used as the main outcome measure. The results indicated that with every unit increase in total homocysteine, the risk of depression increased by 4%. The total homocysteine concentrations were higher in individuals who had the MTHFR 677 TT genotype as opposed to the CC genotype. The authors concluded that decreasing total homocysteine concentration could reduce the odds ratio of depression (Almeida et al. 2008).

A 2010 study used data from NHANES to examine the association of serum folate, vitamin B 12, and total homocysteine concentrations with depressive symptoms. Overall, the mean Patient Health Questionnaire score (used to measure depressive symptoms with “elevated” defined as PHQ >10) was significantly higher in women compared to men, and elevated depressive symptoms were inversely associated with folate status for both sexes. In addition, total homocysteine was positively associated with elevated depressive symptoms. This study suggests that further interventions to improve mental health outcomes should consider dietary and other factors that may increase serum folate levels (Beydoun et al. 2010).

Studies have also tested the effect of folic acid as an adjunct to medication therapy for depression. A meta-analysis of two randomized controlled trials testing the effectiveness of folic acid supplementation either in conjunction with psychotropic medication or as a replacement for it in treating depressive disorders concluded that adding folate to a treatment regimen appeared to be effective in reducing depressive symptoms as measured by the Hamilton Depressive Rating Scale (Taylor et al. 2004). However, there was no difference in outcome when comparing folate treatment alone with use of the psychotropic medication trazodone.

A randomized-control trial with 900 participants that received either 400 micrograms folic acid plus 100 micrograms vitamin B12 daily or placebo, was conducted to determine whether supplementation prevented cognitive decline in a community-dwelling older adult population with depressive symptoms. The study was conducted over 2 years, and individuals were between 60-74 years old. Results indicated that folic acid and vitamin B12 supplementation significantly improved the total recall (p=0.032), immediate memory recall (p=0.046) and delayed recall (p=0.013) scores at the 24 month mark, compared to the placebo group. The study suggests that there may be a role for folic acid and vitamin B12 supplementation in lowering the risk of cognitive decline (Walker et al. 2012).

A double-blind placebo-controlled trial was conducted to evaluate the clinical and cost effectiveness of folic acid as an adjunct treatment for depression (Bedson et al. 2014). Subjects were randomized to take a placebo or 5 milligrams of folic acid for a period of 12 weeks as an adjunct to their antidepressant medication. There was no difference in measures of depressive health, general health, quality of life, or economics between the folic acid treatment and placebo groups. The folic acid treatment group had significantly lower scores compared to placebo on the UK 12-item Short Form Health Survey.        

A systematic review and meta-analysis evaluated whether folate and/or vitamin B12 treatment was beneficial toward depression compared to placebo (Almeida et al. 2015). Eleven studies were included in the analysis. The results indicate that in studies with treatment periods of days to several weeks, treatment with folate and/or vitamin B12 had no significant effect on symptoms of depression in individuals with or without a depressive disorder. However, the results of a single longer-term study where folic acid, vitamin B12, and vitamin B6 was given for a longer period of time (1 year) reported positive effects on the response to antidepressant medication.  

A meta-analysis investigated the efficacy of folic acid and other nutraceuticals as adjunct treatment with antidepressants (Sarris et al. 2016).  Four sets of data related to folic acid, in daily doses ranging from 0.5 milligrams to 10 milligrams and treatment periods from 6 to 12 weeks, were included in the analysis. The pooled data indicated no significant effect of folic acid as an adjunct treatment for depression compared to placebo.

These studies suggest that folic acid, particularly when used for a longer time period, may be beneficial as an adjunct to antidepressant medications in patients suffering from depression.

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