Folic Acid—The Good Guy

Folic Acid Improves
Cognitive Function

Its varied health benefits appear to be independent
(sometimes) of its usual nemesis, homocysteine
By Will Block

Where's the evidence?

© Tolstoy

hen is a villain not a villain? If you’re a fan of Law & Order or of similarly thought-provoking fare in the form of books (remember them?), you undoubtedly have a fine appreciation for the concepts of ambiguous or contradictory evidence, mitigating circumstances, faulty or selective memories, and many other factors that make the good guys’ job frustratingly difficult when they’re trying to nail the bad guys. As we know, most bad guys are not all bad or always bad. Sometimes they’re even innocent.

A trap that detectives and prosecutors sometimes fall into is assuming that a certain bad guy must have done the crime, because he had motive, opportunity, and method, and there’s no evidence that anyone else did it. And they know he’s a bad guy, for Pete’s sake! He must have done it! Along comes a smart-aleck defense attorney and demands to see something more substantial, like actual evidence. How annoying is that?

Apart from the blessing of not having to deal with lawyers, medical research is pretty much like a crime drama. It’s messy, confusing, and contradictory. Things go wrong all the time, and things keep changing in maddening ways. There are pitfalls galore, and no matter what you do or say, there will be critics sniping from the sidelines, demanding to see the evidence. When you finally provide it, they pick it apart and try to find the fatal flaws. All of which helps make research such an exciting, worthwhile endeavor. Seriously.

Folic Acid—Relentless Homocysteine Hunter

When it comes to villains in the medical arena, it’s hard to beat homocysteine, a natural and necessary amino acid that can turn from Dr. Jekyll to Mr. Hyde if its levels in our blood exceed the normal, safe ones our bodies were designed to accommodate. Unfortunately, this phenomenon tends to occur as we age, and excessive homocysteine levels can assault our systems with an array of horrors that would turn even Stephen King’s knees to jelly.

We have written often about homocysteine, almost always in the context of a nutritional savior, folic acid, whose actions in the body depend critically on the assistance of a biochemical buddy, vitamin B12.* These two B-vitamins (folic acid doesn’t have a number) work hand in hand in our bodies, and it’s important that they always be taken together so as to avoid an imbalance of them in the blood. (As a cofactor to folic acid, vitamin B6 is also considered highly beneficial, although cosupplementation with B6 is not absolutely necessary, as it is for vitamin B12.)

*See “Fight Alzheimer’s and Heart Disease with B-Vitamins” (December 2001), “Folic Acid to the Rescue!” (September 2002), “Add Brain Assault to Homocysteine’s Rap Sheet” (February 2006), “Vitamin B12—How Much Is Enough?” (November 2006), and “Folic Acid Improves Memory in the Elderly” (April 2007). For other approaches to homocysteine, see “Choline Battles Homocysteine” (April 2005) and “Can Betaine Beat Homocysteine?” (May 2006).

Folic acid is also called folate, which is the form you get when the acidic hydrogen atom is removed, leaving a negative ion. Physiologically, folic acid and folate are the same, so it doesn’t matter which term is used. What does matter is what this substance primarily accomplishes: reducing homocysteine levels, thereby helping to prevent no end of ills.

Where’s the Evidence?

Among those ills are a decline in cognitive function and an increased risk for dementia, both of which have been associated with high homocysteine levels in numerous studies. Mere association, however, doesn’t prove anything, as any good lawyer or scientist could tell you. You need evidence (preferably proof, but that’s a very tall order) of cause and effect. And the truth is, we don’t know if these associations are explained by homocysteine itself (excessive levels would be to blame) or by something closely related to homocysteine metabolism, such as folic acid or vitamin B12 (deficient levels would be to blame).

MRI brain scan depicting white matter lesions, shown here in pink for easier identification. (From the Leiden University Medical Center, Leiden, The Netherlands.)
To complicate matters, we do know that in some studies that have shown an association between low folate levels and cognitive decline, homocysteine levels appeared not to be a factor—the results were independent of them. There is no good explanation for this, and it’s not known whether folate exerts its beneficial effects via direct action on brain tissue, via vascular mechanisms, or both. Vascular mechanisms are those involving the structure and function of the vascular endothelium, the inner lining of our blood vessels. This thin layer of cells plays a crucial role in regulating blood pressure and blood flow to the brain and everywhere else. Excessive homocysteine levels play havoc with the endothelium and can be a major factor in cerebrovascular disease.

May We Have a Peek at Your Brain?

A group of researchers in the Netherlands, the United Kingdom, and Norway decided that a promising way to investigate the link between folate levels and cognitive function would be to seek evidence (aha!) of a relation between folate levels and changes in brain tissue that are generally considered to be markers of cerebrovascular disease or of the loss of brain cells (severe neurodegeneration).1 To this end, they examined data from the Rotterdam Scan Study, a large prospective study on the causes and consequences of age-related brain changes in the elderly, which had been carried out in 1995–1996.

Blood samples and MRI (magnetic resonance imaging) brain scans from 1033 nondemented individuals, aged 60–90, were available for analysis, as well as the results of cognitive tests. The goal of the new study was to ascertain—and, if possible, explain—associations between folate levels and three factors, two of which could be measured via the brain scans:

  • Cognitive performance – This was assessed in three domains: psychomotor speed (reaction time to a sensory stimulus), memory performance, and global cognitive function.

  • White matter lesions – These lesions in the brain’s white matter are considered to be sensitive markers of cerebrovascular disease; they are associated with an increased risk for cognitive decline and dementia.

  • Hippocampal and amygdalar volumes – The volumes of the hippocampus and the amygdala—brain regions associated with cognitive functions and emotions, respectively—are markers of brain-cell loss and presymptomatic Alzheimer’s disease.*

*The amygdala, a small, almond-shaped structure, is richly supplied with nerve fibers from the olfactory system. This may account for the powerful effect that odors can have in stimulating emotions and evoking memories, sometimes even after decades have elapsed.

Because the study population did not include any demented individuals, the researchers were not able to examine a possible link between folate levels and the risk for dementia.

Folic Acid Improved Cognitive Performance and Reduced Brain Lesions

The results of the cognitive performance analysis showed significant improvements in psychomotor speed and global cognitive function with increasing levels of folate in the blood. There was no improvement, however, in memory performance, a finding that contrasted with those of most previous studies, in which a positive association was observed. The authors speculated that the discrepancy might be due to differences in the way memory function was assessed or to differences in the compositions of the study populations.

Hello? . . . Alice?

The study on folate and cognitive function discussed in the article was methodologically strong, but even strong studies can have weaknesses.1 The authors acknowledged that the cross-sectional design of their study—examining the characteristics of a given population at one moment in time rather than observing the changes that occur in that population over a period of time—could have been a weakness, because it allowed for the possibility of reverse causality, which sounds like something from Alice in Wonderland.

But fear not—we are not exploring alien realms of logic, as Lewis Carroll was so fond of doing (he was a mathematician, by the way). Reverse causality simply means that there could have been a role reversal between what appeared to be cause and effect in this study, with each of them actually being the other! Specifically: what if, instead of low folate’s causing impaired cognitive function in some of these individuals, their impaired cognitive function caused them to alter their dietary habits, resulting in lower folate intake? (Giving up cereal or forgetting to take supplements would do the trick.)

Admit it—you hadn’t thought of that, right? But scientists have to think about things like that (and other things far more subtle and complex) all the time, lest they stumble into one of the innumerable intellectual pitfalls that always surround them. (Guess what? Often they do stumble, because, unlike the rest of us, they aren’t perfetc.)

In this case, the authors opined that reverse causality was unlikely, because the study included only nondemented persons, whose relatively low levels of cognitive impairment would probably not have affected their dietary habits enough to alter the outcome of the study. Plausible sounds that.


  1. de Lau LML, Refsum H, Smith AD, Johnston C, Breteler MMB. Plasma folate concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr 2007;86:728-34.

Analysis of the MRI scans showed that the volume of white matter lesions (WMLs) and the presence of severe WMLs decreased significantly with increasing folate levels, an inverse relationship that indicated a protective effect of folate against cerebrovascular disease. On the other hand, there was no association between folate and hippocampal or amygdalar volumes, suggesting a lack of protective effect against that form of neurodegeneration.

Some Surprising Conclusions

After the initial analysis, the researchers adjusted the data to account for differences in homocysteine levels in the subjects’ blood; they then reanalyzed the data to see whether folate’s beneficial effects were due to its reduction of homocysteine levels or were independent. For cognitive performance (psychomotor speed and global cognitive function), the results were essentially unchanged, meaning that folate acted largely independently of homocysteine.

That does not mean, however, that homocysteine had no effect on cognitive performance. In fact, there was a statistically significant association between higher homocysteine levels and poorer results in the two aspects of cognitive performance in question. This suggests that folate and homocysteine may have effects on cognition that are independent of each other, possibly through different biochemical pathways. It also means that cognitive impairment may be due as much to low folate levels, per se, as to high homocysteine levels. See how complicated this can get?

When the data on WMLs were similarly adjusted for varying homocysteine levels and then reanalyzed, the inverse relationship between folate levels and WMLs also remained essentially unchanged.

All of these findings suggested to the authors (for a variety of reasons that we need not go into) that low folate levels are linked to cognitive decline primarily by cerebrovascular mechanisms rather than by mechanisms involving primary neurodegeneration. Consistent with this opinion is the fact that psychomotor speed is known to be adversely affected by cerebrovascular disease, whereas memory is affected more strongly by neuronal function and hippocampal size.

From 14 Studies We Find that . . .

The authors cited four studies indicating that supplemental folic acid has beneficial effects on dysfunction of the vascular endothelium; such dysfunction (which can take many forms) is a key factor in hypertension and atherosclerosis and is a leading indicator for the risk of cardiovascular disease. In two of the cited studies, interestingly, the effects of folic acid appeared to be independent of homocysteine levels; this jibes with the observations in the cognitive function study.

Folic acid and vitamin B12 work hand in hand.
Three of the four studies cited were included among the 14 that were evaluated recently by means of a meta-analysis.2 This is a complex procedure for combining the results of numerous studies on a given subject in order to extract a conclusion based on the collective data from all of them rather than on the more limited data from any individual one. Such a conclusion should have greater weight by virtue of its broader foundation.

Together, the 14 studies involved 732 individuals who were treated with folic acid (with or without vitamin B6, vitamin B12, or both) or placebo for a median period of 8 weeks. Most of the subjects were middle-aged men. The amount of folic acid used ranged from 400 to 10,000 mcg/day (0.4 to 10 mg/day), with a median value of 5000 mcg/day (5 mg/day).

. . . Folic Acid Might Reduce Cardiovascular Risk

The pooled data from all the studies showed a small but significant improvement, by 1.1%, in flow-mediated dilation, a technique used for evaluating endothelial function. This figure fell slightly when only the lower amounts of folic acid were considered, and it rose slightly when only the higher amounts were considered. It is not clear, however, whether these variations were meaningful or just artifacts caused by differences among the studies involved.

In any case, the authors concluded that the beneficial effect of high doses of supplemental folic acid on endothelial function was probably largely independent of a homocysteine-lowering action. Whether it is or not, though, the effect could potentially reduce the risk for cardiovascular disease, at least a little.

Keep It Clean!

So is homocysteine still the bad guy, and folic acid the good guy? Definitely yes, but, as we have seen, things are not always as clean and simple as we would like. Evidence can be hard to obtain, and even harder to interpret correctly. In the case of folic acid, all the evidence points to its beneficial effects on our health, even if it’s not always on the hunt for homocysteine but is just “doing its own thing.” Are you getting enough folic acid?


  1. de Lau LML, Refsum H, Smith AD, Johnston C, Breteler MMB. Plasma folate concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr 2007;86:728-34.
  2. de Bree A, van Mierlo LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2007;86:610-7.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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