Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford

Folic Acid

Drug Summary: Folic acid, also known as vitamin B11 and naturally found in the form of folate, is important in many biological processes. A recent study conducted over three years with healthy adults 50-70 years old showed that folic acid supplements equal to twice the recommended daily value improved memory and slowed decline in muscle skills and information processing. The supplements used contained 800 micrograms (mcg) of folic acid, while the recommended daily value is 400 mcg. It should be noted that the study was conducted on healthy individuals and further research is needed to determine if there are similar benefits from folic acid supplements for people with neurodegenerative disorders such as Alzheimer’s and HD. Although the mechanism(s) through which folic acid protects the brain are not yet clearly defined, there is evidence that it works at least in part through regulation of a molecule called homocysteine.

What is homocysteine and why is it important in HD?^

Homocysteine is an amino acid closely related to two other amino acids called methionine and cysteine. Homocysteine comes in several different forms. All of these forms are measured together to determine a person’s total homocysteine level (abbreviated tHcy). Certain forms of homocysteine may cause damage through oxidative effects and negative protein interactions. Oxidative stress is thought to play a major role in the HD disease mechanism. (For more information about the role of oxidative stress in HD mechanisms, click here.) Furthermore, it has also been reported that homocysteine can act as a partial activator of NMDA receptors. In HD, nerve cells in the striatum that express NMDA receptors are known to be the most susceptible to damage and the first to degenerate. Extra activation of NMDA receptors due to high levels of homocysteine could make excitotoxic cell damage easier and more severe. (For more information about the role of excitotoxicity in HD, click here.) Having high overall levels of homocysteine may not cause HD, but it seems to contribute to the progression of the disease.

Homocysteine is formed during the metabolism of methionine in the methionine cycle. It is processed and turned into other molecules through two different pathways: trans-sulfuration and re-methylation.

  1. Some homocysteine is converted to cysteine via the trans-sulfuration pathway. This pathway leads to the degradation of homocysteine and its removal from the body through urine. The trans-sulfuration pathway is composed of two reactions. Cysteine, the product of these two reactions, is a precursor to glutathione. Glutathione is a molecule that is very important in preventing oxidative damage to cells.
  2. The second pathway for homocysteine metabolism is called re-methylation. The process of re-methylation simply adds a methyl group (a carbon atom with three hydrogen atoms attached) to the sulfur atom of the homocysteine molecule, thereby modifying its overall structure and function. In this case, the addition of a methyl group changes the homocysteine molecule into a molecule called methionine. The addition of the methyl group is dependent on two enzymes (enzymes are proteins that that help chemical reactions to take place). One of the enzymes, called methyltetrahydrofolate (methylTHF), depends on folic acid because it is formed during the folic acid cycle.

All of this might sound very complicated, so let’s review what we just learned. Folic acid helps to keep homocysteine levels low by aiding one of the two processing pathways. High homocysteine levels are associated with many health problems and may contribute to the progression of HD; consequently, it is important to keep homocystein levels low. In the first processing pathway, homocysteine becomes cysteine, which can become glutathione. The first pathway is important to people with HD because glutathione can help protect against oxidative damage. So, breaking down harmful homocysteine into helpful glutathione is a positive effect of the first pathway. In the second processing pathway, homocysteine becomes methionine, whose creation depends on an enzyme that needs folic acid. By having enough folic acid in the body, we can ensure that homocysteine levels will be kept low, so that the homocysteine does not have significant damaging effects.

Why is the re-methylation of homocysteine important?^

The second pathway of homocysteine processing, the one influenced by folic acid, is called re-methylation. It is important for two reasons. The first reason is that it helps to lower total homocysteine levels. The second, perhaps more significant reason it is important is that the molecule formed by re-methylation is used to form another molecule called S-Adenosylmethionine (SAM). SAM is used to methylate (to methylate is to add a group of atoms called a methyl group) DNA, RNA, proteins, and other important molecules.

What does methylation do? Methylation of DNA is a major biological control of gene expression. While it is usually associated with gene silencing, methylation can also activate genes in some instances. In other words, methylation systems are absolutely essential for proper cell function because they are such important controls over how genes are used by cells. Also, methylation of proteins can change how the protein functions. (For more information on methylation, click here.) The re-methylation pathway of homocysteine processing is therefore also necessary because it results in products needed for regulation of gene expression and normal cell function.

To summarize, homocysteine metabolism is important for two general reasons:

  1. It reduces the total amount of homocysteine available to cause problems like oxidative stress, inflammation, and increased sensitivity to excitotoxicity.
  2. It results in products that cells need to control gene expression and function properly.

Folic Acid and HD^

By lowering total homocysteine levels, folic acid may also lower the oxidative damage that some forms of homocysteine can cause to nerve cells. Lowering homocysteine levels could also lower the risk for homocysteine-mediated apoptosis (programmed cell death) and for excitotoxic cell death (because homocysteine is a partial activator of NMDA receptors). In addition to these possible direct benefits, lowering homocysteine levels also has cardiovascular benefits that result from fewer negative protein interactions, less oxidative damage, and reduced inflammation throughout the body. Increasing cardiovascular health also increases blood flow to the brain, where it is important for the maintenance of nerve cell health and function. The cardiovascular benefits of lower homocysteine levels could be especially important for people with HD; cardiovascular disease, along with pneumonia, is a leading cause of death among people with HD. Although there is still a lack of definitive knowledge regarding the complete interactions of folic acid, homocysteine, and neuroprotection in the brain, research is ongoing.

How can I increase my folate intake?^

Your body treats folate and folic acid as if they are the same molecule. Folate is found naturally, while folic acid is man-made, however both work just the same. Folic acid can be taken as a dietary supplement in the form of a pill. Folate is perhaps best found in a nutritionally well-balanced diet. Folate is naturally found in leafy green vegetable like spinach and turnip greens, as well as in fruits, dried beans, and peas. The Food and Drug Administration (FDA) requires that folic acid be added to cereals, enriched bread, flour, pasta, and other grain products. Studies have shown that a folate rich diet is as effective as folic acid supplements at reducing blood plasma homocysteine concentrations. (To see a table of common foods and the amounts of folate they contain, click here).

What is the right amount of folate?^

The recommended daily allowance for folate intake in adults is 400 mcg. Pregnant women require more folate. Individual requirements may vary from person to person, so it is a good idea to talk with your doctor before taking any supplements.

What are the possible side effects and risks associated with supplemental folic acid?^

The Office of Dietary Supplements rates the health risk of folic acid as “low.” (To read the informative ODS fact sheet on folic acid click here). Because it is a water-soluble vitamin excess folic acid simply leaves the body through urine. However, folic acid may react with some anticonvulsant drugs. Even though it is low risk, it is still important to check with your doctor before taking folic acid supplements.

What other lifestyle factors influence homocysteine levels?^

Homeocysteine levels are generally lower in women than in men, and they tend to increase with age in both genders. Certain drugs can influence homocysteine levels by interfering with absorption of co-factors or increasing the breakdown of vitamins necessary for homocysteine processing. Smoking, high alcohol intake, and high coffee intake also increase the breakdown and decrease the absorption of vitamins. High homocysteine levels are also associated with obesity, lack of physical exercise, and stress. Certain enzyme defects can impair homocysteine metabolism and lead to high total homocysteine levels. Homocysteine levels can be minimized and managed through a combination of folic acid intake and healthy lifestyle choices.

What have studies shown regarding homocysteine and folic acid?^

Many studies have found correlations between high homocysteine levels and an increased risk for cardiovascular disease and mental decline. (It is important to keep in mind the difference between correlation and causation: correlational studies do not prove that a factor causes a condition; correlation simply shows that the two are associated with each other.) High homocysteine levels have also been correlated with an increased risk for Alzheimer’s disease. While it is known that folate/folic acid, along with other B vitamins, positively influences the processing of homocysteine, and that total homocysteine levels with can be lowered with folic acid supplementation, some controversy remains over the effects of folic acid with regard to influence over mental function. A recent study that showed improved memory function and slowed decline in muscle skills and information processing in older adults who were provided with supplemental folic acid takes a step toward resolving this debate and provides encouraging results. Research is still ongoing in this area. With many long-term experiments running around the world, more definitive evidence should be available in the near future.

Research on homocysteine and folic acid^

Kruman et al. (2000) found that homocysteine induces apoptosis (programmed cell death) in the nerve cells of the hippocampus (a specific region of the brain involved in memory) in rats. Homocysteine causes the cells to die by activating a DNA repair enzyme called Poly-ADP-Ribose Polymerase (PARP). The activation of too much PARP uses up the energy of the cell, which results in cell death. Exposure of rat nerve cells to homocysteine led to significant activation of PARP, which in turn led to apoptosis. An inhibitor of PARP protected cells exposed to homocysteine, showing that PARP is indeed involved in the homocysteine mediated cell damage mechanism.

This study also found that levels of free radicals in the mitochondria increased after exposure to homocysteine, implicating another disease mechanism proposed to act in HD. Moreover, homocysteine was also found to sensitize nerve cells to oxidative damage and increase vulnerability to excitotoxic insult from glutamate. (For more information on glutamate’s role in HD, click here.)

While these experiments were conducted using a specific kind of rat nerve cell, homocysteine may also have similar effects in other nerve cells. It has been previously shown that homocysteine is rapidly taken up by other types of nerve cells through a specific membrane transporter. The study concludes by suggesting that dietary folic acid intake could have some helpful effects in combating neurodegenerative disorders because of its ability to regulate homocysteine metabolism.

DiFrancisco-Donoghue et al. (2012) studied the effects of B vitamins on homocysteine levels in patients with Parkinson’s disease. The researchers found that participants who took vitamins B6, B12, and folic acid (5 mg/day) daily for 6 weeks had lower homocysteine levels than a control group.

Kruman et al. (2005) showed that dietary folate deficiency dramatically increases homocysteine levels in mice and inhibits proliferation of neuroprogenitor cells in the adult mouse hippocampus. There is evidence that these neuroprogenitor cells can, under normal conditions, be mobilized to repair damage by replacing nerve cells that have died, even in the adult brain. High homocysteine levels could contribute to neurodegeneration through blocking this repair mechanism.

Andrich et al. (2003) compared total homocysteine (tHcy) levels of both previously treated and untreated people with HD. They found that treated HD patients had significantly higher homocysteine levels than both the untreated group and the control group of people without HD. Treated patients also had, on average, more advanced HD, as indicated by higher scores on the Unified Huntington’s Disease Rating Scale (UHDRS). The difference between the homocysteine levels of people with HD who had been previously treated and those with HD who had not been treated was not due to the effects of drug treatments. The authors therefore hypothesized that total homocysteine levels could be a biomarker for neurodegeneration and that homocysteine might have a pathological role in neurodegeneration. Monitoring total homocysteine levels and using folic acid supplements to keep them low could be particularly helpful for people with HD. Because long-term studies have not yet been performed, it is not yet possible to say for certain if folic acid supplements can help slow neurodegeneration in HD through lowering homocysteine levels.

What is the final word on folic acid supplements, homocysteine levels and their impacts on HD?^

Current research indicates that increased dietary folic acid intake, along with the elimination of unhealthy lifestyle practices, will lower homocysteine levels and is probably effective as a pre-emptive treatment to help prevent damage to nerve cells in the brain and to the cardiovascular system. Keep in mind that it is almost always easier to prevent damage from occurring in the first place than it is to repair the damage that has already been done. While researchers currently do not know just how effective folic acid supplements are at preventing neurodegeneration, a large and constantly growing body of research data looks encouraging. The improvement in memory with folic acid supplements found by a recent study among healthy elderly people suggests that folic acid supplements might have benefits that are even greater than simply preventing damage.

For further reading^

    This website covers many topics related to homocysteine in depth and in a way that is clear and easy to understand.
  2. Andrich et al. “Hyperhomocysteinaemia in treated patients with Huntington’s disease homocysteine in HD.” Movement Disorders. 2004 Feb. 19(2):226-228.
    A short, straightforward presentation of the data and findings showing that treated HD patients have higher tHcy levels than both a control group without the HD allele and people with the HD allele but who have not been treated (and as a group have lower ratings on the UHDRS than the treated patients).
  3. Kruman et al. “Homocysteine Elicits a DNA Damage Response in Neurons That Promotes Apoptosis and Hypersensitivity to Excitotoxicity.” The Journal of Neuroscience. 2000 Sept. 20(18):6920-6926.
    This technical paper describes the finding that homocysteine induces apoptosis in hippocampal rat nerve cells, sensitizes nerve cells to oxidative and excitotoxic injury, and activates PARP.
  4. Kruman et al. “Folate deficiency inhibits proliferation of adult hippocampal progenitors.” Neuroreport. 2005 Jul 13;16(10):1055-1059.
    This technical but concise paper reports that adult mice with a folate deficient diet had significantly higher blood tHcy levels and significantly inhibited proliferation of neuroprogenitor cells in the hippocampus.

-M. Morici, 8-30-05

-Updated A. Zhang, 1-23-12