Folate, Folic Acid and Alzheimer's

Summary: It’s unclear whether folate or folic acid supplementation can help prevent or treat Alzheimer’s and other dementias. Some evidence actually suggests the opposite: an association between high folate intake and increased cognitive decline. In more positive studies, the link between high folate and lower risk of Alzheimer’s may really be due to exercise.

Folic acid supplements can mask symptoms of Vitamin B12 deficiency, especially in older adults. The U.S. National Institutes of Health warns people 50 years of age or older to have their B12 status checked by a doctor before taking supplements containing folic acid.

Pretend you haven’t read the summary above, and take this short quiz:

1. Folate, a B vitamin found in leafy green vegetables and other foods is good for the brain.
_____Yes _____No _____Maybe

2. Folic acid, the synthetic form of folate found in supplements, is also beneficial.
_____Yes _____No _____Maybe

3. Taking a folic acid supplement can help prevent dementia.
_____Yes _____No _____Maybe

4. It’s OK to take a folic acid supplement just to be sure.
_____Yes _____No _____Maybe

A few days ago, I would have checked yes for every question. But it turns out the correct answer for all these questions is “maybe.” This is surprising, given the press reports:

“Folate shows promise in preventing Alzheimer’s” (USA Today, August 14, 2005)
“Higher Folate Levels May Lower Alzheimer's Risk: Study” (Forbes, January 9, 2007)
“Folic acid boosts elderly brains” (BBC, January 19, 2007).

With headlines like these, it’s no surprise that people worried about brain health have been taking folic acid supplements. When a news feed picked up a story on a study by Dalhousie University researchers in Canada suggesting folate may not reduce the risk of Alzheimer’s, this started an online discussion among members of Dementia Advocacy and Support Network International (DASN). One member wrote “I take folate and have had ‘cerebrovascular events’ in the past, now having vascular dementia.” She wondered what the study results meant for her. Several other members (most diagnosed with Alzheimer’s or dementia) responded that they take folic acid supplements in amounts ranging from 400 micrograms to 5 milligrams.

Some of the DASN members are taking folic acid on the advice of their doctors, or because they’ve heard it might be helpful for dementia. But what evidence is this based on?

Theories About Folate and Alzheimer’s

Scientists aren’t sure by what mechanism, if any, folate may prevent or treat Alzheimer’s. Theories about why folate may be linked to a lower risk of the disease center around homocysteine. Some studies have linked high blood levels of this amino acid to heart disease and Alzheimer’s. In 2001, an analysis of data for 1092 people in the Framingham Study by Boston University researchers showed that a high level of homocysteine in the blood was a strong risk factor for developing Alzheimer’s or other dementia. Folic acid appears to help lower homocysteine levels. So if there’s any protective effect from folate, it could be from lowering homocysteine levels.
There’s also a possible link among folate, homocysteine and beta amyloid, the protein many researchers think causes Alzheimer’s. Scientists at the U.S. National Institute of Aging have shown that brain cells without folate, or with added homocysteine, appear to be more vulnerable to damage from beta amyloid.

Lab studies and theories are tantalizing, but what do studies involving humans show?

Folate or Folic Acid for Prevention of Alzheimer’s?

The results of the study from Dalhousie University that generated discussion among DASN members were published in an article in the Journal of the American Geriatric Society. The lead author of the article, Laura Middleton, is a Ph.D. student studying the effects of lifestyle on the risk of Alzheimer's disease and dementia, with a particular focus on exercise.

Laura Middleton

“In our study, we looked at folate levels in the blood,” she says. “Low folate levels are associated with an increased risk of Alzheimer's disease. Conversely, supplementation with folic acid has not been consistently shown to decrease this risk, suggesting that there may be other factors at play. We suggest in our article that exercise may explain this paradox. In our study group, there were no exercisers who had extremely low folate levels. Folate levels may be associated with the risk of Alzheimer's disease because people who exercise both have higher levels of folate and less risk of Alzheimer's disease.”

Ms. Middleton doesn’t think other factors were at work. “We controlled for a number of other variables,” she says, “including age, sex, education, vascular risk factors, and folate/B12 supplementation.”

Folate’s effect on the risk of developing dementia has been the subject of several large studies, and the results have been mixed. Some studies tracking people’s food consumption, folate levels in the blood and health over several years have shown an association between higher folate intake (or higher levels of folate in the blood) and lower risk of developing Alzheimer’s. In 2001, the results of a study by researchers at Karolinska Institutet in Sweden were published in Neurology. The study found that people with low levels of folate in their blood had twice the risk of developing Alzheimer’s. In an article published in 2005, analysis of data from the Baltimore Longitudinal Study of Aging by the U.S. National Institute on Aging, the U.S. Department of Agriculture (USDA), Johns Hopkins University and the University of California showed a high folate intake was associated with a reduced risk of Alzheimer’s. Early this year (2007), a study by Columbia University researchers followed the dietary intake of 965 persons aged 65 or older over several years. These scientists also concluded that a higher folate intake was associated with a decreased risk of Alzheimer’s.

But as the Dalhousie University study suggests, just because high folate intake is sometimes associated with lower rates of Alzheimer’s doesn’t mean there is a cause and effect relationship. Researchers involved in the Baltimore Longitudinal Study of Aging caution that “additional studies are necessary to investigate whether folate or other(s) [sic] unmeasured factor(s) may be responsible for this reduction in risk,” and the authors of the 2007 article on the Columbia University study note “these results require confirmation with clinical trials.”

A systematic review of 24 studies by Tufts-New England Medical Center scientists published this month (July 2007) questions the value of some of these studies due to quality problems and to variations in the way cognitive function was measured and B-vitamin status was categorized.

Some recent studies have shown either no link between folate intake and the risk of developing dementia, or, more worrisome, that increased folate intake is actually associated with increased cognitive decline. At Rush University Medical Center in Chicago, Dr. Martha Clare Morris studies diet and dementia. She co-authored an article published last year in the Journal of Alzheimer’s Disease that describes a Rush study testing whether folate and other B vitamins can protect against Alzheimer’s. Using data from the Chicago Health and Aging Project (CHAP), she and her colleagues tracked 1041 people age 65+ for a median 3.9 years, and found no association between folate intake and the risk of developing Alzheimer’s.

Martha Clare Morris, Sc.D., Associate Professor, Internal Medicine, Rush Institute for Healthy Aging
Assistant Provost for Community Research, Rush University Medical Center

“We have much research to do in this area,” Dr. Morris says. “There is growing evidence to indicate that perhaps too little folate or too much folate can be harmful to our health…. There are some recent studies including our CHAP study that observed greater cognitive decline with high levels of folate intake.” These studies looked at the risk of developing Alzheimer’s; Dr. Morris and her colleagues plan to study the effect of folate on vascular dementia in the near future.

Can Folic Acid Treat Alzheimer’s and Dementia?

Evidence on the use of folic acid to treat dementia is as mixed as that about its use for prevention. A 2003 Cochrane Review of four double blind, placebo controlled, randomized trials found no beneficial effect of 750 micrograms of folic acid per day on measures of cognition or mood in people with mild to moderate cognitive decline and different forms of dementia.

A 2004 review by (London-based) King’s College researchers of six studies that met certain quality criteria concluded that “the evidence does not support a correlation between serum vitamin B (12) or folate and cognitive impairment in people aged over 60 years. Hence, there is little evidence to justify treating cognitive impairment with vitamin B (12) or folate supplementation.”

The results of two studies published in 2007 are more encouraging. In the first, a small trial of folic acid supplements with cholinesterase inhibitors in 57 patients with Alzheimer’s was conducted by researchers at the University of Dundee. They found adding folic acid to cholinesterase inhibitors improved the ability to carry out activities of daily living and “Social Behaviour” scores, but did not improve scores on the MMSE [Mini Mental State Exam]. In the second, Dutch researchers studied 818 participants in FACIT, a trial testing the effect of folic acid on hardening of the arteries. Their results, published in the January 20, 2007 edition of Lancet, showed that “folic acid supplementation for 3 years significantly improved domains of cognitive function that tend to decline with age.”

But in an editorial accompanying the Lancet article, Dr. Morris and her colleague Christine Tangney question whether the results of the FACIT trial apply to everyone. “By design,” they write, “the trial was focused on people whose folate status was inadequate…. The trial was well designed and unique in its approach of targeting individuals who might benefit from folate supplementation. But how well do the folate intakes of these highly selected trial participants correspond to intakes in more representative samples of the population?” They point out problems with measuring folate intake, as well as our lack of knowledge about what folate and homocysteine levels are optimal, and call for more randomized clinical trials.

Risks of Folic Acid Supplementation for Older Adults

So, the benefit of folic acid supplementation for dementia is unclear, and some studies show a link with increased cognitive decline. Are there other risks involved?

The U.S. National Institutes of Health warns in its folate fact sheet “Beware of the interaction between vitamin B12 and folic acid:”

Intake of supplemental folic acid should not exceed 1,000 micrograms (μg) per day to prevent folic acid from triggering symptoms of vitamin B12 deficiency. Folic acid supplements can correct the anemia associated with vitamin B12 deficiency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Permanent nerve damage can occur if vitamin B12 deficiency is not treated.

It is very important for older adults to be aware of the relationship between folic acid and vitamin B12 because they are at greater risk of having a vitamin B12 deficiency. If you are 50 years of age or older, ask your physician to check your B12 status before you take a supplement that contains folic acid. If you are taking a supplement containing folic acid, read the label to make sure it also contains B12 or speak with a physician about the need for a B12 supplement.

Many of us don’t know how much folic acid we get. Because low levels of folic acid are associated with certain birth defects, in the U.S., Canada and some other countries, folic acid is added to flour, breads and other grain products. “With the folic acid fortification program that was instituted in 1998, folate insufficiency is a rare occurrence in the U.S.,” says Dr. Morris. In addition, anyone taking a multivitamin is likely to be getting folic acid - mine contains 400 micrograms, the recommended dietary allowance for folate in the U.S.

So, what does all this mean for DASN members and anyone worried about brain health? It’s been hard to prove that folic acid or any supplement can prevent or treat Alzheimer’s and other dementias, but exercise may be helpful.

“So far, food sources of vitamin E and other antioxidant nutrients look promising for the prevention of dementia,” says Dr. Morris. But, she says, “there is little evidence to support protective benefit through vitamin supplement sources, except perhaps if one is deficient in dietary intake of certain nutrients. There are also a number of animal and observational studies that have shown that fish and n-3 fatty acids are protective against dementia. Verification of these relations through randomized clinical trials is needed before we can confidently recommend dietary intake of these foods and nutrients for dementia prevention.”

Laura Middleton points to the benefits of exercise instead of supplements. “In our studies to date, we have found that exercise not only delays dementia but can also slow the progression and increase the chances of improving even after you have been diagnosed with Alzheimer's disease,” she says. “It is never too late to start exercising. As little as walking three times a week can significantly reduce your risk of Alzheimer's disease and can slow or even pause cognitive decline.”

Comments

You can follow this conversation by subscribing to the comment feed for this post.

First, I like the new format with a leading summary. Very helpful!
This post caught my eye in particular because negotiating my mother's folic acid intake is of concern for me. The cheapest way to get the iron supplement most helpful to her is through prescription. The only form available through prescription is loaded with folic acid! So, in order to control costs AND attempt to control her folic acid level (which her doctor checks fairly frequently), I buy both the Rx and OTC versions and alternate them per dose. In the meantime, the more I read about folic acid, the more confused I become. In addition, because she has anemia due to chronic disease, her B12 levels are also important!
Thank you for researching this and posting all sides of the issue...this post is a great help to me; I'll be bookmarking it.

Posted by: Gail Rae Hudson | July 27, 2007 at 04:15 PM