The Tangled Neuron

Grand Rounds 3:45

...is up at Health Business Blog. The site is an interesting window into the business side of health and medicine.

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.”

Dr. Rudolph Tanzi's Talk on Alzheimer's Genetics and Treatments

Summary: Genetic variations linked with Alzheimer’s provide clues on potential treatments. Many drugs currently in trials are based on these clues.

With advances in technology, software and the Human Genome Database, Dr. Rudolph Tanzi is optimistic about the future for personalized medicine, where prevention and treatments could be tailored to a person’s specific genetic profile.

Because an estimated 70 percent of Alzheimer’s genetics is still unknown, researchers have a lot of work to do before this vision can be realized.

Scientists study genetic variations and how they are linked with pathologies and symptoms to determine who is at risk for developing diseases. But there’s another important reason they study genetic variations: to look for clues about potential treatments.

To understand why genes might hold clues about treatments, it helps to know that genes contain the blueprints for making proteins, which carry out most of the functions of a cell. If one or more of the thousands of proteins working in a cell is missing or malfunctioning, disease can result. So studying the genes associated with Alzheimer’s disease may lead to a better understanding of the proteins those genes encode, and how they might go awry. These proteins are then “targets” for potential treatments – by manipulating them, we may be able to treat or even prevent Alzheimer’s.

This search for potential Alzheimer’s treatments through the study of genes was the focus of Dr. Rudolph Tanzi’s keynote speech at the Alzheimer’s Association Wisconsin Annual State Conference in May. Dr. Tanzi is Professor of Neurology at Harvard University, and the author of Decoding Darkness. He also runs the Genetics and Aging Research Unit at Massachusetts General Hospital.

Rudolph Tanzi, Ph.D. (center) with conference attendees Cambria Anderson and Chuck Jackson

Dr. Tanzi’s Brief History of Alzheimer’s Gene Research

In the early 1980’s, Dr. Tanzi says, he was working with Dr. James Gusella who discovered the Huntington Disease gene. Dr. Tanzi was inspired to try to accomplish the same thing with Alzheimer’s; eventually his lab would be involved with the discovery of all three of the early onset familial Alzheimer’s genes.

In the mid-1980’s, two different teams of researchers found that the plaques in Alzheimer’s brains are made up of a protein called beta amyloid. One of the researchers, George Glenner, found that the plaques in Alzheimer’s are similar to those in Down Syndrome. “Because people with Down Syndrome have three (instead of the usual two) copies of Chromosome 21, Glenner predicted that beta amyloid was made from a gene found on Chromosome 21,” says Dr. Tanzi.

A few years later, researchers did in fact find a gene called amyloid precursor protein (APP) on Chromosome 21. “APP is a long protein, and when it gets cut apart, it results in beta amyloid,” Dr. Tanzi explains. Later research linked variants of APP to early onset Alzheimer’s disease.

By the mid-1990’s, two more gene variants, called presenilin 1 (PSEN1) and presenilin 2 (PSEN2) had also been linked to early onset Alzheimer’s disease. The PSEN genes are related to the presenilin enzymes [proteins] that cut APP to make beta amyloid.

With these discoveries, scientists knew that variations in three genes were linked to inherited or familial early onset Alzheimer’s disease. But even these genes don’t account for all familial early onset Alzheimer’s. Twenty-one mutations have been identified in the APP gene, accounting for seven percent of familial Alzheimer’s. One hundred sixty-five mutations in PSEN1 account for about 40%, and eleven mutations in PSEN2 account for three percent. This means that rare variations in these three genes account for only about 50 percent of familial early onset Alzheimer’s.

For late onset Alzheimer’s, variations in one gene is a confirmed risk factor. “As you probably know, the APOE4 variant increases the risk of developing Alzheimer’s,” Dr. Tanzi says. “About ten percent of the population carries two alleles or copies, which is associated with a tenfold increase in risk. Another 20 percent carry one allele, which brings threefold increase. About 75 percent of us carry the APOE3 variant, which is neutral with regards to risk of Alzheimer’s, and about two percent have the APOE2 variant, which in combination with APOE3 decreases the risk.”

What Alzheimer’s Genes Tell Us About Treatments

“All four genes point to excessive accumulation of beta amyloid peptides [proteins] in the brain as a common event,” Dr. Tanzi says. “Either you produce too much, and this may be early onset, or you clear too little, which may be the case with late onset. Normally, beta amyloid is produced by the brain and eight minutes later, cleared out. APOE variants affect how rapidly you can clear it out.”

But does this accumulation of beta amyloid really cause Alzheimer’s? “You will have heard that the amyloid hypothesis might not be correct,” says Dr. Tanzi. “The problem is that plaques are end-game stuff. You have to back up to where a single beta amyloid peptide is made. At that point, it’s neutral. But if it binds with zinc or copper, it forms assemblies called oligomers. These assemblies lodge in the synapses, and cause short-circuits in synaptic function. It looks more and more like this is what causes the problem. If the oligomers clump together, you get plaques. Maybe way before the plaques, oligomers cause cognitive problems. In the end, Alzheimer’s is a disease of the synapses. It’s really the loss of connections between nerve cells that causes problems.” This view is the basis for drugs under development by his company, Prana Biotechnology.

According to Dr. Tanzi, most drugs currently in trials are based on newer discoveries linked to APP, PSEN1 and PSEN2. Here’s his rundown of some of the treatments being tested:

Vaccines - This approach traps beta amyloid in the blood using antibodies. A new approach, passive immunization, involves making antibodies in lab. Vaccines are being tested in Phase 2 trials.

M1 Muscarinic Agonists - “First, you need to know that you can’t remove beta amyloid intact, but a ‘good’ enzyme – alpha secretase – cuts beta amyloid in half.” Dr. Tanzi says. M1 muscarinic agonists work to activate alpha secretase.

Gamma and Beta Secretase Inhibitors - “There are also ‘bad’ enzymes – beta and gamma secretases – that release beta amyloid. Developing gamma and beta secretase inhibitors is a huge industry. The problem is that both of these enzymes have to clip other proteins too. Gamma secretase can make two forms of beta amyloid – either AB40, which may have a normal role, or AB42, which is more likely to form oligomers. Now there are gamma secretase modulators that instead of eliminating the enzyme, tweak it to produce more AB40 than AB42. But a great concern is that in trials, this has caused problems with microhemorrhages.”

Substances That Reduce the Trace Metals [Zinc and Copper] Needed to Form Oligomers - Dr. Tanzi’s company is working to develop a Metal-Protein Attenuating Compound (MPAC) based on this approach. “It’s not a chelator, because you need metals for other things,” he says. “It just prevents oligomers from forming. One candidate, Clioquinol, showed a 50 percent reduction in beta amyloid in mice, but there were problems with a contaminant,” he says. “PBT2, a second generation MPAC, reduces beta amyloid levels, rescues communication among nerve cells, and improves mouse cognition after five days of treatment. It’s now being tested in Alzheimer’s patients in Sweden”

According to Dr. Tanzi, other possible approaches include:

*increasing blood flow to the brain which turns on the gene for an enzyme called neprolysin, which degrades beta amyloid. It’s not clear whether this can be done safely.

*preventing hypoxia, or lack of oxygen, to regulate beta secretase activity.

*ACAT inhibitors (his wife’s research) – these cardiovascular drugs lower beta amyloid levels, and can be administered nasally.

There’s a lot of work to do. Dr. Tanzi estimates 80 percent of all cases of Alzheimer’s are inherited, but 70 percent of Alzheimer’s disease genetics are unknown. He heads up an initiative called the Alzheimer’s Genome Project, which is working towards identifying that elusive 70 percent.

“We’re seeing the next wave of genetics,” he says. “There have been huge advances the last two years in technology, software and the Human Genome Database. The ultimate goal is to target drugs to your specific genes that put you at risk. This is called pharmakinetics, pharmagenetics or personalized medicine.”

One obstacle to progress, at least in the U.S., is the fear that genetic information could be used to deny employment or insurance. Because of this, an important first step towards preventative medicine in the U.S. is to pass the Genetic Information Nondiscrimination Act, and to add long term care insurance to the bill.

“By 2050,” says Dr. Tanzi, “we will not wait for life-threatening illness to strike.” That seems like a long way off. In the meantime, let’s hope he and other researchers identify new genetic variations linked to Alzheimer’s, and that these discoveries lead to effective treatments.

Grand Rounds Is Up

...at Aetiology. Under the Research and Findings heading, there is a link to an interesting piece about hormones and cognition.

Gail Rae Hudson's Comments on Dementia Caregivers Share Their Stories

A couple of posts ago, I wrote about a book I really like - Dementia Caregivers Share Their Stories: A Support Group In A Book - and about meeting Lynda Markut, one of the authors. Over at The Mom and Me Journals, Gail Rae Hudson has also been reading the book - one or two more bloggers and we'll have an online book club! You can check out her comments here and here.

Early Memory Loss Forum

In late October, I’ll be going out to Los Angeles to attend a one-day symposium for people with early memory loss. The symposium, called “Living Our Lives, Planning Our Futures” will feature talks by David Shenk, the author of The Forgetting, and Dr. Gary Small, Director of the UCLA Center on Aging and author of several books on improving memory and brain health. The event is hosted by the Alzheimer’s Association California Southland Chapter, in cooperation with the University of Southern California (UCLA) and the UCLA Alzheimer’s Research Center.

The real meat of the program will be the eight breakout sessions on topics such as “Communications and Relationships,” “Stimulating the Brain,” and “Re-defining Early Stage Dementia.” Persons with early memory loss or dementia will be on session panels, and audience participation is encouraged.

The event is the brainchild of Rich Bozanich and Jay Smith, both of whom have been diagnosed with early onset Alzheimer’s disease. Rich, a former journalist, and Jay, a former architect, met in a support group in southern California. When the New York chapter of the Alzheimer’s Association put on a conference for people with early memory loss, both men were intrigued. They decided to develop a similar conference in LA, and the local chapter agreed to help.

Rich Bozanich (left) and Jay Smith
photo courtesy of James Smith

Now co-chairs of the symposium, Rich and Jay have worked for over a year to develop the event to meet the specific needs of persons with early memory loss, mild cognitive impairment and early-stage dementia. They chose the breakout session topics based on the results of a survey they sent out to members of various support groups.

“We have people planning to attend from New York, Colorado, Minnesota, Oregon, Hawaii, British Columbia, and Washington, D.C., among other places,” Rich says. He expects attendees will be a mix of persons with early memory loss, care partners and professionals.

Rather than the typical format - educational sessions for care partners and “day care” for persons with memory loss - all attendees will be welcome at all sessions. Jay and Rich hope that care partners and professionals will learn from the panelists and attendees who have memory loss.

The idea of services and support for persons with memory loss by persons with memory loss seems to be an emerging trend. Two online support groups, DASN International and DementiaUSA are run by persons with dementia. Another group, forMemory, is being organized to share information about treatments for early onset Alzheimer’s and related diseases. After all, who knows best what people with memory loss need?

The Early Memory Loss Forum will be held on October 27, 2007 at the Skirball Cultural Center in Los Angeles. For more information, please call 323-900-3180 or email earlystageforum@alzlarsb.org.