In a just-published article, statnews.com science writer, Sharon Begley, reviews the history of failure of Alzheimer's drugs in clinical trials. The latest casualty, a drug called LMTX that targets a prion-like protein, called tau, bitterly disappointed the research community. In a 2012 blog I wrote for CTV.ca, I reviewed the pathology of Alzheimer's Disease (AD), discussed the controversy surrounding the relevance of tau and  another prion-like protein, beta-amyloid, and reported on exciting rodent research showing that tau spreads through the central nervous system like an infection, affecting the same brain memory centres in mice that are involved in humans with AD . Commenting on the study, one expert suggested that, to be effective, treatment for Alzheimer's must target both tau and beta-amyloid. Although a drug called PBT2 that I mentioned at the end of my article also subsequently failed in a phase 3 study, I remain hopeful that just-announced trials of  nilotinib (Tasigna), already in clinical use for the treatment of chronic myeloid leukemia, may turn the corner on both Parkinson's and Alzheimer's therapy. Time will tell...

New discoveries raise hope for more effective Alzheimer's treatment
by Dr. Lorne Brandes  February 15, 2012 
 
"The ‘Big C’ has to be the worst of all diseases,” many people comment when they learn than I am an oncologist.
My answer often surprises them: “I would rather take my chances with cancer than be diagnosed with Alzheimer’s.”
My reasoning? A diagnosis of early cancer still leaves lots of room for hope; our treatments are increasingly effective and commonly lead to complete recovery. Even in its advanced, incurable stages, many cancers can be palliated for months or, in some cases, years. Even at the end of the road, the mind usually remains intact, allowing people to reminisce about the good times, mend broken fences, and say their final goodbyes to friends and loved ones.
Alzheimer’s dementia (AD) is quite another story. Since it was first described in 1906 by Dr. Alois Alzheimer, a German psychiatrist and neuropathologist, this ever-increasing degenerative brain disease has remained poorly understood. Despite the recent availability of drugs, such as donepezil (Aricept), that can sometimes slow down early AD for a few months, there remains no effective treatment to prevent its relentless progression.
As a result, to be diagnosed with Alzheimer’s, even at an early stage, currently leaves little, if any, room for optimism or hope. What can be worse than the uncomprehending, blank stare of a previously vital human being whose memories of people, places and events have been progressively erased over a relatively short time?
But now, two newly-published papers suggest that we may be closer than previously believed to understanding what goes wrong in the brains of Alzheimer’s patients. As a result, we now have promising new leads on how to stop the disease in its tracks. Indeed, one novel therapy, based on a concept reported in one of the papers, has already shown promise in an early (phase 2) clinical trial, with a follow-up study now underway.
To understand these new discoveries, let us first review what is known about two abnormal structures, called plaques and tangles, observed under the microscope in brain tissue of patients with AD.
Plaques (also called “senile plaques”) are made up of clumps of a structurally abnormal (misfolded) protein, called beta amyloid. Thin fibres of this substance first accumulate around nerve cells in a vital memory area of the brain, called the entorhinal cortex.
Eventually, smaller, soluble beta amyloid molecules, called “ toxic oligomers”, break away from the plaques. This dissolvable form of beta amyloid is thought to interfere with chemicals (called neurotransmitters) through which the brain sends out signals over nerve networks.
Beta amyloid is derived from “ amyloid precursor protein” (APP), made by a gene on chromosome no. 21. Why is this important to know? Because patients with Down syndrome, resulting from an extra chromosome 21, all develop AD if they live long enough. That is probably the most persuasive reason for linking AD with an abnormal buildup of beta amyloid in the brain.
Tangles (also called “ neurofibrillary tangles”) form the second piece of the Alzheimer puzzle. We now know that, like plaques, thin spaghetti-like tangles are also made up of clumps of an abnormally folded protein, in this case, a substance called “tau”.
Whereas beta amyloid plaques accumulate outside nerve cells, toxic amounts of tau accumulate inside, where they disrupt a tubular canal system (called microtubules) that serve as conduits for vital nutrients and chemicals that help nerve cells function and remain healthy. In addition, tau also increases the toxic effects of a second cell-damaging protein, called alpha (α)-synuclein , implicated in many neurodegenerative diseases, including AD, Parkinson’s and multiple sclerosis.
While recent studies suggest that beta amyloid drives the formation of tau, a fierce debate continues over whether either of these misfolded proteins actually cause the disease.
Indeed, leading Alzheimer researcher, Dr. Rudy Castellani, believes that the beta amyloid hypothesis is “deeply flawed and certainly unproven.” He, and others, have suggested that beta amyloid is irrelevant, simply part of the flotsam and jetsam resulting from cell damage caused by some yet undiscovered cause.
Calling for a fresh start, Castellani says , “I think we have to throw the kitchen sink at the problem. Everything should be on the table, including a poly-therapy approach that encompasses multiple constructs and hypotheses.” But, although his discouragement over the lack of progress is understandable, the two new studies, to which I alluded earlier, give fresh insight into why both beta amyloid and tau may be important factors in AD.
The first , led by scientists Karen Duff and Scott Small of New York’s Columbia University, used mice that were genetically-engineered to specifically produce abnormal human tau protein in cells in the entorhinal cortex. Over a period of several months, the aberrant tau protein was found to spread “ like an infection” along nerve networks connecting the entorhinal cortex to other memory centres of the brain, a process that closely mimics the progression of AD in humans.
Prior to this experiment, doctors wondered if AD starts in the entorhinal cortex because its cells are somehow the most vulnerable to beta amyloid damage. According to this hypothesis, the disease eventually affects memory cells in other “bad neighborhoods” in the brain where beta amyloid deposits occur.
But now, says Alzheimer expert, Dr. John Hardy of London’s University College, “with the [new] mouse studies, the issue of a bad neighborhood is settled….It isn’t a bad neighborhood. It is contagion from one neuron to another…[and] if tau spreads from neuron to neuron, it may be necessary to block both beta amyloid production, which seems to get the disease going, and the spread of tau, which continues it, to bring Alzheimer’s to a halt.”
One way to prevent the spread of tau is to develop a specific antibody that, by latching on to the abnormal protein, arms the immune system to remove it; another is to identify membrane-blocking drugs that prevent tau from leaving cells so that it can not travel along nerve networks.
As for blocking beta amyloid, therapies that reduce its level in the brain have been, so far, unsuccessful in reversing dementia, a fact duly noted by Dr. Castellani and other critics of the beta amyloid hypothesis.
However, skepticism about the value of attacking beta amyloid may be about to change as a result of the second new study, published by a research team led by Dr. Susan Lindquist of the Whitehead Institute for Biomedical Research in Cambridge, MA. Lindquist’s group is interested in trace metals, such as iron, copper and zinc, that are required by enzymes and neurotransmitters to function normally. They have identified a family of compounds, called 8-hydroxyquinolines (8-OHQ), that protect yeast cells from TDP-43, a metal-binding neurotoxic protein implicated in amyotrophic lateral sclerosis (ALS) that appears to behave like beta amyloid.
One 8-OHQ derivative mentioned in Lindquist’s study is PBT2, an AD drug currently being tested by Prana Biotechnology, a small Australian drug company. According to Prana, PBT2 specifically blocks the ability of soluble beta amyloid to tie up copper and zinc in the small spaces (called synapses) between nerve endings, an effect they believe explains the significant improvement in cognitive function observed in an earlier phase 2 study.
“Unlike other [beta amyloid] strategies, we target the initial disease progression steps that result in A‐beta becoming toxic, [that] being the interaction with metals in the brain… PBT2 targets these metals, restoring neuronal function to treat the disease,” the company states.
Now, with a new trial of PBT2 finally underway, that hypothesis will be put to the test. Needless to say, the study and its outcome will be followed with great interest. 

For some years, scientists have argued over whether a chemical, called 4-methylimidazole (4-MI), that gives colas their characteristic caramel color, poses a cancer risk to humans. The latest example is a study, published in 2015 by researchers at Johns Hopkins in conjunction with US Consumer Reports, that called for action to reduce the amount of 4-MI in various soft drinks. Once more there was a swift rebuttal from industry; moreover, the FDA, which has been studying 4-MI for several years, does not believe that there is yet enough scientific evidence on which to act, so the argument continues to go round and round. Here is an examination of the issue that I posted on CTV.ca/health in 2011.

​Does the colour in cola cause cancer? A reality check
by Dr. Lorne Brandes  February 23, 2011 
​
First, I must make the following disclosure: I can’t remember the last time I drank a Coke, Pepsi or any other brand of cola. If it had to depend on me, the soft-drink industry would not exist.
Second, I must share a fond, but quirky, memory with you. Back in my medical school days, I had a wonderful professor of dermatology, the late Dr. William (Bill) Pace, who introduced my wife and me to his favorite dessert, a delicacy his family unappetizingly dubbed “boiled can”.
Its name was derived, literally, from boiling a small unopened can of Carnation condensed milk in a pot of water for a precise number of minutes. After cooling the can to room temperature, the lid was opened and the container overturned on a plate. Out plopped a light brown-coloured pudding with an out-of-this-world taste.
“Boiling turns the sugar in the milk to caramel, but you mustn’t overboil it or the whole thing will turn dark and bitter,” Bill explained.
Such was my unexpected introduction to the process of caramelization, a chemical reaction that results when various types of sugar (fructose and glucose, for example) are heated to form caramel, the substance that imparts its distinctive, pleasantly sweet flavour to a wide assortment of food, candy and beverages.
In addition, caramel adds colour, ranging from gold to brown, to a wide range of products, from colas to Worcestershire sauce, coffee, wine and baked goods. However, to meet the many different uses of caramel by the food industry, its properties are manipulated by heating sugars with chemical additives, such as ammonia and sulfite, to form what are called “E150 caramels”.
For example, colas require negatively-charged caramel molecules, generated when ammonia is added to the sugar; otherwise, if positively charged, the caramel would react with phosphoric acid (the substance that gives colas their “tang”) and precipitate out of solution, resulting in a loss of the brown colour.
However, heating sugar in the presence of ammonia generates many other compounds in addition to caramel; among them are by-products called “methylimidazoles”.
Rodent studies carried out in 2008 by scientists at the U.S. Government’s National Institute of Environmental Health Sciences revealed that a two-year exposure to increasing concentrations of 4-methylimidazole (4-MI), present in colas, caused a significant increase in a type of lung cancer, called alveolar/bronchiolar carcinoma, in both male and female mice, but not in rats. There was a non-significant trend towards an increase in a type of leukemia in female rats, but no evidence of carcinogenicity in male rats.
Based on these findings, in 2009 the state of California posted its intention to list 4-MI as a carcinogen under the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65).
Now, following California’s lead, a Washington, DC organization, called the Center for Science in the Public Interest (CSPI), has just petitioned the Food and Drug Administration (FDA) to “revoke regulations authorizing the use [of] caramel colorings that are produced by means of an ammonia or ammonia-sulfite process and contain 2-methylimidazole and 4-methylimidazole, both of which are carcinogenic in animal studies.”
"If consumers want another reason to avoid soda pop, this is a good one. It makes no sense to leave these in the food supply," the group's Executive Director, Michael F. Jacobson, commented.
The response from the beverage industry was swift: "The safety of our products is the foremost priority for our companies. Consumers can take confidence in the fact that people have been safely drinking colas for more than a century, as well as consuming the wide variety of foods and beverages containing 4-MI, from baked goods and breads to wine and coffee. 4-MI is found in trace amounts in a wide variety of foods and beverages, including Coca-Cola. In fact, it forms normally in the 'browning reaction' while cooking, even in one's own kitchen."
As for the FDA, in answer to an inquiry about the CSPI petition from a blog site called Consumer Ally, the agency noted that “its assessment [of the data] will dictate what, if any, regulatory action needs to be taken.” According to the website, in making this statement, the FDA acknowledged that 4-MI is on a list of chemicals to be reviewed for carcinogenicity by the World Health Organization’s International Agency for Research on Cancer.
What is the truth here? Clearly, 4-MI, a by-product of caramelization in the presence of ammonia, is a carcinogen in the mouse, but not in the rat. As for humans, who have been “safely drinking colas for more than a century”, who knows? There are no human studies of 4-MI from which to remotely glean an answer.
So, will the FDA act to remove the ammonia/caramel colouring from colas? Don’t bet on it.
The reality is that any cancer danger from non-diet Coke and Pepsi arises far less from their small content of 4-MI than from their astronomically high content of sugar. Published studies show that the daily consumption of sugar-rich soft drinks, colas among them, contribute significantly to the epidemic of obesity in our society. And make no mistake about it, up to half of all cancers, whether in rodents or humans, are directly related to obesity, and may be prevented by staying slim and trim.

Despite the Cancer Moonshot initiative spearheaded by VP Joe Biden, there is still no shortage of people who believe that a cure for cancer has already been found but is being suppressed by the multi-billion dollar "Cancer Industry". When it comes to the conspiracy theorists, nothing seems to change their minds...witness a blog I posted for CTV.ca/health in 2009.​

​
​Is there a conspiracy to suppress a cure for cancer?
by Dr. Lorne Brandes  November 11, 2009 

Do you remember the movie “Conspiracy Theory”? It was about a New York taxi driver who witnessed life through paranoid-coloured lenses. Except, as it turned out, a government conspiracy to “get him” really was lurking in the wings.
Yet, do not believe for a moment that “conspiracy theorists” are just a Hollywood invention. They also exist in real life. For example, there are people who believe that drug companies don’t want to find a cure for cancer.
As proof, you need look no further than two comments posted online in response to one of my blogs describing the hard realities of cancer drug development.
“Why would the Pharma companies want a cure for cancer? Their bottom line would suffer ... It’s all about money to them…” wrote someone calling himself “Steve in Toronto”.
And he isn’t alone. Linda from the UK added, “….[Steve's] dead right about the pharmaceutical companies. It's a sad state of affairs, but it's true. Money, money, money.”
While most of you may disagree with Steve and Linda, I suspect that more than a few believe, as they do, that curing cancer is not in the financial interest of big pharma or, for that matter, of anyone in the “cancer establishment”, including oncologists such as me.
And quite frankly, it is all too easy to be suspicious of big pharma. Good behaviour is not the drug industry’s strong suit.
Just recently, Pfizer, was slapped with a $2.3 billion fine by the U.S. Justice Department for the fraudulent “off-label” promotion of some of its major drugs. This is the fourth time since 2002 that Pfizer , or one of its subsidiaries, has been fined over illegal marketing practices. As a result, one might be justified in wondering what other deceptions lurk in the shadows of the corporate boardroom.
Drug companies aside, is there a high-level conspiracy to suppress a cancer cure? One only has to surf the internet to see the depth of conviction, even among some notable “experts”, that there is.
For example, the late Dr. Robert Atkins, of high-fat, low-carbohydrate diet fame, was quoted on one website as saying, “There is not one, but many cures for cancer available. But they are all being suppressed by the ACS (American Cancer Society), the NCI (National Cancer Institute) and the major oncology centres. They have too much interest in the status quo.”
Truth be told, at the same time as he was impugning the ACS and NCI, Dr. Atkins was pushing his own “model of cancer treatment” that included his diet, and a variety of unproven or disproven substances such as laetrile, 714-X and essiac.
On the other hand, after examining all the facts, Michael Higgins, an Australian engineer afflicted with cancer, came to a very different conclusion.
“I know there isn't any cancer conspiracy because I know that the people doing and running the research are human,” he wrote. “Their lives, like mine, have been touched by cancer. They, like me, would do anything to save the lives of the people they love. Furthermore, I assume that any treatments associating themselves with a conspiracy theory have something to hide—the simple fact that [they don’t] work.”
But let’s face it. No matter what anyone says, cancer conspiracy advocates will not be swayed from the belief that, to insure their own survival, the “cancer treatment establishment” in general, and the pharmaceutical industry in particular, is not interested in curing cancer.
While I, myself, have strongly criticized the exorbitantly high prices that pharmaceutical companies command for new, often marginally-effective, anti-cancer drugs, and have described their reluctance, for financial reasons, to develop new uses for old drugs that might benefit cancer patients, I do not believe for one minute that they, let alone anyone else in the “establishment”, are suppressing anything.
How can I be so sure?
As the late Michael Higgins so eloquently observed, few have been untouched by this terrible disease. That’s reason in itself.
So if there exists a conspiracy among all those involved, however imperfectly, in the war against cancer, it is simply this: to find the cure. Period.
 

Last October, neuroscientists at Washington's Georgetown University (GU) made headlines with a small study in 12 patients with advanced Parkinson's Disease (PD), including PD with Lewy Body Dementia, eleven of whom responded rather dramatically to a low oral daily dose of the chronic myeloid leukemia drug, nilotinib (Tasigna). When the drug was stopped, the patients' conditions returned to baseline.
Now, in a press release coinciding with publication of that study in the Journal of Parkinson's Disease, the GU investigators have announced the launch of 2 new placebo-controlled phase II trials of nilotinib in patients with PD/Lewy Body Dementia and Alzheimer's Dementia (AD). A small companion study testing nilotinib in patients with amyotrophic lateral sclerosis (ALS) will also be conducted.
As one who has a great deal of interest in the science behind this approach, I am reprinting the GU press release. We all wish for a successful outcome of this potentially ground-breaking therapy!

WASHINGTON (July 11, 2016) — A small phase I study provides molecular evidence that an FDA-approved drug for leukemia significantly increased brain dopamine and reduced toxic proteins linked to disease progression in patients with Parkinson’s disease or dementia with Lewy bodies. Dopamine is the brain chemical (neurotransmitter) lost as a result of death of dopamine-producing neurons in these neurodegenerative diseases.
Researchers from Georgetown University Medical Center (GUMC), say the findings, described in the Journal of Parkinson’s Disease, support improved clinical outcomes observed and first reported at the Society for Neuroscience annual meeting in October 2015.
The study tested nilotinib taken daily for six months. A much smaller dose of nilotinib (150 or 300 mg once daily) was used compared to the dose for chronic myelogenous leukemia (300-400 mg twice daily). Twelve patients were enrolled in the clinical trial — one patient withdrew due to an adverse event. Researchers say the drug appears to be safe and well tolerated in the remaining 11 participants who completed the study.
In addition to safety, the researchers also examined biological markers in the blood and cerebral spinal fluid as well as cognitive, motor and non-motor improvement. They found significant signs that nilotinib may provide benefit for patients with these neurodegenerative diseases.
“These results need to be viewed with caution and further validated in larger placebo controlled trials, because this study was small, the patients were very different from each other, and there was no placebo,” says the study’s senior investigator, Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherpeutics Program.

Among the biomarker findings were that:

(1) The level of the dopamine metabolite homovanillic acid — an indicator that dopamine is being produced — steadily doubled, even with the loss of most dopamine neurons. Most study participants were able to stop using, or reduce their use of, dopamine replacement therapies;
(2) The level of the Parkinson's related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and
(3) The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.
In addition, Moussa adds that it appears nilotinib attenuated the loss of CSF alpha-synuclein, a toxic protein that accumulates within neurons, resulting in reduced CSF levels in both Parkinson’s disease and dementia with Lewy bodies.

The researchers also said that all 11 patients who tolerated the drug reported meaningful clinical improvements. All patients were at mid-advanced stages of Parkinsonism and they all had mild to severe cognitive impairment.
“Patients progressively improved in motor and cognitive functions as long as they were on the drug — despite the decreased use of dopamine replacement therapies in those participants with Parkinson’s and dementia with Lewy bodies,” says the study’s lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherpeutics Program and director of the Movement Disorders Program at MedStar Georgetown University Hospital.
But three months after withdrawal of the drug, participants returned to the same reduced cognitive and motor state they had before the study began, Pagan adds.
Some serious side effects were reported including one patient who withdrew at week four of treatment due to heart attack and three incidents of urinary tract infection or pneumonia. The researchers say these incidents are not uncommon in this patient population, and additional studies are needed to determine if the adverse events are related to use of nilotinib.
“Long term safety of nilotinib is a priority, so it is important that further studies be conducted to determine the safest and most effective dose in Parkinson’s, says Pagan.
The researchers designed the clinical trial to translate several notable observations in the laboratory. The preclinical studies, led by Moussa, showed that nilotinib, a tyrosine kinase inhibitor, effectively penetrates the blood-brain barrier and destroys toxic proteins that build up in Parkinson’s disease and dementia by turning on the “garbage disposal machinery” inside neurons.
Their published studies also showed nilotinib increases the levels of the dopamine neurotransmitter — the chemical lost as a result of neuronal destruction due to toxic protein accumulation — and improves motor and cognitive outcomes in Parkinson’s and Alzheimer’s disease animal models.
“Our hope is to clarify the benefits of nilotinib to patients in a much larger and well controlled study. This was a very promising start,” Moussa says. “If these data hold out in further studies, nilotinib would be the most important treatment for Parkinsonism since the discovery of Levodopa almost 50 years ago.”  
He adds, “Additionally, if we can validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the first treatments for dementia with Lewy bodies, which has no cure, and possibly other dementias.”
Two randomized, placebo-controlled phase II clinical trials are planned for summer/fall in Parkinson’s and Alzheimer’s diseases. The Translational Neurotherpeutics Program is also planning a small trial in ALS (Lou Gherig’s disease).
According to Novartis, the cost (as of Oct. 2015) of nilotinib for the treatment of CML was about $10,360 a month for 800 mg daily. The dose used in this study was lower —  150 and 300 mg daily.
The phase I study received philanthropic funding and was supported by the Georgetown-Howard Universities Center for Clinical and Translational Science.
Moussa is listed as an inventor on a patent application that Georgetown University filed related to the use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases. 

Vitamin supplements continue to be a multi-billion dollar industry despite the fact that multiple large population studies have failed to show any benefit to health in well-nourished individuals. Indeed, people who consume daily high doses of some vitamins may increase their risk of certain cancers. For example, in two separate studies, smokers who took daily beta carotene supplements had a higher risk of developing lung cancer than smokers who did not.  
Another supplement that has been linked to increased cancer risk is folic acid. On the other hand, naturally-occurring folate in food may be beneficial. Here is a CTV.ca/health blog I posted in 2009 that reported on an increased risk of prostate cancer in men who took folic acid supplements.

Folic acid and prostate cancer: Too much of a good thing?
by Dr. Lorne Brandes  March 13, 2009 
 
This week brings yet another cancer study pointing to the potential danger of a vitamin supplement. This time it's folic acid, a synthetic form of folate, one of the essential B-complex vitamins that naturally occurs in green leafy vegetables (the word folate is derived from folium, Latin for "leaf").
In addition to playing a vital role in the production of our cells' DNA, folate is essential for the normal development of the nervous system in the fetus and also for preventing anemia. Short and simple, folate is necessary for life.
Now for the bad news.
In a paper just published in the Journal of the National Cancer Institute, researchers from the University of Southern California studied the development of prostate cancer in 643 men who were randomized to take a daily placebo pill or a daily 1 mg folic acid pill.
Here's the story on CTV.ca: Folic acid linked to higher risk of prostate cancer
Somewhat shockingly, after 10 years of follow-up, those who took folic acid had a prostate cancer rate 2.6 times higher than those who took the placebo!
It should be pointed out that the prostate cancer study was actually an extension of another published study, conducted between 1994 and 2006, called the Aspirin/Folate Polyp Prevention Study (AFPP). That study, published in the Journal of the American Medical Association, found that while aspirin reduced the risk of colon polyps, folic acid appeared to increase the risk of advanced and multiple polyps.
Should we be concerned by these findings? No and yes.
No, because the current study is rather small. As a result, its conclusion that folic acid supplements may be associated with an increased rate of prostate cancer could be due to chance alone. Indeed, blood tests in the two groups of men showed no significant difference in folate levels to account for the observed increase in prostate cancer in men who took folic acid.
Yes, because in the 1940s, Dr. Sidney Farber observed that giving folic acid to children with acute leukemia actually made the disease worse. He reasoned that, since folate increases the production of DNA, it may actually have caused the leukemia cells to divide faster.
Acting on Farber's hunch, his colleague, Dr. Y. Subbarao, Research Director at Lederle Laboratories, soon formulated an anti-folate drug, called methotrexate, that prevents the vitamin from building DNA. The result? Not only was methotrexate the first effective drug treatment for acute leukemia, it is still a mainstay in the treatment of many cancers!
Clearly, then, folate appears to be a double-edged sword: not enough and health suffers; too much and adverse effects, such as increased cell division, possibly resulting in cancer, may result.
The story is also complicated by the fact that folic acid as a supplement may fundamentally differ from natural folate in its biological effects. For example, studies suggest that folate (as opposed to folic acid) may actually protect against stomach and pancreatic cancer.
Yet, because cereals and other grains are now being fortified with folic acid, it is becoming increasingly difficult to separate naturally-occurring folate from the synthetic form in many of the foods we eat. As a result, and because of the studies reported here, I would be concerned that too much fortification could tip the balance from benefit to risk.
That aside, once again the bottom line is this: get your vitamins naturally, in the good food you eat, rather than in a bottle from the health food store. With each new published study comes increasing evidence that, as opposed to a healthy diet rich in fruits and vegetables, most vitamin and mineral supplements do you no additional good and, in some cases, may cause harm.