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Science Teenager Sharon Moalem suspected his grandfather's Alzheimer's was linked to a buildup of iron in his brain. Years later, he proved it

Sharon Moalem was 15 years old when his beloved grandfather, a Holocaust survivor who lived in Israel, was diagnosed with disease. His grandfather also suffered from a disorder that left reddish-brown splotches on his skin and too much iron in his organs.

The teenager became convinced that the two conditions were somehow linked. Perhaps iron was building up in his grandfather's brain and causing the dementia that made it increasingly difficult to have a conversation with the 71-year-old, who until he got sick had been a regular visitor to Canada.

But no one paid any attention to the young man's suspicions. He spent hours at the library, learning everything he could about Alzheimer's and the hereditary condition called hemochromatosis.

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"He was a sweet loving warm grandfather and that is what drove me to do this," Mr. Moalem says. "Whenever someone is sick, you feel helpless. My way of coping was to go to the library and try to find out what was going on, and try to find something to help him."

His research didn't yield any proof that the two diseases were connected, but it helped him feel as though he was doing something useful as his grandfather slowly drifted away, dying at the age of 76.

By then, Mr. Moalem was doing his undergraduate biology degree at the University of Guelph. After finishing, he took a year off, working at an orphanage in Thailand, but he knew that the next step in his career would include returning to the puzzle of hemochromatosis and Alzheimer's disease.

It was a personal as well as a professional quest. Besides his grandfather, two great uncles died of probable Alzheimer's. There are signs that they also may have suffered from hemochromatosis.

"I looked all over the world for someone who would be receptive to the idea," Mr. Moalem says.

That someone was Maire Percy, a University of Toronto scientist who was already looking at approaches that might slow the progression of Alzheimer's or prevent the disease.

Ms. Percy suspected that metals were involved, and she had proposed looking at hemochromatosis and Alzheimer's a few years earlier. But the genetic mutation that causes the iron-overload disorder had not yet been identified, making it difficult to establish a link between the two diseases.

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By the time Mr. Moalem joined her lab in 1999, the mutation had been found. Ms. Percy says she was enthusiastic about the young researcher's idea of looking to see if a significant number of people with Alzheimer's also had hemochromatosis. She had a freezer full of blood drawn from people with an inherited form of Alzheimer's -- the material that might help him find the answer he was looking for.

Mr. Moalem and Ms. Percy began to screen the samples for the gene that causes hemochromatosis, and they quickly noticed a pattern. He had been right. There was a link.

"I thought I would be really happy, but it kind of made me sad. This is something you don't want to be right on, because it was too late to do anything for my grandfather," Mr. Moalem says. "But I guess it made me happy at the same time, knowing that other people might be spared. ''

Their conclusion wasn't as simple as saying people with hemochromatosis have a much higher risk of getting Alzheimer's. They found that the genes for hemochromatosis increase the risk of Alzheimer's in males if they are paired with another gene called APOE-4, a known risk factor for a neurological disorder that may cause high levels of cholesterol in the brain.

This makes sense, Mr. Moalem says. The theory is that iron reacts with oxygen, producing toxic free radicals that can wreak havoc in the brain and other parts of the body. High cholesterol levels could exacerbate the damage, because the free radicals would feed on the fat.

This time, people paid attention to Mr. Moalem, who was still working on his master's degree. He was invited to international conferences to discuss his discovery. The offers from prestigious universities started arriving -- Harvard, Cambridge, the Massachusetts Institute of Technology -- but he decided to stay at the University of Toronto to continue his work with Ms. Percy.

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It turned out that labs in Italy and the United States had also been investigating hemochromatosis and Alzheimer's. Mr. Moalem's findings involved a relatively rare inherited form of Alzheimer's disease -- about 5 to 10 per cent of all cases. But other researchers established the same link in the more common form. An Italian team has found that having two copies of the hemochromatosis gene, one from each parent, can lower the age of the onset of Alzheimer's by five years.

There is other evidence of the link. Researchers have found iron in the plaques taken from the brains of patients with Alzheimer's. In 1991, a U of T study found that a drug that absorbed iron and aluminum in the brain slowed down the disease's progress. This month, a study suggested that a drug, clioquinol, which removes extra metals in mice with a disease similar to Alzheimer's, improves the condition of humans with the disease.

Today, at 30, Mr. Moalem is still a student. He has his PhD, but has deferred his first year of medical school to continue his research.

He recently noticed the telltale splotches of hemochromatosis on his own arms and legs. "I asked my mom, and she said it is exactly like what my grandfather had."

Yet he is not depressed about his inheritance, even though it may eventually strip him of his memories. He believes that the genes that make him susceptible to Alzheimer's are the reason he is here today. "Overall, it is probably a good thing," he says.

How could it be a good thing to have genes that may predispose you to Alzheimer's? That is the question Mr. Moalem began asking after he first established a link between it and hemochromatosis.

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"It was an enigma. Thirty per cent of Europeans have one copy [of the hemochromatosis gene] That doesn't make any sense. It is the most common genetic mutation from people from that region and nowhere else. We couldn't figure it out. Then, you have that flash: It must be protective against something.''

He did some biological sleuthing.

The first clue came from geneticists, who suggested that the gene emerged 60 to 70 generations ago, around 600 to 1100 AD. During that period, the bubonic plague, also known as the Black Death, was ravaging Europe. In the 14th century, a third of the population succumbed.

Mr. Moalem's theory is that the gene for hemochromatosis somehow protected people from the Black Death and other bacterial infections, including typhoid fever and tuberculosis. The key is iron. Bacteria love iron. They need it to fuel their invasive lifestyles.

Since people with hemochromatosis have excess iron, it would seem they would be more vulnerable to infection. Yet they aren't. It turns out that people with the disorder have extra iron in every cell but their macrophages, the front-line soldiers of the immune system that gobble up invading bacteria.

Particularly wily bacteria actually use macrophages as places to hide out. They can act as Trojan horses, carrying bacteria back to lymph nodes, from where it can more easily mount a full-scale invasion of the body. But the macrophages of people with hemochromatosis are a dead end. They don't have enough iron for plague bacteria to survive.

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This meant that people with even one copy of the hemochromatosis gene had a much better chance of surviving the Black Death, because half their macrophages wouldn't have carried enough iron for the bacteria to survive.

The plague survivors passed the mutation on to their children. In one generation, the gene became dramatically more prevalent, and those who carry it today are the descendents of survivors. This explains why some of the regions that have the highest prevalence of the hemochromatosis gene, Northern Europe, Belgium, England and France, had the highest mortality rates from the Black Death.

Mr. Moalem's theory is being tested in a U.S. lab where researchers have bred animals with a gene similar to the one that causes hemochromatosis. The animals are being infected with the bacteria that causes bubonic plague. If they are resistant, it will be a piece of evidence that the scientist is right to believe that hemochromatosis has a good and a bad side.

His work is already being seen as a significant development in the field of evolutionary medicine, which involves understanding how genes that were helpful thousands of years ago may cause disease in our modern age. The field provides a fascinating insight into the dual nature of genes, their power to heal as well as to hurt.

In Mr. Moalem's case, it means that he embraces his genetic heritage. "I feel like I'm a living history," he says. "All my ancestors are all in me, and everything that they've gone through. I feel like I'm a product of all their trials and tribulations. Even if I could change things genetically, I wouldn't. There is a reason for how I am. The things that on the surface that may seem negative ultimately might be the most positive things."

His work also raises questions about what kind of screening should be done for Alzheimer's disease. If you knew you carried the hemochromatosis gene, you could take steps to reduce your intake of iron and other metals.

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For example, Mr. Moalem eats a vegetarian diet and regularly donates blood, getting rid of cells overloaded with iron. "With hemochromatosis, relatively modest lifestyle changes can make a difference," he says.

In Ontario, people can be screened for the hemochromatosis gene only if they have elevated levels of iron in their blood, Ms. Percy says. Knowing you have the gene might make it difficult to get private health or life insurance. As well, more than one mutation probably causes hemochromatosis, which means people could still be at risk even if they don't have the mutation targeted in the existing test.

The work of Mr. Moalem and Ms. Percy is part of an approach to Alzheimer's emerging in a scientific community that for years has been fixated on understanding the genetics behind the formation of plaques and tangles linked to the disease. Remi Quirion, scientific director of the neuroscience institute at the Canadian Institutes of Health Research, says a growing number of scientists are concluding that Alzheimer's disease is a syndrome, with many different causes.

Judes Poirier, a researcher at McGill University in Montreal, is an expert on the cholesterol transport gene, APOE-4, that has been linked to Alzheimer's in a far more concrete way than the hemochromatosis gene. He believes that cholesterol, which the brain makes itself and needs to repair damage, is the key to understanding the root cause of the disease.

His theory, supported by growing evidence, is that Alzheimer's patients either have trouble making cholesterol in the brain, or have trouble getting deliveries of the stuff from other parts of the body. Perhaps too much is being dumped in the wrong parts of the brain.

Mr. Poirier argues there is probably a central mechanism involved in Alzheimer's. But there are different ways to trigger it, much like with cancer. Whether you get the disease depends on the combination of your genes and environment.

One of those genes -- and there may turn out be dozens -- appears to be the gene for hemochromatosis. Fifteen-year-old Sharon Moalem had been right from the start.

Anne McIlroy is The Globe and Mail's science reporter.

Tale of two afflictions

Hemochromatosis is the most common of any genetic disease yet identified. Some studies estimate that more than 40 per cent of people of European descent carry at least one copy of the genetic mutation related to the condition, which means that they inherited it from either their mother or their father.

People with one copy probably have extra iron in their systems, but no visible symptoms. People with two copies of the mutation, which means they got a copy from both parents, can store enough excess iron to damage their liver, pancreas, heart, spleen, joints and, it now appears, their brains.

In the past, many people with hemochromatosis didn't live past their 40s or 50s, but improved treatment, including drugs that remove iron from their systems, means that many live to an old age.

Women in their reproductive years are much less affected, because they lose iron every month when they menstruate. Men who regularly give blood also do better. But like many genetic diseases, hemochromatosis can vary dramatically from person to person. Some people can have two copies of the mutation and may not experience any symptoms. Others can be seriously ill.

Alzheimer's disease is even more complicated. Researchers don't know what causes it, but they know it results in physical changes to the brain. Brain cells shrink or disappear and are replaced with dense plaques made of proteins and other compounds. Thread-like tangles appear that choke healthy neurons.

Researchers have focused on trying to find the genes linked to these plaques and tangles, believing that they hold the key to understanding a disease that affects an estimated 238,000 Canadians over 65.

Inflammation in the brain plays a role. Researchers also believe that genes involved in transporting cholesterol are part of the picture.

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