Shots - Health Blog
1:31 pm
Wed July 11, 2012

Gene Mutation Offers Clue For Drugs To Stave Off Alzheimer's

Originally published on Thu July 12, 2012 2:03 pm

Finally, there's some good news about Alzheimer's disease.

It turns out that a few lucky people carry a genetic mutation that greatly reduces their risk of getting the disease, an Icelandic team reports in the journal Nature.

The mutation also seems to protect people who don't have Alzheimer's disease from the cognitive decline that typically occurs with age.

The mutation is very rare, but its discovery is generating fresh optimism about experimental drugs that act on the same system in the brain.

"I'm very excited by it," says Robert Vassar of Northwestern University, who has spent much of his career studying the process that causes plaques to form in the brains of people with Alzheimer's.

Those plaques are made of a substance called amyloid beta. The mutation discovered by the Icelandic researchers alters a gene that affects production of amyloid beta.

A study of the genomes of about 1,800 Icelanders found that the mutation "confers a very, very strong protection against the disease," says Kari Stefansson, a geneticist at deCODE genetics in Reykjavik and one of the study's authors.

People who had the mutation produced about 40 percent less of the proteins that become amyloid beta plaques, Stefansson says.

Previous genetic studies had found only mutations that increased a person's chance of getting Alzheimer's because they increased production of amyloid beta.

"This current mutation actually reduces amyloid beta production," Vassar says, "and it's protective for Alzheimer's disease."

One reason scientists are excited by the discovery is because of the way the mutation works, he says.

In order to form amyloid beta, the brain has to first cut up a larger molecule. It does this using an enzyme called BACE1.

"BACE 1 is like a pair of molecular scissors and what the mutation does is sort of interfere with the way the molecular scissors can cut," Vassar says. "It sort of dulls the blades."

That's exactly what drug companies are trying to do with experimental drugs known as BACE1 inhibitors. Several of these drugs are now being tried in people, although definitive results are probably years off.

If the experimental drugs do work against Alzheimer's, they might also help older people who don't have the disease, Stefansson says.

Ordinarily, people in their 70s, 80s and 90s have a slow but steady decline in memory and thinking, he says. But the Icelandic researchers found that this happened more slowly in people who carried the mutation.

The finding suggests amyloid beta is involved not only in Alzheimer's disease, Stefansson says, but also in the typical memory and thinking problems associated with aging.

The new study also makes it clear that amyloid beta is the key to finding a treatment for Alzheimer's, according to Rudolph Tanzi of Harvard Medical School and Massachusetts General Hospital, a researcher who helped discover the gene studied by the Icelandic team.

Tanzi says Alzheimer's researchers and drug companies need to attack amyloid beta with the same determination that heart disease experts began attacking cholesterol several decades ago.

"We've got to have that same focus with Alzheimer's disease, and I'm hoping that this paper will galvanize us to say, 'OK, this is our target,' " Tanzi says.

Most researchers agree. But some still think amyloid isn't the whole story. They point out that so far, no drug that targets amyloid has managed to slow down Alzheimer's.

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Transcript

MELISSA BLOCK, BYLINE: And now some promising news in the fight against Alzheimer's disease. Researchers in Iceland have discovered a genetic mutation that protects people from the disease. The mutation is very rare, but as NPR's Jon Hamilton reports, this discovery is generating fresh optimism about experimental drugs that act on the same system in the brain.

JON HAMILTON, BYLINE: For decades, researchers have been struggling to understand a gene that's involved in Alzheimer's. The gene affects production of amyloid beta, which forms plaques in the brains of people with the disease.

Robert Vassar of Northwestern University has spent much of his career studying the process that leads to these amyloid plaques. He says his work took on a new urgency in the 1990s when his mother was diagnosed with Alzheimer's.

ROBERT VASSAR: I think she was 61 when she got the disease and then, you know, the course took about 12 years and then she finally passed, so it's one reason why I'm very interested in this disease and I want to see it cured.

HAMILTON: Vassar says the new mutation, described in the online edition of the journal Nature, represents an important step toward that goal.

VASSAR: Well, I was very excited by it.

HAMILTON: Excited because previous genetic studies had found only mutations that increased a person's chance of getting Alzheimer's by increasing production of amyloid beta, often called A beta.

VASSAR: Now, with this current mutation, that mutation actually reduces A beta production and it's protective for Alzheimer's disease.

HAMILTON: Vassar says he's also excited because of the way the mutation works. In order to form amyloid beta, the brain has to first cut up a larger molecule. Vassar says it does this using an enzyme called BACE 1.

VASSAR: BACE 1 is like a pair of molecular scissors and what the mutation does is sort of interfere with the way the molecular scissors can cut. It sort of, like, dulls the blades.

HAMILTON: And that's exactly what drug companies are hoping to do with several experimental drugs. They're trying to see if a drug can also reduce the number of larger molecules being cut up so that amyloid plaques are less likely to form. Vassar says a drug like that might have helped his mother.

VASSAR: I would have hoped to have caught her by the age of 50 and then put her on a drug right then and there that would slow the production of the beta amyloid or help clear the beta amyloid out of the brain.

HAMILTON: The Icelandic scientists who discovered the new mutation are also pretty pumped up about it.

KARI STEFANSSON: It's always a thrill to make a discovery like this. It is almost as good as chocolate.

HAMILTON: Kari Stefansson is a geneticist with the company, deCODE genetics in Reykjavik. He says the study of nearly 1,800 Icelanders found that those carrying the mutation produced 40 percent less of the substances that form amyloid plaques in the brain. And Stefansson says his team learned something else by studying cognition in thousands of elderly people who did not have Alzheimer's.

STEFANSSON: If you look at people between the ages of 80 and 100 years of age, you will see a slow but steady decline in cognition. What we did was that we showed that this mutation slows down this decline.

HAMILTON: That suggests amyloid beta is involved not only in Alzheimer's disease, but also in the typical memory and thinking problems associated with aging.

Rudolph Tanzi at Mass General Hospital helped discover the Alzheimer's-related gene studied by the Icelandic team. He says the new finding makes it clear that amyloid beta is the problem and that the solution will be drugs that reduce amyloid.

RUDOLPH TANZI: We knew, in heart disease, from genetics first, that cholesterol was the target and now incidence of heart disease is going down. We've got to have that same focus with Alzheimer's disease and I'm hoping that this paper will galvanize us to say, OK. This is our target.

HAMILTON: Most researchers agree, but some still think amyloid isn't the whole story. They point out that, so far, no drug that targets amyloid has managed to slow down Alzheimer's.

Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.