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Defects on gene linked to Alzheimer's

By STEPHEN NOHLGREN
Published January 15, 2007

When scientists finally unlock the secrets of Alzheimer's disease, Dominicans may have played a small part.

People from the Dominican Republic get Alzheimer's at a much higher rate than people from elsewhere. Suspecting an inherited defect, scientists at Columbia University in New York more than a decade ago began taking DNA samples from Dominican families.

They finally hit pay dirt - genetic defects that apparently can lead to late-onset Alzheimer's, by far the most common kind.

Colleagues around the world then found similar defects in hundreds of Alzheimer's patients from various ethnic backgrounds.

The defects occurred on a gene called SORL1. It's too soon to tell how much those gene versions raise the risk of getting Alzheimer's, or what percentage of cases they account for - perhaps 5 percent to 10 percent - the researchers said. They said the effect on risk appears to be modest.

But the discovery could open new avenues for research and possible treatment.

"We are eager to investigate the role of this gene further," said Richard Hodes, director of the National Institute on Aging. "This discovery provides a completely new genetic clue about the late onset forms of this very complex disease."

A paper describing the defects was published Sunday in the online edition of Nature Genetics. Forty-two scientists from six countries are listed as authors.

Scientists aren't sure what causes the vicious destruction of brain cells from Alzheimer's. But they do know one thing: Dissected Alzheimer's brains contain sticky clumps, or "plaques," of protein bits called amyloid.

Lab mice bred to develop Alzheimer's often perform better on tests when amyloid levels are reduced in their brains. That makes amyloid a key suspect.

The less amyloid floating around, the healthier the brain - or so the thinking goes.

Amyloid is created inside neurons, the brain's thinking and memory cells, when a protein called APP breaks apart.

That's where the SORL1 gene comes in. The gene produces a substance, also called SORL1, that acts like a traffic cop. In healthy brains, it directs APP to float around the neuron. When SORL1 levels drop, however, APP wanders off and breaks apart into amyloid bits, which eventually clump into the plaques.

In the 6,000 people tested by the international research team, people with Alzheimer's had less than half as much SORL1 in their brains than their healthy relatives. Many also had mutations on their SORL1 gene, leading to the suspicion that the genetic defect lowers SORL1 levels, which in turn produces higher levels of amyloid.

"Most of our drug discovery efforts are going into anti-amyloid drugs. We should hear some results about those drugs this summer," said Dr. Sam Gandy of the Alzheimer's Association. The SORL1 discovery "reassures those of us working on amyloid that we are on the right path."

As a target for possible drugs, the workings of the SORL1 gene could mean an advantage over other drugs now in clinical trials, Gandy said.

Suppose a pill could boost SORL1 levels in the brain without ill side effects. That might prevent amyloid from being created in the first place - years before it clumps into plaques.

Some drugs in development are aimed at clearing the brain of amyloid after it has formed.

"Plaques are present probably 10 years before the first symptoms," Gandy said "You want to get into treatment as soon as possible, before people forget the car keys for the first time."

SORL1 may be the most promising genetic discovery in more than a decade, said Dr. Creighton Phelps, who oversees NIA's Alzheimer's Research Centers.

In the early to mid 1990s, three defective genes were found in families with early-onset Alzheimer's, which hits before age 65. Only 5 percent to 10 percent of Alzheimer's cases are early-onset, but those genetic defects proved immensely valuable when scientists found ways to introduce them into lab mice, guaranteeing that the mice would develop Alzheimer's.

Mouse brains can be dissected at every stage of the disease to figure out what's going on. Mice can chow down on experimental drugs without fear of ill effects.

Research and understanding of Alzheimer's exploded after the early-onset defects were identified and grafted into the mice.

In the mid 1990s, researchers discovered a mutation of a lipid-transporting gene that probably causes 20 percent to 30 percent of Alzheimer's cases. Unfortunately, drug development involving lipids is complicated and fraught with side effects.

Since then, other genetic defects have been linked to families with a high incidence of Alzheimer's, said Phelps, but none seems as widespread as SORL1, which was found in African-Americans, Northern Europeans, Israelis and Arabs, as well as the Dominicans.

"With 6,000 people, it's one of the largest studies ever done," he said. "Because of the ethnic diversity, and the number of different samples and finding it in so many people, makes it seem that this must be real."

The more Alzheimer's can be tied to genetic defects the better. Once drugs are developed to slow down or prevent Alzheimer's, genetic testing will be one key to early intervention.

The Associated Press contributed to this article.

[Last modified January 15, 2007, 01:35:36]