Richard Saltus / Boston Globe 22dec00
Researchers say they've found evidence for a new genetic risk factor that makes some people more prone to developing the most common type of Alzheimer's disease, the fatal brain disorder that affects about 4 million Americans.
Having a mutant form of this gene doesn't assure that someone will develop late-onset Alzheimer's, but makes the person more prone to the disease, in which the brain becomes dotted with sticky plaques and brain cells die.
The researchers from three scientific groups who discovered the genetic variant emphasized that they haven't found the exact location of the gene within human DNA, and they don't know how many people carry it or how much it increases Alzheimer's risk.
The discovery is only the second gene that's been found to affect one's risk of getting late-onset Alzheimer's, which usually appears after age 65 or 70 and makes up 90 percent of all Alzheimer's cases. The first one discovered is a variant known as ApoE4, which appears to act independently of the new genetic change.
"This is an important discovery," said D. Stephen Snyder, a program director for studying the causes of Alzheimer's disease at the National Institute on Aging. He speculated that the gene itself would be found within the next two years, allowing development of tests to determine who carries the risk factor and, one day, perhaps new treatments.
LOCATION OF TROUBLE SPOT
The just-discovered trouble spot lies in a narrow stretch of DNA on Chromosome 10, according to the three reports in the current issue of the journal Science. One of the groups is headed by Dr. Rudolph Tanzi, an Alzheimer's gene-hunter at Massachusetts General Hospital. The other groups are headed by scientists at the Mayo Clinic in Jacksonville, Fla., and Washington University in St. Louis.
"I wouldn't be surprised if this turns out to be a bigger Alzheimer's gene than ApoE4," said Tanzi. Although ApoE4 is a factor in about 50 percent of late-onset Alzheimer's cases, it "is not necessary or sufficient to cause the disease on its own. You can have the gene and still live to be 90" and not develop the disease, he said.
Except in rare cases, genes don't cause Alzheimer's by themselves, researchers say. Instead, the disease most often results from a complex interplay of genes with each other and environmental factors that aren't yet known.
ROLE OF BAD GENE
The investigators don't know precisely what the bad gene does, but they suspect it's involved in the accumulation of amyloid in the brain. Amyloid is a sticky substance that's found in abundant plaques among dead brain cells in Alzheimer's patients, who initially suffer lapses of memory but eventually become unable to remember much of anything and can't recognize even familiar faces.
The three research groups used somewhat different methods to home in on the Chromosome 10 area. Tanzi and his colleagues did it with linkage analysis, a powerful way of narrowing a search for an unknown gene that could be located on any of the 23 pairs of human chromosomes that together hold some 80,000 or more genes.
Key to their success was the availability of families in whom late-onset Alzheimer's seem more common than average. About 500 families have been identified over the past two decades by researchers at the National Institute of Mental Health, said Tanzi.
The Massachusetts General researchers compared DNA samples of individuals in these families who developed Alzheimer's and those who remained healthy, and found that certain distinctive bits of DNA -- called genetic markers -- were more common in people who became ill. The scientists mapped those genetic markers to specific regions of chromosomes, which told them where the unknown Alzheimer's risk gene was likely to be -- at least approximately.
Findings by the Massachusetts General group and the other scientists yielded a tantalizing clue: It seems that the new gene is very likely to play a role in the body's production of a protein called AB42. AB42 is the protein that makes up the plaques scattered through the brains of Alzheimer's patients,
and it is made in the body by an abnormal process out of a larger protein.
A leading theory of Alzheimer's is that it's caused by an imbalance in the production of AB42 and its removal from the body. Overproduction can cause AB42 to pile up in the brain, just as too-slow removal can.
The finding of the gene causing a heightened risk of the disease won't change the treatment of Alzheimer's anytime soon, though it points to a new genetic command point that future drugs might be directed at.
ABOUT ALZHEIMER'S
Here are some facts about Alzheimer's disease - a progressive, degenerative disease of the brain. -- Alzheimer's affects about 4 million Americans. -- One out of every 10 people over the age of 65 has Alzheimer's. -- A person with Alzheimer's lives an average of eight years and as many as 20 years from the onset of symptoms. -- The federal government devoted nearly $500 million to Alzheimer's research this year.
Source: Alzheimer's Association
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