Study links gene trait to Alzheimer's disease Discovery may help cure fatal disorder

August 13, 1993|By New York Times News Service

A genetic trait already linked to heart disease has now been revealed as a powerful risk factor for Alzheimer's disease, scientists have reported.

The discovery could account for half of all patients with the common neurological disorder, scientists said, and it points the way toward devising treatments to block or at least delay the harrowing and ultimately fatal symptoms of the disease.

The finding is the first detection of a trait predisposing people toward contracting Alzheimer's after age 65, the time when the great majority of patients come down with the incurable illness.

Other recent reports of genes associated with Alzheimer's disease have not focused on the late-onset variety but instead on the less frequent familial forms of the disorder that strike relatively early in life.

About 4 million Americans now suffer from Alzheimer's disease, and the number is expected to increase sharply as the population ages.

"It's the first biological risk factor that's been identified for late-onset Alzheimer's, and it gives us hope that we may be able to eventually dissect this disease," said Dr. Margaret A. Pericak-Vance of Duke University Medical Center in Durham, N.C.

Dr. Pericak-Vance, Dr. Elizabeth H. Corder, Dr. Allen D. Roses and their colleagues report the new work in today's issue of the journal Science.

In the latest finding, the researchers studied a gene that allows the body to manufacture apolipoprotein E, or ApoE, an essential protein that shepherds cholesterol through the bloodstream.

Scientists have known for years that the gene comes in three varieties, called E2, E3 and E4, and they have known that patients with the E4 version of the gene have a small but notably elevated risk of cardiovascular disease.

The new work demonstrates that possession of the E4 variant is an even greater risk factor for Alzheimer's disease than it is for heart disease.

The researchers studied 234 people from 42 families afflicted with late-onset Alzheimer's.

All genes of the body come in two copies, one donated by the mother, the other by the father. The study found that patients with two copies of the E4 gene had eight times the risk of people with a combination of either the E2 or E3 varieties.

Even inheriting one copy of the E4 gene turns out to be bad news, doubling or tripling the risk of Alzheimer's over that of people having no E4 genes at all.

Researchers do not yet know how the gene predisposes people to the disease but, although it has not yet been proved, Dr. Roses says he believes there is a direct cause and effect.

"This study is very fascinating," said Dr. Robert W. Mahley, director of the Gladstone Institute of Cardiovascular Disease at the University of California at San Francisco. "We've been working on apolipoproteins for close to 20 years, and E4 is turning out to be quite an interesting character."

The E4 variant also lowers the age at which Alzheimer's disease begins. In people without any E4 genes, about 20 percent come down with Alzheimer's by age 75.

In those with one copy of the gene, more than 60 percent suffer from the disorder by that age, while in patients with two copies, more than 90 percent have the disease by then.

The number of people bearing a double dose of the E4 gene is very small, perhaps 2 percent of the population, scientists said. But up to 33 percent of people have one copy of the gene and hence are at heightened risk of the neurological disorder.

The Duke researchers were prompted to propose E4 as a risk factor through a fortuitous convergence of genetic and biochemical studies.

Several years ago, while analyzing the DNA patterns of people with late-onset Alzheimer's, the team proposed that the disease was linked to some unknown gene on chromosome 19, out of the 23 pairs of chromosomes in all human cells.

Independently, they and others detected a biochemical relationship between apolipoprotein E and the pathological lesions found in the brains of Alzheimer's patients.

When the Dr. Roses' lab realized that the gene for apolipoprotein E is located on chromosome 19, the researchers enthusiastically explored the connection in depth.

"It's a first step that tells us where it's worthwhile to point our efforts," said Dr. Roses. "But I'm optimistic enough to predict that in 10 to 15 years, we'll have a safe and effective medication that a 50-year-old could take every day to prevent Alzheimer's disease."

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