Researchers identify genetic risk for Alzheimer's disease

December 20, 2000

Investigators at Washington University in St. Louis led an international research team that has identified a new genetic risk factor for Alzheimer's disease. The researchers still are working to isolate the specific gene, but they have isolated the region of DNA that contains it.

In this week's Science, the researchers report that a region on chromosome 10 likely contains a gene that increases susceptibility to late onset Alzheimer's disease. About 4 million Americans have Alzheimer's, the most common form of dementia in the elderly and the fourth leading cause of death in the United States. The vast majority have the late onset form, which occurs after age 65.

One other gene is known to increase the risk of late onset Alzheimer's disease. People with the E4 version of APOE (apolipoproteinE) are three to eight times more likely to develop the disease than those with other versions of the gene. But only about half of Alzheimer's patients have APOE4, so other genetic and environmental factors must be important also.

"Two things about this new risk factor seem very significant," said senior investigator Alison M. Goate, Ph.D., professor of psychiatry and genetics at Washington University School of Medicine in St. Louis. "First, it appears to have as big an effect on risk as APOE4 in our sample. Secondly, it has that effect independent of APOE. It doesn't interact with that gene at all."

APOE protein is found in the lipid-protein complexes that move fats around the body. Research in mice has shown that it also interacts with a protein fragment called amyliod-beta42 (Aß42) to make fibrils. Such fibrils are found in the plaques that dot the brains of Alzheimer's patients.

The newly-identified region on chromosome 10 also might affect Aß42. In an accompanying paper in the Dec. 22 issue of Science, a research team led by Stephen Younkin, M.D., Ph.D., professor of pharmacology at Mayo Clinic in Jacksonville, Fla., reports a potential mechanism. The researchers tested members of families with high levels of amyloid-beta in their blood plasma. They looked at five regions previously identified by Goate and colleagues and found linkage to the chromosome 10 region identified by Goate's team.

That's important because genetic mutations that contribute to early onset Alzheimer's, which begins before age 65, are known to increase Aß42 levels. In 1991, Goate was the first to identify such a mutation when she found that families with inherited Alzheimer's had an abnormality in the gene for the large protein that gives rise to amyloid-beta. This gene sits on chromosome 21. Later, presenilin genes called PS1 (on chromosome 14) and PS2 (on chromosome 1) were identified as other causes of early onset Alzheimer's. All three genetic abnormalities result in Aß42 overproduction.

"Obviously, there's still a long way to go in that we have found only a linkage and not a gene," Goate said. "But the accompanying Mayo Clinic paper suggests that elevated amyloid-beta levels are the mechanism by which this gene on chromosome 10 increases the risk for Alzheimer's."

Early genetic studies of the disease used large families with inherited, early onset forms, but those types of families don't exist for the study of the more common, late onset Alzheimer's. For this project, Goate's team studied pairs of siblings who had the disease.

The researchers analyzed data from 429 of sibling pairs. The DNA samples came from the National Institute of Mental Health, the National Institute on Aging and a large group of affected pairs from the United Kingdom. All siblings had been clinically assessed to determine that they had Alzheimer's disease. The DNA was isolated from blood samples.

Goate's team looked for unusual markers in the DNA. Siblings share 50 percent of their genome by chance, but a region involved in risk for Alzheimer's disease should show more than 50 percent sharing when hundreds of sibling pairs are compared. In 1999, the researchers found preliminary evidence of a linkage to the risk for Alzheimer's in 16 regions of DNA. In the current paper, they present follow-up data showing increased evidence for linkage on chromosome 10.

The next task is to find the gene in this chromosomal region. Goate and colleagues are looking for a normal variation in a gene, rather than a mutation because the late onset disease is so common.

"We think the effect of that genetic variation will be to raise amyloid-beta levels in plasma and presumably in the brain as well. Over 50 or 60 years it would increase the amount of amyloid deposited in the brain to the point where a person gets Alzheimer's," she said.

The team's finding has important implications for therapy, Goate believes. If a gene on chromosome 10 causes Aß42 to build up to abnormally high levels, many of the drugs being developed to decrease amyloid-beta levels would be useful for patients with the chromosome 10 variation. And the study by the Mayo Clinic researchers provides a method of testing for this genetic variation.

"But even with a test, we could identify only risk," Goate said. "As with APOE4 carriers, people with this gene won't definitely get the disease. So clinicians would have to decide the point at which it's appropriate to start any treatment."

At the very least, people with high levels of Aß42 in blood plasma could be followed closely to look for the very earliest signs of Alzheimer's, Goate said. Then treatments that come along might save them from further brain damage.
This research was supported by grants from the National Institute on Aging and from the Medical Research Council of the United Kingdom. Myers A, et al. Susceptibility locus for Alzheimer's disease on chromosome 10. Science, vol. 288 pp. 2304-2305, Dec. 22, 2000.

Washington University School of Medicine

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