Genetic Risk for Alzheimer's

Since 1993, researchers have known that a gene encoding a cholesterol transport protein, APOE, is associated with an increased risk for Alzhimer's disease. One particular variant of APOE, e4, appeared to be most strongly associated with the disease. Researchers have know for an even longer time that a protein called beta-amyloid is involved in the formation of tangles of tissue called plaques in the brains of Alzhimer's patients.

Now scientists at  the Washington University School of Medicine in St. Louis and the University of Madrid, Spain, have found a genetic link between APOE and beta-amyloid. The two groups evaluated the brains of patients with Alzheimer's disease and compared them with individuals of the same age who did not have Alzheimer's disease.

The researchers found three normal variations, or polymorphisms, in the promoter region of the APOE gene, one of which was linked to a higher frequency of Alzheimer's disease. That polymorphism caused a higher level of expression of APOE, regardless of whether the APOE gene was the e4 variety. Patients with this  polymorphism were approximately three times more likely to have Alzheimer's disease than those who did not. When the researchers removed the data from subjects who carried an APOE e4 gene, the risk was four times higher than in people without the polymorphism.

"We've discovered changes in the APOE gene that can alter your risk, and we found those changes in the regulatory part of the gene, which controls how much APOE protein our cells produce," said Alison M. Goate, Ph.D., associate professor of genetics in psychiatry and a lead author of the study.

The researchers did laboratory studies to determine how this polymorphism affected production of the APOE protein. They discovered that it caused higher levels to be produced.

"So we believe that the higher levels of APOE expression are contributing to an increase in the risk for Alzheimer's disease," Goate explained. "And we believe the mechanism involves another protein called amyloid."

Other researchers have shown in animal studies that increased APOE levels can raise the amount of amyloid  deposited in Alzheimer plaques, she noted.

"So it would seem that a likely explanation for our data is that by increasing the level of APOE expression, this polymorphism might increase the amount of amyloid you deposit in your brain. In turn, that could increase your risk of getting Alzheimer's disease. From our data, we might predict that APOE acts as a chaperon for the amyloid protein. With what we know from in vitro studies, it would make sense that APOE is inducing more of the normally soluble amyloid to deposit in the brain as plaques.

"I think this is the first result that has really suggested a connection between APOE expression and amyloid deposition, and it makes me more optimistic that the drugs being developed to inhibit amyloid production or deposition may be effective therapies for Alzheimer's disease," said Goate.

A related study by researchers at Northwestern University Medical School found further clues to the actions of beta-amyloid. They determined that an enzyme found in very low levels in healthy brains, butyrylcholinesterase (BChE), was greatly increases in brains affected by Alzhimer's disease. The increase is seen at the stage when beta-amyloid plaques in the brain become compact and insoluble.

This study suggests that BChE may help transform benign amyloid protein deposits in the brain into the compact plaques associated with the nerve degeneration and dementia of Alzheimer's disease.

"Our evidence suggest that BChE probably is inserted into the amyloid plaque at an advanced stage of maturation, at a time when the plaque is becoming associated with pathogenic properties," said Alzheimer's disease researcher M.-Marsel Mesulam, M.D., professor of neurology and the director of the behavioral and cognitive neurology and Alzheimer's disease program at Northwestern.

The APOE data are reported in the January 1998 issue of Nature Genetics. The BCheE study appeared in the December 1997 issue of the Annals of Neurology. 

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