Dec. 30, 1997 St. Louis -- Investigators at Washington University School of Medicine in St. Louis and the University of Madrid, Spain, have found a genetic variation that appears to increase the risk of developing Alzheimer's disease.
This finding provides a link between two substances previously implicated in the disease - APOE, a cholesterol-carrying protein, and beta-amyloid, a protein that forms plaques in the brain. Replicating the results of this preliminary study would raise hopes that drugs in the pipeline may be effective against the disorder, which affects about 4 million Americans.
Since 1993, scientists have known of a relationship between the APOE gene and Alzheimer's disease. But no one knew of a mechanism by which APOE might lead to the disorder. In addition, there are several forms of APOE, but only the form known as APOE e4 was closely related to the risk for Alzheimer's disease.
The new study, reported in the January 1998 issue of Nature Genetics, shows that other forms of APOE also can increase the risk of Alzheimer's disease and suggests how this might happen.
"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.
Goate's team at Washington University collaborated with Spanish researchers, led by Fernando Valdivieso, Ph.D., professor and chair of molecular biology at the University of Madrid. The two groups studied individuals with Alzheimer's disease and compared them with individuals of the same age who did not have Alzheimer's disease.
In both the American and the Spanish subjects, the investigators found three normal variations, or polymorphisms, in the promoter region of the APOE gene. The promoter is a stretch of DNA that determines how active a gene becomes. One of the genetic variations was linked to a higher frequency of Alzheimer's disease. It caused a higher level of expression of APOE, regardless of whether the APOE gene was the e4 variety. Subjects with this polymorphism were approximately three times more likely to have Alzheimer's disease than those who did not have the variation. 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.
After confirming the relationship between the genetic variation and risk of Alzheimer's disease in both a Spanish and an American population, the investigators did test-tube experiments to determine how this polymorphism affected production of the APOE protein. They found 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."
In animal models of the disease, other researchers have shown that increased APOE levels can raise the amount of amyloid that's deposited in Alzheimer plaques.
"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," Goate suggested.
Amyloid protein contributes to the development of senile plaques, which dot the brain's cortex in Alzheimer patients. Little is understood about the causes of these deposits.
"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," Goate explained. "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."
Next, Goate and colleagues will try to determine whether the genetic variation in APOE really does increase amyloid deposition. Studying brains postmortem, Goate hopes to learn whether individuals who had the high-expressing APOE variation also had higher levels of amyloid in the brain.
Goate does not believe that this variation in the APOE gene is sufficient to cause Alzheimer's disease on its own. "I think several genes will turn out to be involved in Alzheimer's diseases in the plural," she said. "There may be many different ways of producing the dementia that we associate with the disease, but this could be teaching us about one of them."
The Washington University research was funded by the National Institutes of Health and the Metropolitan Life Foundation.
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