New genetic link for late onset Alzheimer's disease discovered

December 20, 2000

BOSTON - Massachusetts General Hospital (MGH) researchers have found a region on human chromosome 10 that could harbor a genetic variant that powerfully predisposes people to develop late onset Alzheimer's disease. Although they have not yet identified the actual disease-predisposing variant, the researchers have evidence that it could be more potent than previously discovered risk factors such as ApoE4 and A2M.

"I wouldn't be surprised if this turns out to be a bigger Alzheimer's gene than ApoE4," says Rudolph Tanzi, PhD, director of MGH's Genetics and Aging Unit. He and his colleagues report their findings in a special triptych appearing in the Dec. 22 issue of Science. Back-to-back with the paper are two others implicating the long arm of chromosome 10 as a likely hunting ground for a new late onset Alzheimer's gene.

Tanzi believes that the findings could help usher in a new era of Alzheimer's treatment in which people are genetically screened and then treated based on their particular constellation of predisposing genetic factors.

"Once we finally have reliable pathogenic gene changes, we can screen people for these genetic factors--with genetic and psychological counseling and with legal safeguards--and then use that genetic profile to predict who is going to get the disease, with what probability, by what age, and what is the best drug for them based on their genetic profile," he says. He and his colleagues located the genetic hotspot by comparing the genetic makeup of Alzheimer's patients and their unaffected siblings in 435 families enrolled in the National Institute of Mental Health database. Using standard statistical methods along with a novel method, the family-based association program, they focused on a constellation of six genetic markers in the vicinity of the gene for insulin-degrading enzyme on chromosome 10. Siblings with Alzheimer's disease were found to be significantly more likely to carry particular versions of two of the genetic markers. One of these markers appears to be located quite close to the actual disease-causing mutation.

Employing different statistical techniques and a different sample, a research team at Washington University and the Mayo Clinic, Jacksonville, have found a linkage between late onset Alzheimer's and a region on chromosome 10. Another team at the Mayo Clinic, Jacksonville, has found that people carrying a particular genetic marker located on chromosome 10 are more likely to have elevated levels of the Alzheimer's disease-causing protein, A beta, in their plasma.

"So we have this convergence of three totally different approaches all landing on chromosome 10. Is there a big gene there? We think so," says Tanzi.

Based on the strength of the statistical associations found by his group, Tanzi believes that the genetic variant could--like the early onset Alzheimer's genes APP and the presenilins--cause disease directly rather than merely increase susceptibility. "Until we get the actual genetic change we cannot yet predict if this is going to be a susceptibility gene like ApoE4, a dominant gene like APP or presenilin, or a recessive gene," he says.

As for the whereabouts of the pathogenic variant, while the two genetic markers--chosen from a database of DNA signposts--are harmless, they lie near a promising candidate, the insulin-degrading enzyme (IDE) gene. IDE appears to play a role in breaking down A beta, one of the processes that can go awry in late onset Alzheimer's.

Yet this kind of reasoning can be deceiving, says Tanzi. More than two years ago, he and his colleagues identified a variant of a gene, A2M, that tripled a person's risk for developing late onset Alzheimer's disease. Like IDE, A2M plays a role in degrading A beta. Convinced that the A2M variant was contributing to the disease, they assessed the biological consequences of the variant and found no effect. "We couldn't implicate that variant. It was innocent," he says. He now believes that the disease-causing genetic culprit lies nearby and that owing to their proximity, the two genetic changes--innocent and pathogenic--have been inherited together. This could be true of the more than two dozen late onset Alzheimer's disease genes that have been proposed in the last 10 years. Many of these genes have passed early statistical tests only to be shot down by later analyses.

"All those genes may actually be in areas of the genome where there are Alzheimer's mutations. You're just not on the mutations yet. You're only looking at a polymorphic allele that's along for the ride," he says.

The same could be said of IDE. "I look at it this way. IDE led us to the right place to find a very strong genetic link that implicates a very strong Alzheimer gene on chromosome 10," says Tanzi. "We do not have evidence that it is IDE. In fact, I would not be surprised if it is wasn't IDE."

He and his collaborators at Neurogenetics Inc., San Diego, are sequencing IDE and genes lying to either side "until we find the pathogenic mutation," he says.

The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $200 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
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Tanzi, who is co-author of the recently published "Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease" (Perseus Publishing, 2000), is a shareholder in Neurogenetics, Inc.

Massachusetts General Hospital

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