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GENETICS Genetic Link Discovered for Late Onset Alzheimer's Findings Suggest New Era in Alzheimer's Treatment The long arm of human chromosome 10 harbors a gene that could powerfully predispose people to develop late onset Alzheimer's disease, Massachusetts General Hospital researchers have found. Although they have not yet identified the actual gene, they have evidence that it could be more potent than previous risk factors. "Whatever the gene is, the robustness of the link says it's probably going to be a major late onset Alzheimer's gene. So we need to find it," says Rudy Tanzi. Photo by Graham Ramsay "I wouldn't be surprised if this turns out to be a bigger Alzheimer gene than APOE4," said Rudolph Tanzi, HMS professor of neurology and director of MGH's Genetics and Aging Unit. He and his colleagues report their findings in a special triptych appearing in the Dec. 22 Science. 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 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 said. Lars Bertram, HMS research fellow in neurology, is lead author on the paper. What's Hot, What's Not Bertram, Tanzi, and their 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 family-based association program, they focused on six genetic markers in the vicinity of the gene for insulin-degrading enzyme, which is believed to help degrade the Alzheimer's disease-causing protein A-beta. Siblings with Alzheimer's 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, Fla., have found a link between late onset Alzheimer's and a similar region on chromosome 10. Another team at the Mayo Clinic has found that people carrying a particular genetic marker located on chromosome 10 are more likely to have elevated levels of A-beta in their plasma. "So we have this convergence of three different approaches all landing on chromosome 10. Is there a big gene there? We think so," said Tanzi. Based on the statistical associations, he 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 predict if this is going to be a susceptibility gene like APOE4, a dominant gene like APP or presenilin, or a recessive gene," he said. Tipoff Tanzi and his colleagues began their hunt on chromosome 10 as a result of a suggestion by Dennis Selkoe, HMS professor of neurology. Selkoe and his colleagues had evidence that a protein, insulin-degrading enzyme, played a role in disposing of A-beta in brain cells. Seizing on Selkoe's tip, the researchers ran a battery of statistical tests on the NIMH Alzheimer's families, including parametric lod score analyses, to see if variations in known genetic markers in the region of chromosome 10 containing the insulin-degrading enzyme gene might be associated with the disease. Typically, the parametric analyses detect links between disease and dominant and recessive mutant genes but have a harder time picking up links between disease and more subtle susceptibility polymorphisms. To the researchers' surprise, the tests picked up a significant genetic link between Alzheimer's and variants in two of the markers—suggesting that whatever is influencing disease could be doing so quite powerfully. While the researchers knew that the two genetic markers—chosen from a DNA database—were harmless, further tests indicated that one of them could lie near the pathogenic variant. The family-based association test, which typically picks up disease-causing mutations or genetic variations lying close to such mutations, showed a positive result for one of the two markers. To pinpoint the mutation, the researchers have been scouring the insulin-degrading enzyme gene. Yet the likelihood that the gene plays a role in breaking down A-beta is no guarantee that it will be shown to harbor the disease-causing variant, Tanzi said. 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 (see Focus Aug. 14, 1998). Convinced that the A2M variant was contributing to the disease, they assessed its biological consequences and found no effect. He now believes that the real culprit lies in another region of the A2M gene or in a nearby gene, and that due 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, said Tanzi. 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." The lesson may apply to their most recent findings. "I look at it this way: insulin-degrading enzyme led us to the right place to find a very strong genetic link that implicates a very strong Alzheimer's gene on chromosome 10," said Tanzi. "We do not have evidence that it is the insulin-degrading enzyme gene. In fact, I would not be surprised if it wasn't the insulin-degrading enzyme gene." He and collaborators at Neurogenetics Inc, San Diego—of which Tanzi was scientific founder—will sequence not only the insulin-degrading enzyme gene but genes lying to either side "until we find the pathogenic mutation," he said. "Hopefully, in the future, we'll never let the amyloid accumulate," said Tanzi. "We'll look at the genetic factors which are going to influence whether a person accumulates too much A-beta, doesn't clear it fast enough, or aggregates it too soon. And then based on whatever that genetic profile says about the course of amyloid production in this person's brain as he or she ages, we can say this is the best drug for you. "So that's the future. And that's going to happen in 10 years," he said. "Twenty years and it will be passé." —Misia Landau