Search Still on for Second Alzheimer Gene After New Findings Fail to Confirm Harvard Team's Findings
In the world of science research, independent confirmation of research findings is the only way to substantiate a hypothesis. And these days of breakneck races to find disease-causing genes make replication of results even more important.
That's why this week's announcement by an international research team that they could not confirm the presence of a suggested second gene linked with Alzheimer disease is so key, said Duke senior investigator and professor of medicine, Margaret Pericak-Vance.
The finding, which appears in the May issue of the journal Nature Genetics, showed no evidence for a link between a genetic variant of a gene called "alpha-2-macroglobulin" and Alzheimer disease (AD), as had been reported last year by Harvard researchers. Those investigators had suggested A2M-2 variant is at least as strong a risk factor as another variant gene, called APOE-4, which was discovered by Duke researchers in 1993, and which accounts for almost half of all patients with the disease. That earlier discovery marked the first time that a genetic risk factor had been identified for Alzheimer disease.
Besides Duke Medical Center scientists, the team reporting the new findings included researchers from Boston University, the University of Toronto and Vanderbilt University. Their work was funded by the National Institutes of Health, the Medical Research Council of Canada, the Alzheimer Society of Ontario and the Alzheimer Association.
"Our results have important implications for future research," Pericak-Vance, who is director of Duke's Center for Human Genetics. "We have shown that the A2M-2 gene is simply a natural variant that does not cause Alzheimer disease and therefore will not be useful in developing therapeutic strategies." Pericak-Vance added that, as she and her colleagues proposed in 1997, there is still strong evidence that human chromosome 12 does harbor an Alzheimer gene and the search is still on for that gene.
In their study, the scientists reexamined the proposed link between A2M-2 and AD in more than 100 families that had more than one member affected, as well as in nearly 400 "sporadic" or individual cases of the disease. They also searched for the gene in an equal number of unaffected people. The scientists could find no consistent association between people carrying the A2M genetic variant and those who developed Alzheimer disease. In addition, the research team studied the role of the A2M protein produced by the gene and found that the suspected variant gene appeared to have no biological effect on the A2M protein product. The A2M protein interacts with many other proteins in the body, and its biological role is still being investigated.
Pericak-Vance and her colleagues first announced that chromosome 12 probably harbors a gene for AD in the Oct. 15, 1997, issue of the Journal of the American Medical Association. At that time, the researchers had already narrowed their search to a tiny piece of the chromosome. The exact gene has still not been found, but studies show that the defect may eventually account for up to 15 percent of those with the late-onset form of Alzheimer.
The chromosome 12 gene appears to work independently of the previously discovered apolipoproteinE gene associated with AD, and this preliminary finding was confirmed independently by researchers at Boston University and the University of Toronto.
"Alzheimer is a complex disease with multiple genetic risk factors that are difficult to sort out, so it is doubly important that suggested associations can be replicated," Pericak-Vance said. "Our results with the APOE-4 variant have been replicated by investigators hundreds of times worldwide, but the search continues for the Alzheimer gene on chromosome 12."
AD is the leading cause of dementia in the elderly, with about 4 million people affected. People with AD accumulate abnormal clumps of nerves and tangled bundles of fibers in their brains. They lose nerve cells in areas of the brain that are vital to memory and other mental abilities. The devastating disorder robs older adults of their ability to think clearly and to care for themselves.
In their earlier studies, the Duke research team found that the APOE gene comes in three versions, and people who inherit the version called APOE-4 are much more likely to develop AD later in life. The APOE gene is the blueprint for a protein that helps deliver cholesterol, a critical building block of the membranes of newly forming cells.
Since this discovery, the team has continued to search for other genetic risk factors to explain cases of AD that are not linked to APOE. Other genes associated with AD -- including amyloid precursor protein (APP) and Presenilin 1 and 2 (PS1, PS2) -- account for only a tiny fraction of AD, less than 5 percent, mostly in early-onset cases.
To find other genes that are involved in the more common late-onset form, the scientists scanned the human genome seeking additional genetic segments shared among people with AD. In an initial screen done four years ago, the researchers identified several regions of DNA that might be linked to AD, including the potential region on chromosome 12.