A team of researchers from the University of Toronto, Boston University School of Medicine, Duke University and Vanderbilt University, has determined that recent findings suggesting a gene on chromosome 12 was a strong genetic risk factor for Alzheimer's disease cannot be replicated. The results of the investigation will appear in the May issue of Nature Genetics.
It had been reported that the A2M-2 variant of the alpha-2-macroglobulin gene on chromosome 12 was a strong risk factor for Alzheimer's. Investigators had suggested that the increase in risk related to A2M-2 was equal to (or possibly greater than) the strongest known existing risk factor, the e4 variant of apolipoprotein E.
However, the multinational consortium investigating the suspected association could not replicate those results after evaluating A2M in more than 100 Alzheimer's families. Families consisted of multiple members afflicted with the disease. The investigation also included nearly 400 cases of sporadic Alzheimer's disease, and 320 age-matched cognitively normal controls. There was no evidence for an association between the A2M-2 and increased Alzheimer's risk in any patient sample. Researchers determined that the A2M-2 was likely to be a natural genetic variant which does not cause Alzheimer's disease.
"Alzheimer's 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," said Margaret Pericak-Vance, PhD, professor of medicine and director of the Center for Human Genetics, Duke University Medical Center. "Our results with the e4 variant of apolipoprotein E have been replicated by investigators dozens of times worldwide, but the search continues for the Alzheimer's gene on chromosome 12," she added.
Despite negating the suspected association, the researchers maintain that there is strong and reproducible evidence for another genetic defect, which does cause Alzheimer's, elsewhere on the chromosome. According to investigator Lindsay Farrer, PhD, professor of medicine, neurology and public health, and the chief of the Genetics Program at Boston University School of Medicine, "We're looking in the right place, and chromosome 12 becomes increasingly important in identifying the real genetic foundations of Alzheimer's."
"While we know that the A2M-2 variant of alpha-2 macroglobulin is not the cause of Alzheimer's Disease, there is strong evidence that there is another genetic defect elsewhere on chromosome 12 which does cause Alzheimer's Disease. The next step will be to try and find that missing gene," said Professor Peter St. George-Hyslop, director of the Centre for Research in Neurodegenerative Diseases at U of T.
"We think it's pretty clear that the search for the chromosome 12 Alzheimer's gene must continue. There are several other genes in this region that we are looking at now," said Jonathan Haines, PhD, associate professor of molecular physiology and biophysics and director of the Program in Human Genetics at Vanderbilt University School of Medicine.
The work was supported by grants from the National Institutes of Health, the Medical Research Council of Canada, the Alzheimer Society of Ontario, and the Alzheimer Association.
Additional Contacts:
Gina DiGravio, Public Affairs
Boston University Medical School
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Karyn Hede
Duke University Public Affairs
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Leigh MacMillan
Vanderbilt University Public Affairs
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Journal
Nature Genetics