January 5, 2001

MGH researchers have found a region on human chromosome 10 that could harbor a genetic variant that 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 the MGH's Genetics and Aging Unit. He and his colleagues report their findings in the Dec. 22 issue of Science. Along with the paper are two others implicating chromosome 10 as a likely place for a new late onset Alzheimer's gene to be found.

Tanzi says he 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 set 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.

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.