Just eight months after researchers found the first genetic defect that causes Alzheimer's disease, another research group has discovered, in precisely the same spot, a second defect that also causes the disease.
The new finding, which is being reported today in Science magazine, will soon be joined by a report of yet a third genetic defect at the same spot on the same gene that also causes Alzheimer's.
Dr. John Hardy of St. Mary's College in London, who found the first gene defect, will report the third one in a few weeks, according to his collaborator, Dr. Allen Roses of Duke University.
Together, the discoveries show that a mutation at a crucial position in a normal brain chemical, amyloid precursor protein, will cause brain cells to crumble and die, resulting in Alzheimer's, scientists said.
In addition, in their report in Science, the researchers who found the second defect have, for the first time, shown the inheritance of an Alzheimer's disease gene through more than one generation. By looking back at stored tissue samples of 31 family members from three generations, they established that every family member who got the disease had inherited the altered gene.
The researchers, led by Dr. Merrill D. Benson of the Indiana University School of Medicine, also found that family members who did not inherit the gene escaped unscathed. And they identified younger family members who carry the defect and thus are expected to be stricken.
The three genetic defects are probably the cause of a relatively small proportion of Alzheimer's cases. Investigators suspect that there may be several genes that can cause the disease. They are uncertain whether the disease is always inherited or whether it can be brought on by a virus or some as yet undiscovered toxin.
But scientists said the latest discovery would be invaluable in providing clues to the cause of the disease and could help in diagnosing it.
"This is a major advance," said Dr. Rudolph Tanzi, an Alzheimer's disease researcher at Brigham and Women's Hospital in Boston. "Seeing a second mutation in the same spot really nails it down. It means we have a bona fide gene defect, which we can now start studying."
Dr. Gene Cohen, acting director of the National Institute on Aging, said the discovery of Alzheimer genes could help in diagnosis. The disease is now diagnosed by exclusion: If, after a number of tests, no other cause can be found for a set of symptoms, the diagnosis is Alzheimer's.
An estimated 4 million Americans have Alzheimer's disease, a degenerative brain disorder that is characterized by a relentless loss of brain cells, accompanied by a gradual loss of memory and the ability to reason. People who have the disease eventually become severely disoriented and unable to care for themselves and die about a decade after the symptoms begin.
The search for Alzheimer's genes has centered on families in which the disease is clearly passed through the generations.
The latest finding involved a careful study of the genes from a family in which about half the members got Alzheimer's disease relatively early in life; their first symptoms occurred around the age of 40. Most cases occur when people are over 65.
Dr. Benson, a lead author of the Science paper, said the gene mutation is in amyloid precursor protein, a substance made by brain cells. The protein normally protrudes from the surface of cells like a ball of yarn, with a long string leading from the ball through the cell membrane and into the cell.
When people get Alzheimer's, amyloid precursor protein is snipped in two. As a result, fragments of the protein are created and accumulate like tangled spaghetti around dead and dying cells. Many researchers think that if they could prevent the protein from being snipped, they could prevent Alzheimer's.
All three Alzheimer's disease genes alter the amyloid precursor protein in the string-like portion that passes through the cell membrane. They all change the same amino acid, No. 43 out of the string of 770 that make up the protein.