By Sean Henahan, Access Excellence

SEATTLE/BOSTON- A gene identified in an extended German family with a high prevalence of Alzheimer's disease adds an important piece to the research puzzle, report researchers.

The study began with an analysis of a familial group known as the Volga German (VG) kindreds, a group of related families with ties to Germany, Russia and the United States. The families in the group emigrated from Germany to an area in Russia in the 18th Century and then came to the United States earlier this century. Members of this group were observed to be at much higher than average risk for early-onset Alzheimer's disease, a type which develops before age 65.

A series of genetic studies produced a candidate gene on chromosome 1, called STM2. The chromosome 1 STM2 protein sequence resembles that observed in another gene localized on chromosome 14 earlier this year. Researchers have also previously identified a gene associated with Alzheimer's disease on chromosome 21.

"We are very excited by the discovery of this new Alzheimer's gene-- it opens new scientific avenues to researchers," said Gerard D. Schellenberg, Ph.D., Associate Director For Research, Seattle VA Medical Center.

The newly discovered mutation of STM-2 is quite rare, but the new gene may code for an unknown protein that is part of the poorly understood process leading to Alzheimer's disease in all patients. Some 70 percent of patients with early-onset Alzheimer's disease have the chromosome 14 defect, while the defect in chromosome is found in about 25 percent of cases. The chromosome 21 mutation is seen in approximately five percent.

"Finding out the function of the protein made by this gene and how that function is altered when the gene is mutated has great potential consequences for developing new therapies that could help all Alzheimer's patients," said Rudolph Tanzi, Ph.D., Director of the Massachusetts General Hospital Genetics and Aging Unit, Boston, MA.

The discovery of this gene gives researchers an important new clue towards a better understanding of what causes the formation of amyloid-beta, a toxic substance found in the brains of patients with Alzheimer's. Determining the function of the proteins associated with the three Alzheimer's genes should help researchers develop a drug to slow or stop the disease process.

"Discovery of this gene probably completes the roster of genetic causes for inherited early onset Alzheimer's," said Wilma Wasco, Ph.D., a member of the MGH team. Dr. Tanzi added, "Every new gene and mutation that we find brings us closer to an effective treatment, and maybe a prevention, for this devastating disease."

Adds Dr. Schellenberg, "Genetics has proven to be the most powerful tool by far for understanding diseases like this one. Though we still have a long way to go to find a cure, identifying this new Alzheimer's gene allows us to `connect the dots' -- so to speak -- to earlier discoveries made in this area."

Alzheimer's disease is a progressive, degenerative disease of the brain that results in impaired memory and dementia. Alzheimer's disease, named for Alois Alzheimer, the German neurologist who first described the pathology of the disease nearly 100 years ago, is the fourth leading cause of death in the developed world, after heart disease, cancer, and stroke. Alzheimer's disease costs the nation nearly $60 billion/year.

"The great news is that we have located the genetic mutations that account for almost all families with early-onset familial Alzheimer's,'' said Leonard Berg, M.D., chair of the Alzheimer's Association's Medical and Scientific Advisory Board. "`We're much further ahead than we were even four years ago. The difficult task ahead is to find the steps between mutation and disease, and then identify those we can address through intervention,'' said Berg, professor of neurology and director of the Alzheimer's Disease Research Center at Washington University in St. Louis. "The task is difficult because it is likely that none of the known mutations acts alone. They may be impacted by a number of genetic and environmental factors.''

The current research, a collaborative effort among scientists at the Seattle Veteran's Affairs Medical Center's Geriatric Research Education and Clinical Center, the Massachusetts General Hospital, and Darwin Molecular Corporation, is reported in the Aug. 18, '95 issue of Science.