Oct. 15, 1997 CHICAGO -- The same research team that found the first gene for late-onset Alzheimer's disease has reported locating another gene that probably accounts for the genetic component of the disorder in up to 15 percent of those with the late-onset form. The gene appears to work independently of the previously discovered gene, which accounts for almost half of all patients with the disease.
While the scientists have not yet isolated the gene, they have narrowed its location to a tiny piece of human chromosome 12. The researchers cannot determine the gene's purpose until it is pinpointed and more closely studied.
"This finding is another tile in the complex genetic mosaic that helps define who is at risk for Alzheimer's disease (AD)," said Margaret Pericak-Vance of the Duke University Medical Center, lead author of the study. "Little by little, we are piecing together a picture of how environmental exposures combine with genetic predisposition to trigger Alzheimer's disease."
"Our understanding of the genetic component of AD is far from complete," she emphasized in an interview. "Nearly half of the genetic basis is still unexplained and these genes may hold the key to better treatments and eventually a cure."
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.
The new research findings are reported in the Oct. 15 issue of the Journal of the American Medical Association. The research was funded by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Alzheimer's Association and the Joseph and Kathleen Bryan research fund.
"This is an exciting result that is the product of true collaboration between many scientists from different disciplines, including clinicians, genetic epidemiologists and molecular geneticists," said co-investigator and senior author Jonathan Haines of the Vanderbilt University Medical Center, Nashville, Tenn. Other authors of the paper are Henry Terwedow of Massachusetts General Hospital, Charlestown, Mass.; P. Michael Conneally of Indiana University Medical Center, Indianapolis; Gary Small of the University of California at Los Angeles; Meredyth Bass, Larry Yamaoka, Pete Gaskell, William Scott, Marisa Menold, Dr. Jeffery Vance and Anne Saunders of Duke; and Dr. Allen Roses, vice president and worldwide director of genetics, Glaxo-Wellcome, London.
The research team discovered the first major genetic risk factor for AD in 1993. They found that people who inherit a certain version of the gene called apolipoprotein-E (ApoE) are at significantly increased risk for developing AD. The ApoE gene is the blueprint for a protein that helps deliver cholesterol, a critical building block of the membranes of newly forming cells.
The ApoE gene comes in three versions, and people who inherit the version called ApoE4 are much more likely to develop AD later in life. Researchers aren't sure why a protein that ferries cholesterol around the body leads to AD, but they do know the ApoE4 gene accounts for up to 50 percent of all late-onset AD.
The researchers sought other AD genes, knowing that a genetic basis likely exists for the unexplained portion of the disease. To find the gene, they scanned the human genome seeking additional genetic segments shared among people with AD.
In an initial screen two years ago, the researchers studied 16 families in which several generations were affected by AD. They compared the DNA of 52 family members who developed AD with 135 who did not. In this search -- the most extensive ever conducted for new AD genes -- they identified several regions of DNA that might be linked to AD, including the potential region on chromosome 12.
The researchers narrowed their quest for the new gene by studying an additional 216 people in 38 families with a high incidence of AD. They found that regions on chromosomes 4, 6 and 20 might also harbor genes involved in AD, but the strongest link continued to be on chromosome 12. Based on their findings, the researchers say the chromosome 12 gene could account for up to 15 percent of AD cases.
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.
Now that the scientists say they are in the right neighborhood of the gene on chromosome 12, they will use a more detailed genetic map of the region, further narrowing down the possible gene location. Finally, the researchers will methodically screen individual gene candidates.
However, even before the gene itself is isolated, the chromosomal location is valuable because it has narrowed the search for this new genetic factor to less than 1 percent of the human genome.
"The Alzheimer's Association is very pleased to support research that generates new knowledge about susceptibility genes and other factors that may have an impact on the age of onset of Alzheimer's disease," said Zaven Khachaturian, director of the association's Ronald & Nancy Reagan Research Institute.
"As we learn more about these mechanisms, the possibility of delaying the onset of Alzheimer's becomes more real," said Khachaturian. "If we can delay the onset of the disease for five years, we can cut in half the number of people who get the disease, add years of independence to people's lives and save this country billions of dollars in health care costs."
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