Researchers Locate Second Late-Onset Alzheimer's Disease Gene

While the scientists have not yet isolated the gene, they have narrowedits location to a tiny piece of human chromosome 12. The researchers cannotdetermine the gene's purpose until it is pinpointed and more closely studied.

"This finding is another tile in the complex genetic mosaic that helpsdefine who is at risk for Alzheimer's disease (AD)," said Margaret Pericak-Vanceof the Duke University Medical Center, lead author of the study. "Little bylittle, we are piecing together a picture of how environmental exposures combinewith genetic predisposition to trigger Alzheimer's disease."

"Our understanding of the genetic component of AD is far fromcomplete," she emphasized in an interview. "Nearly half of the genetic basis isstill unexplained and these genes may hold the key to better treatments andeventually a cure."

AD is the leading cause of dementia in the elderly, with about 4million people affected. People with AD accumulate abnormal clumps of nerves andtangled bundles of fibers in their brains. They lose nerve cells in areas of thebrain that are vital to memory and other mental abilities. The devastatingdisorder robs older adults of their ability to think clearly and to care forthemselves.

The new research findings are reported in the Oct. 15 issue of theJournal of the American Medical Association. The research was funded by theNational Institute of Neurological Disorders and Stroke, the National Instituteon Aging, the Alzheimer's Association and the Joseph and Kathleen Bryan researchfund.

"This is an exciting result that is the product of true collaborationbetween many scientists from different disciplines, including clinicians,genetic epidemiologists and molecular geneticists," said co-investigator andsenior author Jonathan Haines of the Vanderbilt University Medical Center,Nashville, Tenn. Other authors of the paper are Henry Terwedow of MassachusettsGeneral Hospital, Charlestown, Mass.; P. Michael Conneally of Indiana UniversityMedical Center, Indianapolis; Gary Small of the University of California at LosAngeles; Meredyth Bass, Larry Yamaoka, Pete Gaskell, William Scott, MarisaMenold, Dr. Jeffery Vance and Anne Saunders of Duke; and Dr. Allen Roses, vicepresident and worldwide director of genetics, Glaxo-Wellcome, London.

The research team discovered the first major genetic risk factor for ADin 1993. They found that people who inherit a certain version of the gene calledapolipoprotein-E (ApoE) are at significantly increased risk for developing AD.The ApoE gene is the blueprint for a protein that helps deliver cholesterol, acritical building block of the membranes of newly forming cells.

The ApoE gene comes in three versions, and people who inherit theversion called ApoE4 are much more likely to develop AD later in life.Researchers aren't sure why a protein that ferries cholesterol around the bodyleads to AD, but they do know the ApoE4 gene accounts for up to 50 percent ofall late-onset AD.

The researchers sought other AD genes, knowing that a genetic basislikely exists for the unexplained portion of the disease. To find the gene, theyscanned the human genome seeking additional genetic segments shared among peoplewith AD.

In an initial screen two years ago, the researchers studied 16 familiesin which several generations were affected by AD. They compared the DNA of 52family members who developed AD with 135 who did not. In this search -- the mostextensive ever conducted for new AD genes -- they identified several regions ofDNA that might be linked to AD, including the potential region on chromosome 12.

The researchers narrowed their quest for the new gene by studying anadditional 216 people in 38 families with a high incidence of AD. They foundthat 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 theirfindings, the researchers say the chromosome 12 gene could account for up to 15percent 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 ofAD, less than 5 percent, mostly in early onset cases.

Now that the scientists say they are in the right neighborhood of thegene on chromosome 12, they will use a more detailed genetic map of the region,further narrowing down the possible gene location. Finally, the researchers willmethodically screen individual gene candidates.

However, even before the gene itself is isolated, the chromosomallocation is valuable because it has narrowed the search for this new geneticfactor to less than 1 percent of the human genome.

"The Alzheimer's Association is very pleased to support research thatgenerates new knowledge about susceptibility genes and other factors that mayhave an impact on the age of onset of Alzheimer's disease," said ZavenKhachaturian, director of the association's Ronald & Nancy Reagan ResearchInstitute.

"As we learn more about these mechanisms, the possibility of delayingthe onset of Alzheimer's becomes more real," said Khachaturian. "If we candelay the onset of the disease for five years, we can cut in half the number ofpeople who get the disease, add years of independence to people's lives and savethis country billions of dollars in health care costs."