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Researchers Locate Second Late-Onset Alzheimer's Disease Gene

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CHICAGO, IL -- 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.

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