|
MGH study identifies potential Alzheimer's
risk gene
Finding could further improve understanding
of disease mechanism, lead to new treatmentss
BOSTON - March 2, 2005 - Researchers from the MassGeneral
Institute for Neurodegenerative Disorders (MIND) have identified
a gene variant that may increase the risk of late-onset Alzheimer's
disease. In the March 3 New England Journal of Medicine they
report that specific changes in the gene for a protein called ubiquilin-1
are associated with an increased incidence of Alzheimer's in two
large study samples. The discovery could lead to improved understanding
of the disease mechanism and a new target for the development of
preventive and treatment strategies.
"We believe this variant moderately but significantly raises
the risk of Alzheimer's disease," says Lars Bertram, MD, of
the Genetics and Aging Unit at MIND, lead author of the study. "We
now have to pinpoint the biological defects that accompany this
finding, which also needs to be independently replicated in other
Alzheimer's sample groups." Bertram is an assistant professor
of Neurology at Harvard Medical School (HMS).
Mutations that raise the risk of Alzheimer's have been found in
four genes. Three of these - involving the amyloid precursor, presenilin
1 and presenilin 2 proteins - cause rare, inherited, early-onset
forms of the devastating disorder. The only genetic variation associated
with the more common late-onset form is ApoE4, which increases risk
but does not directly cause the disease. Researchers expect that
several additional genes that affect the risk of developing Alzheimer's
may be found.
In 2003, the same research team published results of a full-genome
screen of Alzheimer's patients and their affected siblings in a
sample of 437 families compiled by the National Institute of Mental
Health (NIMH). That study identified several potential chromosome
"hotspots" that could be associated with increased risk,
one of the strongest on chromosome 9. Since the gene for ubiquilin-1,
which is known to interact with the presenilins, resides in the
same area of chromosome 9, the researchers chose to test it as a
candidate gene.
For the current study the investigators analyzed several sequence
variations in ubiquilin-1 and two other candidate genes located
nearby on chromosome 9. With the assistance of colleagues from Neurogenetics,
Inc., the MIND researchers used a technique called family-based
genetic association analysis to evaluate 19 sequence changes in
these three genes, searching for alterations more likely to appear
in patients with Alzheimer's. After first screening families from
the same NIMH study group examined in the 2003 full-genome screen,
they retested potential associations in a separate group of 217
sibling pairs. The results confirmed that particular changes in
the ubiquilin-1 gene sequence occurred more frequently in individuals
with Alzheimer's than in their unaffected siblings.
"The same variants of this gene conferred increased risk for
Alzheimer's in both of these large study groups," says Rudolph
Tanzi, PhD, director of the Genetics and Aging Unit and senior author
of the study. "It was very encouraging to have the results
confirmed in so many families."
The researchers then studied brain tissue from Alzheimer's patients
and controls to see if the identified gene variants actually change
the production of ubiquilin-1. In both groups, the same gene variants
that increased the risk of Alzheimer's also led to increased production
of a shorter form of ubiquilin-1, an overproduction that was even
more pronounced in the patients. "Now we need to figure out
what's wrong with too much ubiquilin-1 and with this different form,"
says Tanzi. "We need to look at how this variant interacts
with the presenilins and what effect that may have on the production
of A-beta," the protein that accumulates in the amyloid plaques
found in the brains of Alzheimer's patients. Tanzi is a professor
of Neurology at HMS.
The MGH researchers estimate that the increased risk accompanying
these ubiquilin-1 gene variants is less than half that conferred
by ApoE4. They and other research groups expect that 4 to 7 additional
gene variants may be found that confer similar levels of risk.
Co-authors of the NEJM report are Mikko Hiltunen, PhD, Michelle
Parkinson, Martin Ingelsson, MD, Karunya Ramasamy, Kristina Mullin,
Rashmi Menon, Andrew Sampson, Monica Hsiao, Thomas Moscarillo, Bradley
Hyman, MD, and Deborah Blacker, MD, ScD, all of the MGH; Christoph
Lange, PhD, Harvard School of Public Health; and Kathryn Elliott,
Gonul Velicelebi, PhD, Steven Wagner, PhD, and David Becker, PhD,
Neurogenetics, Inc. The study was supported by grants from NIMH,
the National Institute on Aging, the Alzheimer Association, the
Deutsche Forschungsgemeinschaft, the Harvard Center for Neurodegeneration
and Repair, and the National Alliance for Research on Schizophrenia
and Depression.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $450 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
|
|
 |
