NIA News: AD Research Update
Scientists Pinpoint Gene Influencing Age-at-Onset
of Alzheimer's, Parkinson's
October 21, 2003
from ADEAR
WEBSITE
Scientists at Duke University Medical
Center have located a gene on chromosome 10 that they
believe influences the age-at-onset of Alzheimer's
disease and Parkinson's disease. Using a novel method
to match the genes of people affected with these diseases
with the age at which study participants started developing
symptoms, the scientists found that one gene, GSTO1
(glutathione S-transferase, omega-1), suspected to
be involved in inflammatory responses in the body,
was significantly associated with late onset of both
Alzheimer's and Parkinson's.
"This important work gives us a
new gene to look at which may affect the timing of
late-life forms of these devastating neurodegenerative
diseases," says Marcelle Morrison-Bogorad, Ph.D.,
associate director of the NIA for the Neuroscience
and Neuropsychology of Aging Program, which supported
the study, along with funding from the National Institute
of Neurological Disorders and Stroke (NINDS) and the
National Institute of Mental Health (NIMH).* "Further
study of this gene and how it works could open up
new avenues of research for delaying the onset of
Alzheimer's and Parkinson’s diseases, which share
some clinical and pathological characteristics."
The findings will be reported in the
December 15, 2003, issue of Human Molecular Genetics
(published online October 21) by lead investigators
Yi-Ju Li, Ph.D., Margaret Pericak-Vance, Ph.D., Jeffrey
M. Vance, M.D., Ph.D., and colleagues at Duke University
Medical Center, Durham, NC, along with Jonathan Haines,
Ph.D., of Vanderbilt University Medical Center, and
collaborators at Harvard University, University of
California Los Angeles, and the GlaxoSmithKline Genetics
Research Directorate.
The GSTO1 finding comes days after Duke
scientists from the same laboratory reported genes
associated with age-at-onset of AD in regions of two
chromosomes not previously linked to the disease:
a region on chromosome 2 strongly linked with early
onset AD and another on chromosome 15 with very late
onset AD. That study, by William Scott, Ph.D., and
Dr. Pericak-Vance at Duke and Dr. Haines at Vanderbilt,
appears in the November 2003 issue of the American
Journal of Human Genetics (published online October
17) and was funded primarily by the NIA, based on
Drs. Pericak-Vance and Haines' genomic screen in AD.**
Genetic factors affecting the risk of
developing these diseases have long been studied and
several have been identified. But neuroscientists
have also become increasingly interested in a specific
set of genes that might regulate the age-at-onset
of neurodegenerative diseases, influencing not whether,
but when, a person might develop a disease. Delaying
the onset of symptoms of Alzheimer’s disease
by even 5 years could greatly reduce the numbers of
people who will get the disease, Dr. Morrison-Bogorad
adds.
Last year, Drs. Pericak-Vance and Li
with colleagues at Duke reported a region on chromosome
10 that harbors at least one gene affecting age-at-onset
of the diseases. The current study used an approach
that these researchers term "genomic convergence"
to identify candidates from among the large number
of genes in that region which could be associated
with age-at-onset of the two conditions.
The approach applied gene expression
studies (which look at changes in the amount of any
gene products, such as proteins, in the brains of
people with the disease), genetic linkage studies
(finding out which regions in a chromosome harbor
genes that have effects on the age-at-onset of the
disease), and allelic association studies (looking
at how different forms, or alleles, of a gene affect
the variation of age-at-onset within family members)
to discover that the GSTO1 gene and possibly its neighbor
GSTO2 were the genes most likely to be involved in
the regulation of age-at-onset. Studies in other populations
with other study approaches will be required to confirm
the GSTO1 association, Dr. Morrison-Bogorad of the
NIA points out.
The research involved an Alzheimer's
study population of 2,600 people (1,773 with AD and
the others as controls) from four sites (Duke, Vanderbilt,
NIMH, and Indiana University) supported by the NIA.
The brain tissue samples were collected by the Kathleen
Bryan Alzheimer's Disease Research Center at Duke
University. There were 1,362 participants in the Parkinson's
research (635 with PD, and the others as controls)
collected in coordination with Duke's Morris K. Udall
Parkinson's Disease Research Center of Excellence,
supported by NINDS and directed by Dr. Vance. In this
study, the mean onset of Alzheimer's disease occurred
at about age 71 and mean onset of Parkinson's disease
occurred at about age 59.
The discovery of GSTO1 is of particular
interest, researchers say, because another recent
study has suggested that it is involved in modifying
the inflammatory molecule interleukin 1 beta. Inflammation
may play a role in the brain in both Alzheimer's disease
and Parkinson's disease, and research is underway
to see if reducing inflammation in the brains of patients
with these diseases will reduce symptoms or even prevent
the diseases.
Currently, the NIA is expanding its
Alzheimer's Disease Genetics Study in an effort to
speed up the discovery of genes involved in AD. The
study, coordinated by Columbia University with participation
of Indiana University's National Cell Repository for
AD (NCRAD), features a partnership with the Alzheimer's
Association to recruit more than 1,000 families with
late-onset AD. A related press backgrounder giving
additional details on the genetics study is available
by calling NIA at 301-496-1752.
The NIA leads the Federal research effort
on AD and age-related cognitive change. More information
on AD, including downloadable graphics for the media,
may be found at www.alzheimers.org, the NIA's Alzheimer's
Disease Education and Referral (ADEAR) Center web
site. ADEAR can also be reached toll-free at 1-800-438-4380.
NIA, NINDS, NIMH, and NCRR are components of the National
Institutes of Health, part of the U.S. Department
of Health and Human Services.
*Funding for Li et al research was also
provided by the American Federation for Aging Research,
the Alzheimer's Association, the Institut de France,
the California Department of Health Services, the
Fran and Ray Stark Foundation Fund for Alzheimer's
Disease Research, and GlaxoSmithKline, Inc.
**Support for the Scott et al paper comes from the
NIA, the National Institute for Neurological Disorders
and Stroke (NINDS), the National Institute of Mental
Health (NIMH), National Center for Research Resources
(NCRR), and the Alzheimer's Association.
