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.
*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.
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.nia.nih.gov/alzheimers, 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.