Gene Controls Age at Onset of Alzheimer's and Parkinson's Diseases

DURHAM, N.C. - By applying a new technique that combines independent lines of genomic evidence, Duke University Medical Center researchers and colleagues have identified a single gene that influences the age at which individuals first show symptoms of Alzheimer's and Parkinson's diseases.

Such genes that can impact patients' age at onset for the two very prevalent neurological disorders are of particular interest as alternative targets for treatment, said Margaret Pericak-Vance, Ph.D., director of the Duke Center for Human Genetics. Drugs that delay the onset of Alzheimer's or Parkinson's diseases beyond the normal human lifespan would effectively prevent them in patients at risk for the disorders, she added.

Alzheimer's disease is the most common cause of dementia among people over the age of 65, affecting up to 4 million Americans. Parkinson's disease -- characterized by tremors, stiffness of the limbs and trunk, slow movements and a lack of balance -- afflicts approximately 50,000 Americans each year. Both are complex disorders involving multiple genes.

"Although physicians generally consider Alzheimer and Parkinson diseases to be distinct disorders, the two exhibit a lot of overlap both clinically and pathophysiologically," said Jeffery Vance, M.D., director of Duke's Morris K. Udall Parkinson's Disease Research Center and associate director of the Duke Center for Human Genetics. "This study emphasizes the similarity between the two diseases by highlighting a single gene that influences their age of onset."

The team reports their findings in the Dec. 15, 2003, issue (available online Oct. 21) of Human Molecular Genetics and will present the work as a keynote paper at the annual meeting of the American Society of Human Genetics, which will be held Nov. 4-8, in Los Angeles. The major funding for the study was provided by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the Alzheimer's Association, the Institute de France, and the American Federation for Aging Research.

The team's earlier work identified a broad chromosomal region linked to the age at onset of Alzheimer's and Parkinson's diseases. The new research -- led by Pericak-Vance, Vance, John Gilbert, Ph.D. and Yi-Ju Li, Ph.D., of the Duke Center for Human Genetics and Jonathan Haines, Ph.D., of Vanderbilt University Medical Center -- narrows that region of the genome, which contained many hundreds of genes, to a single gene known as glutathione S-transferase omega-1 or GSTO1.

The researchers overlaid three independent lines of genetic evidence to reveal those genes more likely to play a role in the disorders' age at onset -- a method, called genomic convergence, which the Duke team developed.

The researchers first focused on Alzheimer's disease by comparing the activity of genes in the hippocampus -- a part of the brain affected by the disorder -- of unaffected individuals and Alzheimer's patients. The experiment uncovered four genes, including GSTO1, located in the region of the genome earlier linked to age at onset, the researchers report.

An additional analysis involving 1,773 patients with Alzheimer's disease and 635 patients with Parkinson's disease later found that of those four genes, only GSTO1 showed genetic differences associated with age at onset.

"By combining evidence based on gene expression and genetic association, we found a gene that modifies when the diseases start," said Li, the study's first author. "Understanding the role this gene plays in Alzheimer and Parkinson diseases may, in the future, lead to a means to delay the disorders' onset," she added, noting that even a short delay would benefit at-risk patients.

The international research team included scientists representing 17 institutions in the United States, the United Kingdom and Australia. Additional funding was provided by the Hilles Families Foundation, the U.S. Public Health Service, the California Department of Health Services, the Fran and Ray Stark Foundation Fund for Alzheimer's Disease Research and GlaxoSmithKline.

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