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Back To Vidyya Scientists Suspect New Genetic Risk Factor for Late Onset Alzheimer's Disease

A Gene Or Genes On Chromosome 10 May Be Risk Factors For AD

Three new, separate research studies suggest that a gene or genes on chromosome 10 may be risk factors for late onset Alzheimer's disease (AD). The findings, reported in the December 22, 2000, issue of Science, are important new evidence that more than one gene may play a role in development of AD later in life.

AD is a progressive, degenerative disorder, characterized by amyloid plaques and neurofibrillary tangles in the brain, resulting in loss of memory and, finally, in loss of mental and physical function. Scientists involved in the trio of studies reported today by teams at a number of different laboratories think that this newly discovered genetic influence on late onset AD may possibly involve the processing of the amyloid protein (A), a peptide important in the formation of AD's hallmark amyloid plaques.

For the past several years, a particular form of the apolipoprotein E (APOE) gene on chromosome 19 has been the only widely recognized genetic risk factor in late onset Alzheimer's disease. Scientists have long suspected that more than one gene may be involved in increasing an individual's risk of developing late onset AD. Some reports have shown evidence of a risk factor gene on a region of chromosome 12, and investigators worldwide have searched intensively for other genes, on other chromosomes, that might also play a role.

The studies reported in Science this week were funded by the National Institute on Aging (NIA) and the National Institute of Mental Health (NIMH), parts of the National Institutes of Health (NIH). Scientists at these Institutes note that the findings are part of an accelerating pace of exciting research on AD.

"With the aging of the baby boomers, the urgency to understand Alzheimer's disease increases every day," says NIA Director Richard J. Hodes, M.D. "These findings of genetic loci associated with the disease can help us further identify the risk factors and describe the biological mechanisms at work in AD, bringing new promise in the search for ways to diagnose, treat, or prevent this devastating illness."

Steven E. Hyman, M.D., director of NIMH, says, "It is gratifying that three separate groups using different methods and datasets have implicated chromosome 10. We expect these important studies to set the groundwork for the discovery of a new gene that contributes to the vulnerability to Alzheimer's disease."

Even with such progress, considerably more testing to pinpoint the identity of the suspect genes needs to be done, researchers say. Scientists will have to sort through each of the hundred or so genes in these chromosome regions to find the gene or genes that might be at work in AD.

These latest findings involve:

  • Alison Goate, Ph.D., Washington University School of Medicine, St. Louis, Mo., and colleagues at the Mayo Clinic, Jacksonville, Fla.; University of Wales College of Medicine, Cardiff; Institute of Psychiatry, London, U.K.; and Institut de Biomedicina de Valencia-CSIC, Spain -- Goate's group confirmed their preliminary observation last year that chromosome 10 might harbor a genetic risk factor for late onset AD. Their latest analysis is the second of a two-stage screen, looking at the genetics of hundreds of pairs of siblings, each of whom had developed AD. Here, the group narrowed its focus to a specific region on chromosome 10 "suggestive" of a link with AD. The AD susceptibility gene in this region of chromosome 10, the group suggests, could be as important as APOE in its influence.

  • Michael Hutton, Ph.D., and Steven Younkin, M.D., Ph.D., of the Mayo Clinic in Jacksonville, Fla., and their colleagues at Mayo and the Southwest Foundation for Biomedical Research, San Antonio, Tex. - The Hutton/Younkin study, which was spearheaded by Mayo's Nilufer Ertekin Taner, M.D., conducted a detailed analysis of large AD families, looking at genetic factors among 124 people in five families where the founding AD patient had high blood levels of A42, a specific form of A thought to be a marker for eventual development of late onset AD. They found that the level of A42 in the blood of family members was linked to the same small region of chromosome 10 identified in the Goate study, suggesting that the new AD susceptibility locus acts to elevate A42.

  • Rudolph E. Tanzi, Ph.D., Harvard Medical School, and colleagues at the Harvard School of Public Health; Johns Hopkins University Medical Institutions; and the University of Alabama School of Public Health - Tanzi and colleagues also provided strong evidence of a novel AD locus on chromosome 10, but this one seems to be at some distance from the one found by Goate and Hutton/Younkin. The Tanzi group focused its attention on the chromosome region surrounding the gene for the insulin degrading enzyme (IDE that may be involved in degrading amyloid. Tanzi's analysis of more than 400 families with AD zeroed in on chromosome 10 at regions in close proximity to the IDE gene.

There are two types of AD -- early onset and late onset. In early onset AD, symptoms first appear before age 60. Some early onset disease runs in families and involves autosomal dominant, or inherited, mutations that are believed to be the actual cause of the disease. So far, three early onset genes with AD-causing mutations have been identified. Early onset AD is rare, about 5-10 percent of cases.

The findings reported December 22 concern late onset AD, the most common form of the disease, which develops in people 60 and older and is thought to be less likely to occur in families. Late onset AD may run in some families, but a gene may not be the absolute determinant of whether an individual will develop AD. Rather, the role of genes involved in late onset may be to modify the risk of developing AD by affecting factors involved in the formation of plaques and tangles or other AD-related pathologies in the brain. Scientists hope that by identifying and understanding the function of risk factor genes, as well as possible non-genetic factors like severe head injury, estrogen use, or education that may influence the development of AD, treatments can be developed and the progression of the disease can be slowed or stopped. It is estimated that up to 4 million Americans currently suffer from AD.

The researchers studied a number of populations of people with AD. In part of their research, both the Tanzi and the Goate groups studied families in which two or more family members developed AD. These families are part of the NIMH Human Genetics Initiative, an effort that also includes sets of families in which a number of individuals have mental disorders such as schizophrenia, bipolar disorder, depression, and autism. The NIMH initiative was established as a national resource of clinical data and DNA for use by qualified investigators. Currently, 12 groups are studying the families with AD. (More information on the NIMH Initiative is available at Other populations studied include a group from the NIA-supported Indiana Alzheimer's Disease Center National Cell Repository and cases of AD identified in the United Kingdom by Drs. Mike Owen and Simon Lovestone.

The Goate and Hutton/Younkin studies were funded by the NIA. The NIA is the primary federal agency supporting and conducting research on AD, from genetics and the basic biology of the disease to treatment and prevention and issues confronting caregivers. The Institute sponsors the Alzheimer's Disease Education and Referral (ADEAR) Center, which provides information to the public and health professionals on AD. ADEAR may be contacted at 1-800-438-4380 or through its website at

The Tanzi study was funded by the NIMH. The mission of the NIMH is to reduce the burden of mental illness through research on mind, brain, and behavior. This public health mandate demands that NIMH harness powerful scientific tools to achieve better understanding, treatment, and eventually prevention and cure of mental illness. More information on NIMH may be obtained by phoning 301-443-4513 or on the Web at

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