Search for Alzheimer’s Risk Narrows In on Chromosome 10

For several years researchers have focused on a gene on chromosome 19 as the only recognized risk factor for late-onset Alzheimer’s disease (AD). Three new research studies strongly suggest, however, that a gene or genes on chromosome 10 may also increase one’s risk of developing the most common form of the disease.

The new research reports, appearing in the December 21, 2000, issue of Science, each separately reported the association of late-onset AD with markers within a region of chromosome 10. However, specific locations, or genes, were not identified in these studies. Scientists will have to sort through each of the more than one hundred genes in the chromosome regions identified to find the gene or genes that might be at work in AD.

“With the aging of the baby boomers, the urgency to understand Alzheimer’s disease increases every day,” said Richard J. Hodes, M.D., director of the National Institute on Aging, which funded the research with the National Institute of Mental Health (NIMH).

“These findings,” said Hodes, “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.”

Laying the Groundwork

Steven E. Hyman, M.D., director of NIMH, explained the significance of the independent findings of the three groups. “It is indeed gratifying that three separate groups using different methods and different data sets 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.”

The three studies, one by Alison Goate, Ph.D., at Washington University School of Medicine in St. Louis and colleagues, the second by a group led by Michael Hutton, Ph.D., and Steven Younkin M.D., Ph.D., at the Mayo Clinic in Jacksonville, Fla., and the third directed by Rudolph E. Tanzi, Ph.D., professor of neurology at Harvard Medical School, partly involved the NIMH Human Genetics Initiative.

The NIMH initiative involves families in which two or more family members have developed AD as well as other families with prominent histories of other mental disorders such as schizophrenia, bipolar disorder, depression, and autism. Currently 12 research groups are studying families from the initiative with AD.

Goate’s group looked at the genetics of hundreds of pairs of siblings, each of whom had developed AD. The researchers narrowed their focus to a specific region of chromosome 10 and found a strong “suggestive link” with AD. They believe the AD susceptibility gene is located in this region of chromosome 10 and that the gene could be as important in its influence as the one previously identified on chromosome 19.

Simultaneous Corroboration

Hutton’s Mayo Clinic group conducted a detailed analysis of families with a high incidence of AD, looking at genetic factors among 124 people in five families where the AD patient had high blood levels of A-beta-42, a specific form of the beta amyloid protein thought to be a marker for the development of late-onset AD.

They found that the level of A-beta-42 in the blood of family members was linked to the same small region of chromosome 10 identified by the Goate study, suggesting that the new “AD gene” acts to elevate A-beta-42.

“An important difficulty in this field has been that an apparently interesting new locus will be identified that then fails to be confirmed,” said Mayo Clinic’s Younkin. “But here, the Goate study and our study have obtained mutually confirmatory results using separate subjects and two completely different methods. That’s the power of these new results.”

Tanzi’s group at Harvard also provided strong evidence of a possible new AD gene on chromosome 10, again using a different method in a different population. The group studied more than 400 families with AD and zeroed in on a region of chromosome 10 surrounding the gene for insulin-degrading enzyme (IDE). IDE is thought to be involved in the breakdown of beta amyloid, with a defect in the gene causing the neurotoxic protein to build up in the brain, leading to the development of AD.

Tanzi’s analysis provided strong evidence for a new gene near the IDE location on chromosome 10. However, this region is at some distance on chromosome 10 from the one suggested in the other two reports.

Next Step

Mayo Clinic’s Younkin said that “the race is now on” to find the implicated gene or genes. “We still have a long way to go. The next step will be to find the chromosome 10 genes and to figure out how they work. If things go as they have historically gone in this field that will take us to new therapeutic targets.” Possibilities include the development of medications to counteract or block the gene’s effects or primary gene therapy to replace the defective gene with a normally functioning copy, he explained.

More information on the NIMH initiative as well as the three research reports is available on the Web at www.grb.nimh.nih.gov/gi.html. ▪