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New gene targeted for Alzheimer disease

Press release from Case School of Medicine | January 15, 2007

Cleveland, OH - Robert Friedland, M.D., Professor in the Department of Neurology, and a team of investigators at Case School of Medicine, in collaboration with an international effort by researchers led by Boston University School of Medicine (BUSM), the University of Toronto and Columbia University Medical Center, have uncovered a major new gene SORL1 ֖ for late-onset Alzheimer disease. Replicated in four distinct ethnic groups, SORL1 is only the second gene discovered for late-onset Alzheimers. APOE, the first gene, was identified in 1993.
"Understanding how the forms of the SORL1 gene associated with increase risk alter protein handling will suggest novel pharmacological or lifestyle modifications to slow [Alzheimer disease] progression."
- Robert Friedland, M.D., Professor in the Department of Neurology, Case School of Medicine

In an article published in Nature Genetics (February print edition; Jan. 14 advance online edition), researchers describe how variants in the SORL1 gene were found to be more common in people with late-onset Alzheimers than in healthy people the same age. This suggests that these genetic variations alter the normal function of SORL1, resulting in Alzheimer disease. People with these genetic variants may not produce normal amounts of SORL1, suggesting that this gene has a protective function when working properly. The researchers believe that the reduction of SORL1 in the brain increases the likelihood of developing Alzheimer disease.

An important aspect of their findings was that the association between Alzheimer disease and SORL1 was replicated in four distinct ethnic groups: North American and European Caucasians, African-Americans, Caribbean-Hispanics, and Arabs residing in Israel. Previous studies on the genetics of AlzheimerҒs used data from mostly Caucasian populations of American and European ancestry. This five-year study involved DNA samples from 6,000 volunteers.

Friedland reports that the work illustrates the value of diverse populations and international collaborations for understanding a complex disease such as Alzheimers. He also notes that the discovery of this new gene suggests new ways in which therapies can be developed, which is the ultimate goal of this work. ғCurrently available therapies cannot arrest the progress of the disease, Friedland notes. ԓUnderstanding how the forms of the SORL1 gene associated with increase risk alter protein handling will suggest novel pharmacological or lifestyle modifications to slow progression.

ԓInstead of scanning all the genes in the entire genome, we had an idea of what an Alzheimer disease-causing gene would look like based on past discoveries, said St. George-Hyslop, director of the Centre for Research in Neurodegenerative Diseases at the University of Toronto. ԓWe knew that the abnormalities in APP processing and the accumulation of its toxic Aβ peptide derivative cause Alzheimers, so we hypothesized that other genes associated with APP regulation might also cause the disease.Ҕ

SORL1 represents another critical piece of the Alzheimer disease puzzle. This appears to be the second late-onset Alzheimer disease gene, and there are likely to be other important genetic variants that need to be identified before the entire picture is complete,Ӕ said Richard Mayeux, M.D., co-director of the Taub Institute for Reseach on Alzheimers Disease and the Aging Brain at Columbia University Medical Center.

The research team also included Rivka Inzelberg, M.D., of the Technion Rappoport Faculty of Medicine, Technion-Israel Institute of Technology in Haifa, Israel, who led the study of a community of Arabs in northern Israel in collaboration with Dr. Friedland at CWRU, and Steven Younkin, M.D., Ph.D., chair of Department of Pharmacology at the Mayo Clinic College of Medicine in Jacksonville, FL., who provided DNA samples from several populations studied at the Mayo clinic.

Boston University School of Medicine chief of genetics Linday Farrer, Ph.D., cautions that more studies are needed. ғWhile we have identified several variants in SORL1 that show the same pattern of association across multiple ethnic groups with very different genetic makeup and lifestyle characteristics, it is unclear whether these variants influence the disease process directly or merely mark the location in the SORL1 gene of the biologically important variants, which have not yet been tested. SORL1 is a relatively large gene containing at least 500 known variants called single nucleotide polymorphisms (SNPs). We examined a representative sample of about 30 SNPs across SORL1 and, unfortunately, have not yet found a smoking SNPђ for Alzheimer disease.

Article has been adapted from a news release issued by Case School of Medicine. Click here for the original news release.

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