New Gene Variation a Factor in Alzheimer's disease

The genetic clue, which could lead to a better determination of one cause of AD, was reported January 14, 2007, online in the journal Nature Genetics. The researchers suggest that defective versions of the SORL1 gene contribute to formation of amyloid plaques, a characteristic sign of Alzheimer's in the brains of individuals suffering from the disease. They identified 29 variants that mark comparatively short segments of DNA where disease-causing changes could lie. The study did not, however, identify specific genetic alterations that result in AD.

Richard Mayeux, M.D., from Columbia University (New York, NY, USA), Lindsay Farrer, Ph.D., from Boston University (Boston, MA,USA), and Peter St. George-Hyslop, M.D., from the University of Toronto (Canada), led the study, which involved 14 collaborating institutions in North America, Europe, and Asia, and 6,000 individuals who donated blood for genetic typing. The study was funded by U.S. National Institutes of Health's (NIH; Bethesda, MD, USA) National Institute on Aging (NIA) and National Human Genome Research Institute (NHGRI), as well as by 18 other international public and private organizations.

"We do not fully understand what causes Alzheimer's disease, but we know that genetic factors can play a role,” reported NIA director Richard J. Hodes, M.D. "Scientists have previously identified three genes, variants of which can cause early onset Alzheimer's, and one that increases risk for the late onset form. This discovery provides a completely new genetic clue about the late onset forms of this very complex disease. We are eager to investigate the role of this gene further.”

Scientists believe that in AD, amyloid precursor protein (APP) is processed into amyloid beta protein fragments that make up plaques in the brain. The researchers began their search for genetic effects amongst a group of proteins that transport APP within cells, looking for small changes, or "misspellings,” in seven genes involved in moving APP within cells.

To begin, the researchers reviewed two large data sets of genetic information from families in which more than one individual has Alzheimer's disease. They were soon able to see that many of the families with AD had variations in the SORL1 gene but not consistently in any of the other six genes. They then expanded their search to genetic data sets from families of Northern European, Caribbean Hispanic, Caucasian, African American, and Israeli Arab heritage for changes in the SORL1 gene. Again, they discovered the same association between SORL1 variations and AD. Searching additional data sets provided by Steven Younkin, M.D., Ph.D., from the Mayo Clinic (Rochester, MN, USA) additionally confirmed the association of SORL1 variations and Alzheimer's.

"We are seeing the gene implicated in multiple data sets, across ethnic and racial groups,” said Dr. Farrer. He added that the group was "encouraged and excited” by cell biology studies that demonstrate SORL1's role in production of beta amyloid fragments.

Studying blood cells from individuals with and without AD, the researchers found less than half the level of SORL1 protein in people with AD compared to individuals without the disease. In laboratory studies, they found that changing the levels of SORL1 altered the way APP was traveled in cells, with low levels of SORL1 resulting in increased production of amyloid beta fragments, whereas high levels decreased production. However, the researchers noted, other genetic and non-genetic factors are likely to affect SORL1 production in individuals, and more research is needed to determine the how different versions of the SORL1 gene influence production of the damaging protein fragments.



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