Individuals with particular variants of the gene SORL1 have a modestly elevated risk of late-onset Alzheimer disease, according to a study to be published in the February 2007 issue of Nature Genetics. If confirmed in additional studies, SORL1 represents the second genetic risk factor for this most common form of the disease, usually diagnosed after age 65.
The key event in the progression of Alzheimer disease is the generation of A-beta peptide from a protein called amyloid precursor protein (APP). The A-beta peptide is toxic to neurons, and is thought to be a trigger for the neurodegeneration observed in the disease. Previous research suggests that brain tissue from individuals with the disease had reduced levels of several proteins that modulate the processing of APP into A-beta, but it was unclear whether these were causal changes.
Peter St. George-Hyslop and colleagues searched for variants in genes encoding several APP-processing proteins that might be associated with Alzheimer disease. By analyzing six different populations of individuals from different ethnic backgrounds, they identified two clusters of variants in SORL1 that were significantly overrepresented in those with the disease.
In addition to these genetic data, the authors provided preliminary evidence that individuals with Alzheimer disease tend to have lower levels of SORL1 in blood cells. Moreover, they show that experimentally reducing the level of SORL1 in cultured cells promotes the production of A-beta peptide, suggesting a potential mechanism whereby these SORL1 variants increase the risk of neurodegeneration.
Peter St. George-Hyslop (University of Toronto, Ontario, Canada)
Lindsay Farrer (Boston University School of Medicine, Boston, MA, USA)
Richard Mayeux (Columbia University College of Physicians and Surgeons, New York, NY, USA)
Steven Younkin (Mayo Clinic, Jacksonville, FL, USA)
Abstract available online.
(C) Nature Genetics press release.
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