Genetic variants of a protein involved in determining the fate of amyloid precursor protein are associated with an increased risk of developing Alzheimer's disease, reported Dr. Ekaterina Rogaeva of the University of Toronto and her associates.
The increased risk for the disease appears to be caused by certain haplotypes of the SORL1 gene that decrease the expression of the gene. As a result, more amyloid precursor protein follows a pathway in which excess amyloid-[beta] peptide is produced in the brain--one of the central events in the pathogenesis of Alzheimer's disease (AD), according to the investigators.
Dr. Samuel E. Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia, said the study's results "fit well into the amyloid model for Alzheimer's, and that's certainly the one that's getting the most attention and most assessment clinically."
Dr. Rogaeva and her colleagues found that several overlapping haplotypes in two different regions of the SORL1 gene increased the likelihood of developing late-onset familial Alzheimer's disease (FAD), based on results obtained from two cohorts of families with late-onset FAD and later replicated in a cohort of cases and controls in other studies.
"Taken together, our results suggest that genetic and possibly environmentally specified changes in SORL1 [protein] expression or function are causally linked to the pathogenesis [of Alzheimer's disease] and have a modest effect on risk for this disease," the researchers said (Nat. Genet. 2007 Jan. 14 [Epub doi:10.1038/ngl943]).
The initial "discovery cohort" comprised 124 northern European FAD families and 228 Caribbean Hispanic FAD families. The "replication cohort" consisted of northern European individuals from a case-control study (178 cases with sporadic AD and 242 controls with self-identified white European ancestry), 276 white sib-ships from the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study, 238 African American sib-ships from the MIRAGE study, and Israeli Arab individuals (111 with AD and 114 normal controls from the Wadi Ara population study).
The researchers confirmed the association between AD and the SORL1 gene by genotyping the single-nucleotide polymorphisms that were contained in the haplotypes and then analyzing them at an independent facility in three series of cases and controls of European ancestry from different Mayo Clinic centers (totaling 1,405 late-onset AD cases and 2,124 controls). …