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A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer’s disease

From Roskamp Institute (Dr. Crawford, M.J. Freeman, Dr. Schinka, L.I. Abdullah, Dr. Krivian, M.D. Morris, and Drs. Richards and Mullan), University of South Florida; Novartis Pharmaceuticals Corp (Drs. Hartman and Anand), East Hanover, NJ; Mt Sinai Medical Center (Dr. Duara), Miami Beach, FL; and Bristol Myers Squibb (Dr. Gold), Princeton, NJ.

Address correspondence and reprint requests to Dr. F.C. Crawford, Roskamp Institute, University of South Florida, 3515 E. Fletcher Ave., Tampa, FL 33613; e-mail: fcrawfor{at}com1.med.usf.edu

OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD.

DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls.

RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE 4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset.

CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author’s dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD.

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