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

Objective: To investigate whether or not a coding polymorphism in the cysta tin C gene (CST3) contributes risk for AD. Design: A case-control genetic a ssociation study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. Results: The authors find a signifi cant interaction between the GG genotype of CST3 and age/age of onset on ri sk for AD, such that in the over-80 age group the GG genotype contributes t wo-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon 4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age, Analy sis 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 h as been well reported in the literature, prompting the suggestion that addi tional 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-onse t AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variati on in an amyloidogenic cysteine protease inhibitor may have pathologic cons equences for AD.