Genetic association of a cystatin C gene polymorphism with late-onset Alzheimer disease

Objective: To determine whether the cystatin C gene (CST3) is genetically associated with late-onset Alzheimer disease (AD). Design: A case-control study with 2 independent study populations of patients with AD and age-matched, cognitively normal control subjects. Setting: The Alzheimer's Disease Research Unit at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, for the initial study (n=260). For the independent multicenter study (n=647), an international consortium that included the Massachusetts Alzheimer's Disease Research Center at the Massachusetts General Hospital, Boston; the Scientific Institute for Research and Patient Care, Brescia, Italy; and Alzheimer's research units at the Universities of Basel and Zurich, Switzerland, and Bonn, Goettingen, and Hamburg, Germany. Participants: Five hundred seventeen patients with AD and 390 control subjects. Measures: Molecular testing of the Kspl polymorphisms in the 5' flanking region and exon 1 of CST3 and the apolipoprotein E (APOE) genotype. Mini-Mental State Examination scores for both patients with AD and control subjects. Results: Homozygosity for haplotype B of CST3 was significantly associated with late-onset AD in both study populations, with an odds ratio of 3.8 (95% confidence interval, 1.56-9.25) in the combined data set; heterozygosity was not associated with an increased risk. The odds ratios for CST3 B/B increased from 2.6 in those younger than 75 years to 8.8 for those aged 75 years and older. The association of CST3 B/B with AD was independent of APOE ε4; both genotypes independently reduced disease-free survival. Conclusions: CST3 is a susceptibility gene for late-onset AD, especially in patients aged 75 years and older. To our knowledge, CST3 B is the first autosomal recessive risk allele in late-onset AD.