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

Ulrich Finckh, Heinz Von Der Kammer, Joachim Velden, Tiana Michel, Barbara Andresen, Amy Deng, Jun Zhang, Tomas Müller-Thomsen, Kathrin Zuchowski, Gunnar Menzer, Ulrike Mann, Andreas Papassotiropoulos, Reinhard Heun, Jan Zurdel, Frederik Holst, Luisa Benussi, Gabriela Stoppe, Jochen Reiss, André R. Miserez, Hannes B. StaehelinG. William Rebeck, Bradley T. Hyman, Giuliano Binetti, Christoph Hock, John H. Growdon, Roger M. Nitsch

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1579-1583
Number of pages5
JournalArchives of Neurology
Issue number11
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Neuroscience(all)


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