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

Arch Neurol. 2000;57:1579-1583.

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 KspI 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 4; 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.

From the Departments of Human Genetics (Drs Finckh and Zurdel and Messrs Menzer and Holst) and Psychiatry (Drs Müller-Thomsen and Mann and Ms Zuchowski), University Hospital Hamburg-Eppendorf, Hamburg-Eppendorf, Germany; the Center for Molecular Neurobiology, University of Hamburg, Hamburg, Germany (Drs von der Kammer, Müller-Thomsen, and Nitsch, Mr Velden, Mss Michel, Andresen, Zhang, and Zuchowski); the Department of Neurology, Massachusetts General Hospital, Boston, Mass (Drs Rebeck, Hyman, and Growdon and Ms Deng); the Department of Psychiatry, University of Bonn, Bonn, Germany (Drs Papassotiropoulos and Heun); the Departments of Psychiatry and Human Genetics, University of Goettingen, Goettingen, Germany (Drs Stoppe and Reiss); the University of Basel, Basel, Switzerland (Drs Miserez, Staehelin, and Hock); the Scientific Institute for Research and Patient Care, Brescia, Italy (Drs Benussi and Binetti); and the Division of Psychiatry Research, University of Zurich, Zurich, Switzerland (Drs Hock and Nitsch and Ms Michel).

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