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).


METHODS
A case-control study with 2 independent study populations of patients with AD and age-matched, cognitively normal control subjects.


METHODS
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.


METHODS
Five hundred seventeen patients with AD and 390 control subjects.


METHODS
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 epsilon4; 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.
Finckh
U
U
Division of Psychiatry Research, University of Zurich, August Forel Str 1, 8008 Zurich, Switzerland.
von der Kammer
H
H
Velden
J
J
Michel
T
T
Andresen
B
B
Deng
A
A
Zhang
J
J
Müller-Thomsen
T
T
Zuchowski
K
K
Menzer
G
G
Mann
U
U
Papassotiropoulos
A
A
Heun
R
R
Zurdel
J
J
Holst
F
F
Benussi
L
L
Stoppe
G
G
Reiss
J
J
Miserez
A R
AR
Staehelin
H B
HB
Rebeck
G W
GW
Hyman
B T
BT
Binetti
G
G
Hock
C
C
Growdon
J H
JH
Nitsch
R M
RM
D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D016015:Logistic Models; D008297:Male; D008609:Mental Status Schedule; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012306:Risk
D001057:Apolipoproteins E; C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins