Alpha2 macroglobulin and the risk of Alzheimer's disease.
BACKGROUND
alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56).


METHODS
We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism.


RESULTS
We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors.


CONCLUSIONS
Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.
Dodel
R C
RC
Department of Pharmacology, Indiana University School of Medicine, Indianapolis, USA.
Du
Y
Y
Bales
K R
KR
Gao
F
F
Eastwood
B
B
Glazier
B
B
Zimmer
R
R
Cordell
B
B
Hake
A
A
Evans
R
R
Gallagher-Thompson
D
D
Thompson
L W
LW
Tinklenberg
J R
JR
Pfefferbaum
A
A
Sullivan
E V
EV
Yesavage
J
J
Alstiel
L
L
Gasser
T
T
Farlow
M R
MR
Murphy
G M
GM
Paul
S M
SM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D005091:Exons; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012307:Risk Factors; D000511:alpha-Macroglobulins / Q000235:genetics*
D001057:Apolipoproteins E; D000511:alpha-Macroglobulins