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2 Macroglobulin and the risk of Alzheimer’s disease
From the Departments of Pharmacology and Toxicology (Drs. Dodel, Du, and Gao) and Neurology (Drs. Glazier, Hake, Evans, and Farlow), Indiana University School of Medicine, Indianapolis; the Neuroscience Discovery Research (K.R. Bales and Drs. Altstiel and Paul) and the Department of Statistical and Mathematical Sciences (Dr. Eastwood), Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN; the Departments of Psychiatry and Behavioral Sciences (Drs. Gallagher-Thompson, Tinklenberg, Sullivan, Yesavage, and Murphy) and Medicine (Dr. Thompson), Stanford University School of Medicine, Stanford, CA; the Psychiatry Service (Drs. Tinklenberg and Yesavage), Veterans Affairs Palo Alto Health Care System, Palo Alto, CA; the Center for Health Sciences (Dr. Pfefferbaum), SRI International, Menlo Park, CA; Scios, Inc. (Dr. Cordell), Sunnyvale, CA; the Department of Psychiatry (Dr. Zimmer), Technische Universität, München; and the Department of Neurology (Dr. Gasser), Ludwig-Maximilians-Universität München, Germany.
Address correspondence and reprint requests to Dr. Yansheng Du, Department of Pharmacology and Toxicology, Indiana University Medical School, 635 Barnhill Drive, Indianapolis, IN 46202.
BACKGROUND: 
2 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 2 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-
4 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-4. In one of our three samples there was an interaction between the A2M and APOE-4 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.
Key words: AD—Polymorphism—Apolipoprotein E—2-Macroglobulin
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