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Alpha2 macroglobulin and the risk of Alzheimer's disease
1Department of Pharmacology, Indiana University School of Medicine, Indianapolis, USA.
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.
Insights
A specific gene variant in alpha-2 macroglobulin (A2M) is associated with increased Alzheimer's disease (AD) risk. This A2M gene polymorphism may contribute to AD development, though less strongly than previously reported.
Area of Science:
- Neurogenetics
- Alzheimer's Disease Research
- Genetic Epidemiology
Background:
- Alpha-2 macroglobulin (A2M) is a proteinase inhibitor found in Alzheimer's disease (AD) plaques.
- A previously identified pentanucleotide deletion in the A2M gene showed association with AD in sibpair studies.
Purpose of the Study:
- To investigate the allele frequency of the A2M gene pentanucleotide deletion in independent AD patient and control cohorts.
- To characterize the association between this A2M polymorphism and AD risk.
Main Methods:
- Analysis of three independent association samples (309 AD patients, 281 controls).
- Detection of the A2M gene mutation using PCR and RFLP.
- Statistical adjustment for age, gender, education, and APOE genotype.
Main Results:
- The A2M gene polymorphism was associated with an increased risk of AD (Mantel-Haenszel ratio = 1.5, p=0.025).
- No significant age or gender-dependent effects were observed for A2M allele frequencies.
- An interaction between A2M and APOE-epsilon4 was observed in one sample, but not consistently across all samples.
Conclusions:
- The study supports an association between the A2M gene and Alzheimer's disease.
- The observed association in this cohort was less pronounced compared to prior sibpair study findings.