Genetic association of an alpha2-macroglobulin (Val1000lle) polymorphism and Alzheimer's disease

alpha2-Macroglobulin (A2M) is a proteinase inhibitor found in associationwith senile plaques (SP) in Alzheimer's disease (AD). A2M has beenimplicated biochemically in binding and degradation of the amyloid beta(Abeta) protein which accumulates in SP. We studied the relationshipbetween Alzheimer's disease and a common A2M polymorphism, Val1000(GTC)/Ile1000 (ATC), which occurs near the thiolester active site of themolecule. In an initial exploratory data set (90 controls and 171Alzheimer's disease) we noted an increased frequency of the G/G genotypefrom 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotypeis over-represented in Alzheimer's disease in an additional independentdata set: a group of 359 controls and 566 Alzheimer's disease patients. Inthe hypothesis testing cohort, the G/G genotype increased from 0.07 incontrols to 0.12 in Alzheimer's disease (P < 0.05, Fisher's exact test).The odds ratio for Alzheimer's disease associated with the G/G genotype was1.77 (1.16-2.70, P < 0.01) and in combination with APOE4 was 9.68 (95%CI 3.91-24.0, P < 0.001). The presence of the G allele was associatedwith an increase in Abeta burden in a small series. The A2M receptor,A2M-r/LRP, is a multifunctional receptor whose ligands includeapolipoprotein E and the amyloid precursor protein. These four proteinshave each been genetically linked to Alzheimer's disease, suggesting thatthey may participate in a common disease pathway.