GENETIC ASSOCIATION OF AN ALPHA-2-MACROGLOBULIN (VAL1000ILE) POLYMORPHISM AND ALZHEIMERS-DISEASE

alpha 2-Macroglobulin (A2M) is a proteinase inhibitor found in associa tion with senile plaques (SP) in Alzheimer's disease (AD). A2M has bee n implicated biochemically in binding and degradation of the amyloid b eta (A beta) protein which accumulates in SP. We studied the relations hip between Alzheimer's disease and a common A2M polymorphism, Val1000 (GTC)/lle1000 (ATC), which occurs near the thiolester active site of the molecule. In an initial exploratory data set (90 controls and 171 Alzheimer's disease) we noted an increased frequency of the G/G genoty pe from 0.07 to 0.12. We therefore tested the hypothesis that the G/G genotype is over-represented in Alzheimer's disease in an additional i ndependent data set: a group of 359 controls and 566 Alzheimer's disea se patients. In the hypothesis testing cohort, the G/G genotype increa sed from 0.07 in controls to 0.12 in Alzheimer's disease (P < 0.05, Fi sher's exact test). The odds ratio for Alzheimer's disease associated with the G/G genotype was 1.77 (1.16-2.70, P < 0.01) and in combinatio n with APOE4 was 9.68 (95% CI 3.91-24.0, P < 0.001). The presence of t he G allele was associated with an increase in AP burden in a small se ries. The A2M receptor, A2M-r/LRP, is a multifunctional receptor whose ligands include apolipoprotein E and the amyloid precursor protein. T hese four proteins have each been genetically linked to Alzheimer's di sease, suggesting that they may participate in a common disease pathwa y.