ALPHA-2-MACROGLOBULIN IS GENETICALLY ASSOCIATED WITH ALZHEIMER-DISEASE

Alpha-2-macroglobulin (alpha-M-2; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease ( AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a del etion in the A2M gene at the 5' splice site of 'exon II' of the bait r egion (exon 18) revealed that inheritance of the deletion (A2M-2) conf ers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). T he sibship disequilibrium test (SDT) also revealed a significant assoc iation between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon 4 allele in the same sample, but in contrast to APOE-epsilon 4. A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were una ble to confirm in this sample. A2M, LRP1 (encoding the alpha-M-2 recep tor) and the genes for two other LRP ligands, APOE and APP (encoding t he amyloid P-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neur opathogenic pathway leading to AD.