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Alpha-2 macroglobulin is genetically associated with Alzheimer disease


Alpha-2-macroglobulin (α-2M; 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 Aß, the major component of ß-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2 ) confers increased risk for AD (Mantel-Haenzel odds ratio = 3.56, P = 0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P = 0.00009). These values were comparable to those obtained for the APOE-ε4 allele in the same sample, but in contrast to APOE-ε4, 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 unable to confirm in this sample. A2M, LRP1 (encoding the α-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid ß-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

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Figure 1: Map of chromosome 12 markers.


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The authors would like to thank E. Wijsman, K. Lunetta, N.Cox, D. Neuberg and P. VanEerdewegh for advice regarding statistical genetics; M. Hyde for assistance with data analysis; and S. Moldin and staff at NIMH and at all three sites for assistance with all aspects of the project. The authors are also extremely grateful to the families whose participation made this work possible. This work was supported by grants from the National Institute of Mental Health (NIMH) to M.S.A. (U01 MH46281, U01 MH51066), D.B. (K21 MH01118), N.M.L. (T32-MH17119), S.S.B. (U01 MH46290, U01 MH52042) and R.C.P.G. (U01 MH46373, U01 MH51024). The NIMH Alzheimer Disease Genetics Initiative is a multi-site study performed by three independent research teams in collaboration with extramural staff from the NIMH. The principal investigators and co-investigators from the three sites are: MGH, M.S.A., R.E.T. and D.B.; JHU, S.S.B., G. A. Chase and M. F. Folstein; UAB, R.C.P.G. and L. E. Harrell.

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Correspondence to Rudolph E. Tanzi.

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Blacker, D., Wilcox, M., Laird, N. et al. Alpha-2 macroglobulin is genetically associated with Alzheimer disease . Nat Genet 19, 357–360 (1998).

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