Last year Deborah Blacker, Rudolph Tanzi and their colleagues reported finding a strong association between a deletion of exon 18 in the gene for α2 macroglobulin (A2M) and Alzheimer's disease. The odds ratio was 3.56, comparable to the odds that a person with the Apo4 allele would develop AD.
In this month's issue of Nature Genetics (1999 May; vol 22), Dow et al. (p. 16), Rudrasingham et al. (p. 17), and Rogaeva et al. (p. 19) report that they failed to find this association. "We think it's pretty clear that the search for the chromosome 12 Alzheimer's gene must continue," said Jonathan Haines, one of the authors of the Rogaeva et al. study.
Blacker and colleagues are not convinced, however. In their response (p. 21), they say they are not surprised that the case-control portions of the three studies do not replicate their family-based studies. They cite study design problems in these studies. And they feel vindicated that Rudrasingham et al. did find some (albeit weaker) correlations between A2M and AD when they analyzed some of the same family data Blacker et al. had used. Finally, Blacker et al. argue that there were problems with the application of statistical methods by these other three groups.—Hakon Heimer
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- Dow DJ, Lindsey N, Cairns NJ, Brayne C, Robinson D, Huppert FA, Paykel ES, Xuereb J, Wilcock G, Whittaker JL, Rubinsztein DC. Alpha-2 macroglobulin polymorphism and Alzheimer disease risk in the UK. Nat Genet. 1999 May;22(1):16-7; author reply 21-2. PubMed.
- Rudrasingham V, Wavrant-De Vrièze F, Lambert JC, Chakraverty S, Kehoe P, Crook R, Amouyel P, Wu W, Rice F, Pérez-Tur J, Frigard B, Morris JC, Carty S, Petersen R, Cottel D, Tunstall N, Holmans P, Lovestone S, Chartier-Harlin MC, Goate A, Hardy J, Owen MJ, Williams J. Alpha-2 macroglobulin gene and Alzheimer disease. Nat Genet. 1999 May;22(1):17-9; author reply 21-2. PubMed.
- Rogaeva EA, Premkumar S, Grubber J, Serneels L, Scott WK, Kawarai T, Song Y, Hill DL, Abou-Donia SM, Martin ER, Vance JJ, Yu G, Orlacchio A, Pei Y, Nishimura M, Supala A, Roberge B, Saunders AM, Roses AD, Schmechel D, Crane-Gatherum A, Sorbi S, Bruni A, Small GW, Conneally PM, Haines JL, Van Leuven F, St George-Hyslop PH, Farrer LA, Pericak-Vance MA. An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. Nat Genet. 1999 May;22(1):19-22. PubMed.