6 May 1999. 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.
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. Abstract
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, Pericak-Vance MA, et al. An alpha-2-macroglobulin insertion-deletion polymorphism in Alzheimer disease. Nat Genet 1999 May;22(1):19-22. Abstract
Rudrasingham V, Wavrant-De Vrieze F, Lambert JC, Chakraverty S, Kehoe P, Crook R, Amouyel P, Wu W, Rice F, Perez-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. Abstract