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A common mutation in the alpha2-microglobulin (A2M) gene on chromosome 12 makes carriers 3.5-4 fold more susceptible to the common, late-onset form of Alzheimer's disease [Blacker, D. et al. (1998) Nature Genet. 19, 357-360]. A2M was investigated as a suspect because the protein is known to interact with other proteins implicated in the pathogenesis of Alzheimer's, including beta-amyloid protein and apolipoprotein E. The association between A2M and Alzheimer's risk was uncovered by comparing the frequency of the A2M mutation in Alzheimer's patients with its frequency in their unaffected siblings. The mutation, which is a small deletion, is found in 30% of the population, and increases Alzheimer's risk to the same extent regardless of the APOE genotype (see Alzheimer's disease summary in the Information database for information on the association between the APOE4 allele and Alzheimer's disease risk). In a separate study also reported in Nature Genetics, another group of researchers have found that, within a large group of elderly people, those who developed Alzheimer's disease did so earlier if they carried an APOE4 allele [Meyer, M. et al. (1998) Nature Genet. 19, 321-322]. The suggestion has been made that the A2M mutation may be a strong factor in determining whether someone will get Alzheimer's disease, while the presence or absence of an APOE4 allele determines when (see News and Views article by Jean Marx in the 24 July issue of Science for more details).

Comment: Assuming it can be confirmed by studies in other populations, the A2M association with Alzheimer's makes a major contribution to the understanding of the causes of Alzheimer's disease. Like APOE4 genotype, however, A2M genotype is not a definite predictor of Alzheimer's and there are no grounds for genetic testing or screening for the mutation, except in a research setting. The most important implication of the finding may be the potential for developing new drugs to combat the disease.