28 Jan 2002

Despite much research, it has been difficult to pin down precisely how inflammation contributes to Alzheimer's disease. This endeavor is now drawing fresh support from single nucleotide polymorphism (SNP) analysis. This rapidly growing field has to date linked to increased risk for AD at least 10 polymorphisms in the inflammatory agents interleukin-1α , interleukin-1β, interleukin 6, tumor necrosis factor-α , α₂-macroglubulin, and α₁-antichymotrypsin. These proteins are all upregulated in AD tissue, and some are made by activated microglia and astrocytes in the vicinity of pathological lesions.

In a recent review discussing these polymorphisms, Pat McGeer and Edith McGeer, of the University of British Columbia in Vancouver, write that they are all fairly common in the general population, making it likely that most people have inherited at least one of them. The authors suggest that a given set of inherited SNPs could create a "susceptibility profile" for AD that represents the combined, perhaps synergistic, influence of these high-risk alleles.

To quote a few examples from the review: the IL-1α889 regulatory region exists in a C and a T allele, and four independent groups have reported a link between the T/T allele and early onset AD. A T/T allele of the acute-phase protein α₁-antichymotrypsin appears to be linked to a slight increase in AD risk in an Italian population, but the simultaneous presence of this and the Il-1α889 T/T allele strongly combined to a more robust odds ratio of 5.6 for developing AD over people without those alleles.

Also noteworthy is that the polymorphisms associated with increased AD risk tended to produce chronically elevated levels of the given protein in the serum of the study subjects. Finally, some of the polymorphisms in question had previously been linked to peripheral inflammatory disorders. Together, these findings suggest that people carrying these polymorphisms may be especially sensitive to abnormalities that provoke a chronic inflammatory response, write the McGeers. If larger and more detailed genetic analyses of SNPs enable, in the future, the establishment of inflammatory risk profiles, physicians could consider presymptomatic administration of specific anti-inflammatory drugs (see above story) for those at high risk.—Gabrielle Strobel

See ARF Hypothesis.