28 January 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.
Reference:McGeer P and McGeer E. Polymorphisms in inflammatory
genes and the risk of Alzheimer's disease. Arch Neurol 2001 Nov;58(11):1790-2.
See ARF Hypothesis.