Papassotiropoulos (1201) began his presentation by reviewing the evidence for a role of cathepsin D, an aspartyl protease, in AD. Previous work has implicated catD as a secretase in the cleavage of APP. It is found in plaques and exhibits increased expression in AD. It has also been shown to degrade tau. However, there is no evidence that overall catD activity is increased in AD tissue, and A-beta is still produced in catD knockout mouse, indicating that the enzyme is not required for amyloid production. In the present study, the T allele (causing a valine at position 224 of the catD gene in exon 2) was found to be overrepresented in a population of 102 AD patients versus 191 age-matched controls (odds ratio of 2.6). This effect was independent of the ApoE4 genetic association. However, having both ApoE4 and the catD T allele resulted in a 10-fold greater risk of AD. The catD effect did not influence age at onset.

Altstiel (120.2) revisited the controversy surrounding the reported genetic association of α2-macroglobulin (a2M) with AD (see previous news report). His group, as is the case for several other groups, has not found increased disease risk with the a2M deletion. However, in the results reported at the meeting today, it was found that this deletion is associated with a higher density of neuritic plaques. This retrospective analysis was carried out on sections from five different brain regions from archived autopsy material from approximately 160 patients. Plaque number was found to be greater in tissue that was hemizygous for the deletion and even higher for homozygous deletions. A similar effect was found for E4, confirming previous studies. The effect of the a2M deletion was not age-specific, leading Altstiel to speculate that the impact of the a2M allele is on disease progression. Defining the interactions between the various genetic risk factors will no doubt keep investigators busy for a while yet.-Keith Crutcher.

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