Susceptibility Alleles in IDE Region on Chromosome 10

The effort to identify genes with alleles that influence susceptibility to late onset AD (LOAD) proceeds logically from linkage to association and then to identification of specific susceptibility alleles. Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for LOAD, we obtained linkage at approximately 80 centimorgans (cM) on chromosome 10 (Ch10). Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Pursuing these findings, we have now identified three Ch10 genes (VR22, PLAU, and IDE) with variants that show strong association with LOAD and/or plasma Abeta42. The proposed study focuses exclusively on IDE. There is compelling biological evidence from IDE knockout mice that the insulin degrading enzyme is normally involved in Abeta degradation, so IDE is clearly an excellent candidate gene. In our MCJ series, LOAD showed highly significant (p