Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease

Cerebral accumulation of amyloid beta protein (Aβ) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). Insulin degrading enzyme (IDE) is involved in Aβ degradation, therefore the gene encoding for insulin degrading enzyme is one of the candidate genes risky for AD. In Chinese Han populations we found three polymorphisms in IDE promoter: −1002T/G (rs3758505), −179T/C (rs4646953) and −51C/T (rs4646954). The −1002T and −51C alleles were over-represented in 357 sporadic AD (SAD) patients when compared to those in 331 healthy individuals. Furthermore, −1002T/G and −51C/T were in strong linkage disequilibrium and they constructed a relatively risky −1002T/−51C and a relatively protective −1002G/−51T. Luciferase reporter assay indicated −1002T/−51C had lower transcriptional activity than −1002G/−51T. A more marked increase in −1002T/−51C transcriptional activity was seen when under Aβ25-35 and serum deprivation treatment. The present study provides evidence that IDE promoter polymorphisms that significantly decrease IDE expression levels are associated with development of SAD.