Insulin-degrading enzyme, apolipoprotein E, and Alzheimer's disease.

Insulin-degrading enzyme (IDE) is a protease that degrades insulin and the beta-amyloid (Abeta) peptide implicated in Alzheimer's disease (AD). Hence, factors that influence IDE expression or IDE activity toward Abeta are potentially relevant to the etiology of AD. Hippocampal IDE mRNA levels are lower on average in subjects with an APOE epsilon4 allele, suggesting that the genetic risk conferred by APOE epsilon4 may be mediated in part by this allele's effect on IDE expression. Other factors that influence IDE may be relevant in non-epsilon4 carriers. For example, insulin, a competitive inhibitor of IDE activity toward Abeta, may be elevated in non-epsilon4 cases. We here report IDE gene promoter region variants that are associated with AD in subjects without an epsilon4 allele. If these promoter region variants prove to affect expression levels, they may be relevant to disease as well. Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted.