Insulin degrading enzyme (IDE) is a potential candidate gene for late-onset Alzheimer's disease (LOAD), and it is found on [Chromosome 10]. IDE is a metallopeptidase that degrades a number of peptides including insulin, Aβ and the intracellular signalling domain of APP (Qiu et al 1998 Farris et al 2003 Farris et al 2004
Both positive (Bertram et al 2000 Ait-Ghezala et al 2002 and negative (Abraham et al 2001 Boussaha et al 2002 Nowotny et al 2005 associations have been reported with markers and haplotypes from or near to the IDE locus. No functional differences have been observed between associated haplotype variants, indicating that observed associations may be due to LD with another IDE variant or indeed another nearby gene (Edland et al 2003 Indeed, IDE is found within an LD block of 276kb that also harbours the kinesin family member 1 (KNSL1) and hematopoietically expressed homeobox (HHEX) genes (Prince et al 2003 However, a recent study has identified a novel IDE isoform that has a decreased ability to degrade insulin and Aβ, suggesting that IDE may well be directly involved (Farris et al 2005 Significant association has been reported with quantitative traits pertinent to AD diagnosis and severity, particularly when analysing haplotypes (Prince et al 2003 Age-at-onset (AAO) was one of the quantitative traits examined and the evidence suggests that an LD block in the 3’ region of IDE affects AAO for both AD and Parkinson’s disease (PD) (Blomqvist et al 2004 Furthermore, consistent with its function in A degradation, variation in IDE is associated with the extent of A deposition in the brain, and rather than determining AD risk, variation in this gene may influence disease severity (Blomqvist et al 2005
Conflicting results regarding IDE and LOAD may be due to variation at the APOE locus. Reanalysis of genotyping data from the Abrahams et al study identified 2 blocks of LD, the second of which was associated with AD due to a protective haplotype in APOE ε4 negative subjects (Edland et al 2003 In contrast, closer analysis of a study in the Han-Chinese population reported that observed association between IDE and AD was due to individuals that carried the APOE 4 allele (Bian et al 2004 However, individuals carrying an APOE ε4 allele have decreased brain IDE levels (Cook et al 2003 In addition to a possible role in AD, partial loss-of-function IDE mutations in mice can lead to type 2 diabetes [T2D] (Farris et al 2004 Hyperinsulinaemia is associated with prevalent AD in people who do not have an APOE ε4 allele. Furthermore, insulin-mediated glucose clearance is slower in individuals without an APOE ε4 allele. This suggests that insulin resistance is a feature of ε4 negative AD and that APOE genotype is important in understanding insulin-related risk factors for AD.
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6/6/2012 2:43:17 PM - 188.8.131.52