Genetic Variants in a Haplotype Block Spanning IDE are Significantly Associated with Plasma Aβ42 Levels and Risk for Alzheimer Disease

Nilüfer Ertekin-Taner, Mariet Allen, Daniel Fadale, Leah Scanlin, Linda Younkin, Ronald C. Petersen, Neill Graff-Radford, Steven G. Younkin

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Aβ42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Aβ42 in 24 extended LOAD families and for association with LOAD in two independent case-control series. One series (MCR, 188 age-matched case-control pairs) did not show association (p = 0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age-matched case-control pairs) showed significant (p = 0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR] = 5.1, p = 0.003) and H2(H7) haplotypes (OR = 0.60, p = 0.04) had the same effects previously reported. In this series, the H8 haplotype (OR = 2.7, p = 0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Aβ42 (p = 0.02). In addition, the H5(H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Aβ42 (p = 0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD.

Original languageEnglish (US)
Pages (from-to)334-342
Number of pages9
JournalHuman mutation
Issue number4
StatePublished - 2004


  • AD
  • APP
  • Alzheimer Disease
  • Amyloid beta
  • IDE
  • Insulin-degrading enzyme
  • LOAD

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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