title: Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain.
abstract: Insulin degrading enzyme, encoded by IDE, plays a primary role in the degradation of amyloid beta-protein (A beta), the deposition of which in senile plaques is one of the defining hallmarks of Alzheimer's disease (AD). We recently identified haplotypes in a broad linkage disequilibrium (LD) block encompassing IDE that associate with several AD-related quantitative traits. Here, by examining 32 polymorphic markers extending across IDE and testing quantitative measures of plaque density and cognitive function in three independent Swedish AD samples, we have refined the probable position of pathogenic sequences to a 3' region of IDE, with local maximum effects in the proximity of marker rs1887922. To replicate these findings, a subset of variants were examined against measures of brain A beta load in an independent English AD sample, whereby maximum effects were again observed for rs1887922. For both Swedish and English autopsy materials, variation at rs1887922 explained approximately 10% of the total variance in the respective histopathology traits. However, across all clinical materials studied to date, this variant site does not appear to associate directly with disease, suggesting that IDE may affect AD severity rather than risk. Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Mia E-L
authors.initials: ME
authors.lastname: Blomqvist
authors.forename: Katy
authors.initials: K
authors.lastname: Chalmers
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.forename: Nenad
authors.initials: N
authors.lastname: Bogdanovic
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Wilcock
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Lars
authors.initials: L
authors.lastname: Feuk
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Brookes
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Kehoe
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Prince
mesh_terms: D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002874:Chromosome Mapping / Q000379:methods*; D004252:DNA Mutational Analysis / Q000379:methods; D004739:England / Q000453:epidemiology; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D006801:Humans; D007339:Insulysin / Q000235:genetics* / Q000378:metabolism*; D015810:Linkage Disequilibrium / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D040641:Quantitative Trait Loci / Q000235:genetics; D013223:Statistics as Topic; D013548:Sweden / Q000453:epidemiology
chemical_list: D016229:Amyloid beta-Peptides; D005819:Genetic Markers; D007339:Insulysin