P1‐068: Cognitive phenotypes in Alzheimer's disease and insulin degrading enzyme gene variants

Alzheimer's disease (AD) is usually considered as a condition that initially affects memory, though clinical presentation is variable. ‘Typically’ AD presents with a constellation of memory and other cortical deficits. Other cognitive phenotypes exhibiting more circumscribed deficits have been identified. Such clinical distinctions are topographically mirrored on neuroimaging. Those factors that influence phenotypic variation within the diagnosis of AD are poorly understood, though family history and Apolipoprotein E (APOE) ∊4 allele status are closely associated. We have previously found that APOE ∊4 allele is associated with AD presentations predominantly affecting memory, and thereby temporal lobe dysfunction. Pathogenetically, ApoE protein may act in the brain through facilitating amyloidosis. We explored the hypothesis that other genetic factors favouring β-amyloid deposition, such as the insulin degrading enzyme gene (IDE), may likewise bear phenotypic influence. 181 subjects with a diagnosis of probable AD were included in this study. All subjects had detailed clinical history, neurological examination and neuropsychological profiling. Subjects were classified, according to data obtained at time of initial clinical referral, into one of the following cognitive phenotype categories: typical (TP), amnestic or memory/semantic (Limbic/LT), language (Lang), visual or apraxic (Post) and frontal. Subjects were genotyped for 10 single nucleotide polymorphisms for IDE, representing those tagging variants identified in previously published studies. For analytical purposes, the few subjects with a frontal presentation (n = 3) were excluded. Of the 10 IDE polymorphisms studied, only rs17875327IDE was associated with a particular cognitive phenotype. Homozygosity for the T-allele occurred in 93% of Limbic/LT, 88% Lang, 80% of TP, and 63% of Post cases. The frequency of the TT homozygote in limbic/LT cases, compared to other phenotypic presentations, was statistically significant (p < 0.05). We have previously shown that possession of APOE ∊4 allele is predominant in the Limbic/LT group, compared to other cognitive phenotypes. Here we show a polymorphism in the IDE gene to be similarly associated with cognitive phenotypes predominantly affecting memory. This suggests that the APOE ∊4 allele and this IDE polymorphism might act synergistically to drive an underlying pathogenic mechanism which favours β-amyloid deposition in vulnerable temporal lobe structures such as the hippocampus.