title: Anatomically-distinct genetic associations of APOE epsilon4 allele load with regional cortical atrophy in Alzheimer's disease.
abstract: APOE epsilon4 is the best-established genetic risk factor for sporadic Alzheimer's disease (AD). However, while homozygotes show greater disease susceptibility and earlier age of onset than heterozygotes, they may not show faster rates of clinical progression. We hypothesize that there are differential APOE epsilon4 allele-load dependent influences on neuropathology across the brain. Our aim was to define the relationship between APOE epsilon4 allele load and regionally-specific brain cortical atrophy in Alzheimer's Disease (AD). For this reason voxel-based morphometry (VBM) was performed using T1-weighted MR images from 83 AD patients, contrasting regional cortical grey matter by APOE epsilon4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE epsilon4 (15 epsilon4/epsilon4, 39 epsilon4/- and 29-/-). We observed that grey matter volume (GMV) decreased additively with increasing allele load in the medial (MTL) and anterior temporal lobes bilaterally. By contrast, a 2 degree-of-freedom genotypic model suggested a dominant effect of the APOE epsilon4 allele in the left temporal lobe. Brain regions showing a significant APOE epsilon4 allele load effect on GMV in AD included only some of those typically described as having greatest amyloid plaque deposition and atrophy. Temporal regions appeared to show a dominant effect of APOE epsilon4 allele load instead of the additive effect previously strongly associated with age of onset. Regional variations with allele load may be related to different mechanisms for effects of APOE epsilon4 load on susceptibility and disease progression.
authors.affiliation: The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Filippini
authors.forename: Anil
authors.initials: A
authors.lastname: Rao
authors.forename: Sally
authors.initials: S
authors.lastname: Wetten
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Gibson
authors.forename: Michael
authors.initials: M
authors.lastname: Borrie
authors.forename: Danilo
authors.initials: D
authors.lastname: Guzman
authors.forename: Andrew
authors.initials: A
authors.lastname: Kertesz
authors.forename: Inge
authors.initials: I
authors.lastname: Loy-English
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: Thomas
authors.initials: T
authors.lastname: Nichols
authors.forename: Brandon
authors.initials: B
authors.lastname: Whitcher
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001284:Atrophy / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology*
chemical_list: D053327:Apolipoprotein E4