Anatomically-distinct genetic associations of APOE ε4 allele load with regional cortical atrophy in Alzheimer's disease

APOE epsilon 4 is the best-established genetic risk factor for sporadic Alzheimer's disease (AD). However, while homozygotes showgreater 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 epsilon 4 allele-load dependent influences on neuropathology across the brain. Our aim was to de. ne the relationship between APOE epsilon 4 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 epsilon 4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE epsilon 4 (15 epsilon 4/epsilon 4, 39 epsilon 4/- 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 epsilon 4 allele in the left temporal lobe. Brain regions showing a significant APOE epsilon 4 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 epsilon 4 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 epsilon 4 load on susceptibility and disease progression. (C) 2008 Elsevier Inc. All rights reserved.