Filippini Nicola, Rao Anil, Wetten Sally, Gibson Rachel A, Borrie Michael, Guzman Danilo, Kertesz Andrew, Loy-English Inge, Williams Julie, Nichols Thomas, Whitcher Brandon, Matthews Paul M
The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, Oxford, UK.
Neuroimage. 2009 Feb 1;44(3):724-8. doi: 10.1016/j.neuroimage.2008.10.003. Epub 2008 Nov 1.
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.
APOEε4是散发性阿尔茨海默病（AD）中已明确的最佳遗传风险因素。然而，虽然纯合子比杂合子表现出更高的疾病易感性和更早的发病年龄，但他们可能并未表现出更快的临床进展速度。我们推测，APOEε4等位基因负荷对全脑神经病理学存在不同影响。我们的目的是确定APOEε4等位基因负荷与阿尔茨海默病（AD）中区域特异性脑皮质萎缩之间的关系。因此，我们使用83例AD患者的T1加权磁共振图像进行了基于体素的形态学测量（VBM），根据显性或基因型模型，按APOEε4负荷对比区域皮质灰质。患者符合NINCDS-ADRDA标准，并对APOEε4进行基因分型（15例ε4/ε4、39例ε4/-和29例-/-）。我们观察到，双侧内侧（MTL）和颞前叶的灰质体积（GMV）随等位基因负荷增加而呈累加性减少。相比之下，一个二自由度基因型模型表明APOEε4等位基因在左侧颞叶具有显性效应。在AD中，显示APOEε4等位基因负荷对GMV有显著影响的脑区仅包括一些通常被描述为具有最大淀粉样斑块沉积和萎缩的脑区。颞叶区域似乎显示出APOEε4等位基因负荷的显性效应，而非先前与发病年龄密切相关的累加效应。等位基因负荷的区域差异可能与APOEε4负荷对易感性和疾病进展影响的不同机制有关。
