Northeastern Univ, Center for Translational NeuroImaging, Boston, MA, United States.
Dept of Psychiatry and Neurosciences, Univ California at Davis, United States.
Brain Res. 2020 Nov 15;1747:147030. doi: 10.1016/j.brainres.2020.147030. Epub 2020 Jul 31.
The APOE Ɛ4 genotype is the most prevalent genetic risk for Alzheimer's disease (AD). Women carriers of Ɛ4 have higher risk for an early onset of AD than men. Human imaging studies suggest apolipoprotein Ɛ4 may affect brain structures associated with cognitive decline in AD many years before disease onset. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers. Six-month old wild-type (WT) and human APOE Ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Quantitative volumetric analysis revealed areas involved in memory and arousal were significantly different between Ɛ4 and wild-type (WT) females, with few differences between male genotypes. Diffusion weighted imaging showed few differences between WT and Ɛ4 females, while male genotypes showed significant different measures in fractional anisotropy and apparent diffusion coefficient. Resting state functional connectivity showed Ɛ4 females had greater connectivity between areas involved in cognition, emotion, and arousal compared to WT females, with male Ɛ4 showing few differences from controls. Interestingly, male Ɛ4 showed increased anxiety and decreased performance in spatial and episodic memory tasks compared to WT males, with female genotypes showing little difference across behavioral tests. The sex differences in behavior and diffusion weighted imaging suggest male carriers of the Ɛ4 allele may be more vulnerable to cognitive and emotional complications compared to female carriers early in life. Conversely, the data may also suggest that female carriers are more resilient to cognitive/emotional problems at this stage of life perhaps due to altered brain volumes and enhanced connectivity.
载脂蛋白 E4 基因型是阿尔茨海默病（AD）最常见的遗传风险因素。携带 E4 的女性比男性更早发生 AD 的风险更高。人体影像学研究表明，载脂蛋白 E4 可能在疾病发作前多年就影响与 AD 认知能力下降相关的脑结构。有人假设，与男性携带者相比，女性 APOE E4 携带者的认知功能下降，以及大脑结构和功能的早期变化的神经影像学证据。研究人员使用基于体素的形态计量学研究了 6 个月大的野生型（WT）和人类 APOE E4 敲入（TGRA8960）、雄性和雌性 Sprague Dawley 大鼠的脑结构变化，使用扩散加权成像和各向异性指数改变白质和灰质微观结构，并使用静息状态 BOLD 功能连接研究功能连接。每种模式的图像都通过 3D MRI 大鼠图谱进行配准和分析，该图谱提供了 168 多个不同脑区的特定部位数据。定量体积分析显示，E4 和野生型（WT）女性之间记忆和唤醒相关区域明显不同，而男性基因型之间的差异较小。扩散加权成像显示 WT 和 E4 女性之间差异较小，而男性基因型在各向异性分数和表观扩散系数方面显示出显著不同的指标。静息状态功能连接显示，与 WT 女性相比，E4 女性的认知、情感和唤醒相关区域之间的连接更强，而男性 E4 与对照组相比差异较小。有趣的是，与 WT 男性相比，雄性 E4 表现出更多的焦虑和空间和情景记忆任务表现下降，而女性基因型在行为测试中几乎没有差异。行为和扩散加权成像的性别差异表明，与女性携带者相比，男性携带者在生命早期可能更容易出现认知和情绪并发症。相反，数据还可能表明，女性携带者在这个生命阶段对认知/情绪问题更具弹性，也许是由于大脑体积的改变和连接的增强。
