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.

APOE Ɛ4 基因型是阿尔茨海默病 (AD) 最普遍的遗传风险。Ɛ4 的女性携带者早发 AD 的风险高于男性。人体影像学研究表明，载脂蛋白 Ɛ4 可能会在疾病发作前多年影响与​​ AD 认知能力下降相关的大脑结构。据推测，与男性携带者相比，女性 APOE Ɛ4 携带者会出现认知功能下降和大脑结构和功能早期变化的神经放射学证据。

使用基于体素的形态测量法研究了六个月大的野生型 (WT) 和人类 APOE Ɛ4 敲入 (TGRA8960) 雄性和雌性 Sprague Dawley 大鼠的大脑结构变化，使用扩散加权法研究了白质和灰质微结构的改变具有各向异性指数的成像，以及使用静息状态 BOLD 功能连接的功能耦合。使用提供超过 168 个不同大脑区域的特定部位数据的 3D MRI 大鼠图谱，将来自每种模式的图像注册和分析。

定量体积分析显示 Ɛ4 和野生型 (WT) 雌性之间涉及记忆和唤醒的区域显着不同，雄性基因型之间几乎没有差异。扩散加权成像显示 WT 和 Ɛ4 女性之间几乎没有差异，而男性基因型在分数各向异性和表观扩散系数方面显示出显着不同的测量值。静息状态功能连接显示 Ɛ4 女性与 WT 女性相比，涉及认知、情感和唤醒的区域之间具有更大的连接性，男性 Ɛ4 与对照组几乎没有差异。有趣的是，与 WT 男性相比，男性Ɛ4 在空间和情景记忆任务中表现出焦虑增加和表现下降，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，Ɛ4 等位基因的男性携带者在生命早期可能更容易受到认知和情绪并发症的影响。相反，数据也可能表明女性携带者在生命的这个阶段对认知/情感问题更有弹性，这可能是由于脑容量的改变和连通性的增强。