Wang Xiao, Wang Jinhui, He Yi, Li Huiying, Yuan Huishu, Evans Alan, Yu Xin, He Yong, Wang Huali
Dementia Care & Research Center, Peking University Institute of Mental Health; Key Laboratory for Mental Health, Ministry of Health (Peking University); Beijing Municipal Key Laboratory for Translational Research on Diagnosis and Treatment of Dementia, Beijing, China.
State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China Center for Cognition and Brain Disorders, Hangzhou Normal University, Hangzhou, China Zhejiang Key Laboratory for Research in Assessment of Cognitive Impairments, Hangzhou, China.
J Alzheimers Dis. 2015;45(3):781-95. doi: 10.3233/JAD-142556.
The apolipoprotein E ε4 (APOE ε4) allele is a well-established genetic risk factor for Alzheimer's disease (AD). Numerous studies have suggested that the modulation of APOE ε4 affects cognition and brain structure and function in healthy populations, particularly in the hippocampus, a key area associated with AD pathology. However, the effect of APOE ε4 allele on cognitive performance, hippocampal structural morphology, and specifically on functional characteristics in patients with AD remains poorly understood. Here, we employed a neuropsychological battery test and multi-modal structural MRI and resting-state functional MRI dataset to systematically investigate cognitive performance, hippocampal structural volume, and functional properties (including local low-frequency oscillating amplitude, intra-regional functional synchrony, and inter-regional functional connectivity) in 16 APOE ε4-carriers and 26 non-carriers at early stages of AD. Compared to non-carriers, APOE ε4-carriers exhibited poorer performance on recognition performance, but performed better on the late item generation of the verbal fluency task (associated with executive function). Structural imaging analysis revealed that APOE ε4-carriers exhibited smaller left hippocampal volumes compared to non-carriers, and the result remains significant after correcting for effects of brain size. Functional imaging analysis revealed that APOE ε4-carriers exhibited decreased amplitude of low-frequency fluctuations in the left hippocampus, non-significant changes in intra-regional synchronization within the hippocampus and decreased hippocampal functional connectivity predominantly in components of the default-mode network including the medial frontal and parietal cortices and the lateral temporal cortical regions. Taken together, our results showed APOE genotypic effects on the cognitive profile and hippocampal structural and functional characteristics in patients at early stages of AD, thus providing empirical evidence for the modulation of the APOE genotype on disease phenotype.
载脂蛋白Eε4（APOEε4）等位基因是阿尔茨海默病（AD）公认的遗传风险因素。大量研究表明，调节APOEε4会影响健康人群的认知以及大脑结构和功能，尤其是在海马体中，海马体是与AD病理相关的关键区域。然而，APOEε4等位基因对AD患者认知表现、海马体结构形态，特别是功能特征的影响仍知之甚少。在此，我们采用神经心理成套测试以及多模态结构MRI和静息态功能MRI数据集，系统研究了16名APOEε4携带者和26名非携带者在AD早期阶段的认知表现、海马体结构体积和功能特性（包括局部低频振荡幅度、区域内功能同步性和区域间功能连接性）。与非携带者相比，APOEε4携带者在识别表现上较差，但在言语流畅性任务的后期项目生成（与执行功能相关）中表现更好。结构成像分析显示，与非携带者相比，APOEε4携带者的左侧海马体体积较小，在校正脑大小的影响后，该结果仍具有显著性。功能成像分析显示，APOEε4携带者左侧海马体的低频波动幅度降低，海马体内区域内同步性无显著变化，海马体功能连接性降低，主要发生在默认模式网络的组成部分，包括内侧额叶和顶叶皮质以及外侧颞叶皮质区域。综上所述，我们的结果显示了APOE基因型对AD早期患者认知概况以及海马体结构和功能特征的影响，从而为调节APOE基因型对疾病表型的作用提供了实证依据。
