载脂蛋白E4基因加速认知老化的脑神经机制研究

Alzheimer's disease (AD) is a progressive neurodegenerative disease that tends to progress slowly and over a long period of time. At present, there is a lack of effective treatments, which has made the early detection of and intervention for the disease the primary focus of most research. AD pathological changes have been hypothesized to begin decades before the earliest clinical symptoms occur. Therefore, measuring these biomarkers at different ages to show the full pathologic cascade of events is now particularly important. It is generally believed that the cause of AD may be a combination of various genetic and environmental factors. The most studied of the genetic factors is the inheritance of the ε4 allele of the Apolipoprotein E (APOE). The APOE ε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes and decreases life expectancy by approximately 10-20 years at onset. It seems likely that the earliest signs of AD brain damage start a decade or more before memory and other cognitive problems appear. Therefore, to assess the effects of APOE ε4 allele on different cognitive functions, brain biomarkers at different stages of age are essential to determine early effective markers that may serve as diagnostic indices and predictors. In the present study, to explore the effect of the APOE ε4 allele on cognition, all participants will undergo a battery of neuropsychological tests that assessed their general mental status and other cognitive domains, such as memory, attention, visuospatial processing, executive function and language ability. Additionally, we investigate the effect of the APOE ε4 allele on white matter integrity and brain white matter structural network based on diffusion tensor imaging. In short, on the basis of neuropsychological tests and neuroimaging data, we assess the effects of APOE 4 allele on cognitive aging and explore the related neural mechanisms, which may shed light on how this polymorphism modulates the risk of developing AD. Furthermore, it will provide basic experimental data to aid in the clinical early diagnosis and prediction of diseases.

由于阿尔茨海默病（Alzheimer's disease，AD）具有的病理复杂、病程长、中晚期干预效果不佳等特点，其早期干预和早期诊断显得尤为重要。研究发现，一些高危基因携带者在疾病早期脑内已出现退化，因此，从高危基因入手探索老化过程中脑内影像标记的变化将成为研究AD早期脑内病理变化的最佳切入点。载脂蛋白E（Apolipoprotein E，APOE）ε4等位基因是AD最重要的风险因素，且在临床症状表现的数十年前就已经出现AD病理变化。因此，本研究拟使用成套神经心理学量表，探究APOE ε4基因多态性对老年人高级认知功能的影响；并用基于弥散张量成像技术，分析APOE 4基因老化进程中主要白质纤维完整性及白质结构网络拓扑属性的变化，阐明其认知功能衰退的脑神经机制，揭示认知功能与神经影像标记衰退的变化轨迹及关系，对于确立AD早期预警及防治的神经影像学标记，及深入的机制研究都具有重要的意义。

由于阿尔茨海默病（Alzheimer's disease，AD）具有的病理复杂、病程长、中晚期干预效果不佳等特点，其早期干预和早期诊断显得尤为重要。但是其发病机制仍有争议，遗传因素可能在发病机制中发挥重要作用。载脂蛋白E（Apolipoprotein E，APOE）ε4基因是AD的最大危险因素之一。本研究使用成套神经心理学量表，包括总体认知能力、记忆能力、视空间能力、注意力、执行功能以及言语功能等，对入组的非痴呆老年APOE 4携带者129人，APOE 4非携带者717人进行全面认知评估。发现所有被试的认知功能随着年龄的增长都逐渐衰退。对于APOE 4携带者，其记忆功能和视空间能力的评分比非携带者差，随年龄增长而改变的幅度不显著，而总体认知功能、执行功能、注意功能及言语功能在50岁后随年龄增长急剧下降；而非携带者大部分的认知领域在60岁左右才开始下降。利用弥散张量成像技术，分析了APOE 4携带者全脑20根主要白质纤维束的部分各向异性值（fractional anisotropy，FA），及其与年龄的交互作用。分析表明APOE 4基因主效应影响的纤维束主要为大脑后部纤维，年龄主效应影响的纤维束主要为大脑前部纤维，而APOE 4基因与年龄交互作用影响的纤维束包括了大脑前部与后部纤维束。本研究阐明了APOE 4基因携带者认知功能衰退的脑神经机制，揭示认知功能与神经影像标记衰退的变化轨迹及关系，对于确立AD早期预警及防治的神经影像学标记，及深入的机制研究都具有重要的意义。