Apolipoprotein E, Cognition, and Alzheimer's Disease

鉴于患有阿尔茨海默病（AD）的人数急剧增长，迫切需要用于预防、减缓AD的进展和治疗AD的新方法。如果在不可逆的大脑变化发生之前，在临床前阶段就能检测到AD，那么这些努力将有所帮助。在拟议的研究中遵循的一种方法是检查没有痴呆但由于19号染色体上载脂蛋白E基因（APOE）的ε 4等位基因遗传而导致AD风险增加的个体。携带APOE-ε 4基因型的非痴呆患者在颞叶、顶叶和额叶皮质区的局部脑代谢变化与轻度痴呆患者相似。这些大脑区域包括介导视觉空间注意力和空间工作记忆的分布式网络。因此，拟议中的研究将调查这一假设，即非痴呆APOE ε 4携带者在特定的组件处理操作的基础上的注意力和记忆的选择性缺陷。目的是研究临床前AD在注意力、工作记忆及其神经生物学相关性的组成部分操作中随时间的变化，使用信息处理测试、事件相关脑电位（ERP）和生物标志物（β-淀粉样蛋白和tau蛋白）。这些措施将在中年非痴呆成年人中获得APOE基因型，AD患者和年龄匹配的对照。该研究的一个独特方面是评估纵向变化的综合方法，包括行为，电生理和生物措施。提出了五项研究，一项大规模的研究和四个额外的实验。这些研究将确定APOE在其他无症状成人中的认知影响，并将建立临床前和早期AD中注意力和工作记忆变化之间的关系。这些结果将对AD的早期检测以及理解注意力和记忆力的正常认知操作的遗传基础具有重要意义。

New methods for preventing, slowing the progression of, and treating Alzheimer's disease (AD) are urgently needed given the dramatic growth in the number of people afflicted with AD. Such efforts would be helped if AD could be detected in its preclinical stage, before irreversible brain changes occur. One approach, followed in the proposed research, is to examine individuals who are not demented but are at increased risk for developing AD due to inheritance of the epsilon4 allele of the apolipoprotein E gene (APOE) on chromosome 19. Nondemented persons with the APOE-epsilon4 genotype exhibit regional cerebral metabolic changes in association temporal, parietal, and frontal cortical areas that mirror those seen in mildly demented AD patients. These brain regions include distributed networks that mediate visuospatial attention and spatial working memory. The proposed research will therefore investigate the hypothesis that nondemented APOE-epsilon4 carriers have selective deficits in specific component processing operations underlying attention and memory. The goal is to investigate changes over time in preclinical AD in component operations of attention, working memory, and their neurobiological correlates, using information-processing tests, event-related brain potentials (ERPs), and biological markers (beta-amyloid and tau). These measures will be obtained in middle-aged nondemented adults genotyped for APOE, AD patients, and age-matched controls. A unique aspect of the research is the comprehensive approach to assessment of longitudinal changes, including behavioral, electrophysiological, and biological measures. Five studies are proposed, one large-scale study and four additional experiments. These studies will ascertain the cognitive impact of APOE in otherwise asymptomatic adults and will establish the relationship between changes in attention and working memory in preclinical and early AD. The results will have significant implications for the early detection of AD as well as for an understanding of the genetic basis of normal cognitive operations underlying attention and memory.