Apolipoprotein E, Cognition, and Alzheimer's Disease

鉴于阿尔茨海默病（AD）患者数量的急剧增长，迫切需要预防、减缓和治疗阿尔茨海默病（AD）的新方法。如果阿尔茨海默病能在临床前阶段，即在大脑发生不可逆转的变化之前被检测出来，这些努力将会有所帮助。一种方法，在拟议的研究中，是检查那些没有痴呆，但由于19号染色体上载脂蛋白E基因（APOE）的epsilon4等位基因遗传而患阿尔茨海默病风险增加的个体。具有APOE-epsilon4基因型的非痴呆患者在颞叶、顶叶和额叶皮质区表现出区域性的脑代谢变化，这与轻度痴呆AD患者的情况相似。这些大脑区域包括调节视觉空间注意力和空间工作记忆的分布式网络。因此，该研究将研究非痴呆APOE-epsilon4携带者在潜在的注意力和记忆的特定成分处理操作中存在选择性缺陷的假设。目的是通过信息处理测试、事件相关脑电位（ERPs）和生物标志物（β -淀粉样蛋白和tau蛋白），研究临床前阿尔茨海默病在注意力、工作记忆及其神经生物学相关操作方面随时间的变化。这些指标将在APOE基因分型的中年无痴呆成人、AD患者和年龄匹配的对照组中获得。该研究的一个独特方面是对纵向变化的综合评估方法，包括行为、电生理和生物测量。提出了五项研究，一项大规模研究和四项附加实验。这些研究将确定APOE对其他无症状成人的认知影响，并将建立临床前和早期AD患者注意力和工作记忆变化之间的关系。这一结果将对阿尔茨海默病的早期检测以及对正常认知操作的遗传基础的理解产生重大影响，这些操作隐藏在注意力和记忆之下。

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.