Apolipoprotein E, Cognition, and Alzheimer's Disease

载脂蛋白 E、认知和阿尔茨海默病

• 批准号: 6360066
• 负责人: RAJA PARASURAMAN
• 金额: $ 38.82万
• 依托单位: CATHOLIC UNIVERSITY OF AMERICA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6360066
• 关键词: Alzheimer's disease; age difference; aging; apolipoprotein E; attention; behavioral /social science research tag; cooperative study; early diagnosis; evoked potentials; genetic carriers; human subject; memory; neuropsychological tests; patient oriented research

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.

鉴于阿尔茨海默病(AD)患者数量的急剧增长，迫切需要新的方法来预防、减缓和治疗阿尔茨海默病(AD)。如果在阿尔茨海默病的临床前阶段，在不可逆转的大脑变化发生之前就能发现，这些努力将是有帮助的。在这项拟议的研究中遵循的一种方法是检查没有痴呆但由于遗传了19号染色体上载脂蛋白E基因(APOE)的epsilon4等位基因而患AD风险增加的个体。携带apoE-epsilon4基因的非痴呆者在相关的颞叶、顶叶和额叶皮质区域表现出局部的大脑代谢变化，反映了轻度痴呆AD患者的情况。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，这项拟议的研究将调查一种假设，即非痴呆的APOE-epsilon 4携带者在注意力和记忆潜在的特定成分处理操作中存在选择性缺陷。我们的目标是利用信息处理测试、事件相关脑电位(ERPs)和生物标记物(β-淀粉样蛋白和tau)来研究临床前AD在注意力、工作记忆及其神经生物学相关的组成部分操作中随时间的变化。这些措施将在APOE基因分型的中年非痴呆成人、AD患者和年龄匹配的对照组中获得。这项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、电生理和生物测量。建议进行五项研究，一项大规模研究和四项附加实验。这些研究将确定APOE对没有其他症状的成年人的认知影响，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AD的早期发现以及对注意力和记忆潜在的正常认知操作的遗传学基础的理解具有重要意义。