Apolipoprotein E, Attention, and Alzheimer's Disease

载脂蛋白 E、注意力和阿尔茨海默病

• 批准号: 8067061
• 负责人: RAJA PARASURAMAN
• 金额: $ 48.44万
• 依托单位: GEORGE MASON UNIVERSITY
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067061
• 关键词: Acute; Address; Adult; Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid deposition; Apolipoprotein E; Attention; Behavioral Assay; Biological; Biological Assay; Brain; Cognition; Cognitive; Cognitive deficits; Data; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Early Diagnosis; Early treatment; Elderly; Enabling Factors; European; Event; Exhibits; Frequencies; Future; Genes; Genetic Risk; Genotype; Goals; Gray unit of radiation dose; Health; Impaired cognition; Individual; Individual Differences; Investigation; Lead; Life Expectancy; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediating; Medical; Memory; Modeling; Natural History; Nerve Growth Factors; Neurobiology; Neurocognitive; Neurons; Neuropsychological Tests; Pathologic; Pathway interactions; Patients; Pattern; Population; Prevention therapy; Process; Process Measure; Publishing; Raja; Research; Research Personnel; Role; Sample Size; Sampling; Scandinavian; Short-Term Memory; Specificity; Structure; Symptoms; Testing; Time; base; clinically significant; cognitive change; cohort; cost; gray matter; improved; information processing; middle age; mild neurocognitive impairment; neuropathology; neurotransmission; programs; therapy development; white matter

DESCRIPTION (provided by applicant): The early detection of Alzheimer's disease (AD) continues to be an important goal, given the staggering medical costs associated with this disease. A major approach has been to examine individuals who are not demented but are at increased genetic risk for AD due to inheritance of the e4 allele of the Apolipoprotein E (APOE) gene. The proposed research addresses several acute unresolved issues concerning the role of APOE-E4 in the development of cognitive deficits leading to AD. To achieve the goal of early detection of AD, individuals should be studied in midlife and not in old age. Also, information-processing tests should be used, so that the cognitive processes underlying a particular deficit can be isolated and linked to brain networks. Finally, to better understand when and how APOE-related cognitive changes lead to the cognitive deficits of AD, longitudinal studies in middle-aged adults are needed. The proposed research will advance the goal of early detection by identifying cognitive and neurobiological markers sensitive to APOE-E4 genotype and showing how those markers in midlife predict the development of subsequent deficits leading to mild cognitive impairment (MCI) and to AD. The longitudinal studies will examine effects of APOE on attention and memory in two cohorts of healthy adults, one in midlife (40-59) and the other older (60-75), as well as in MCI patients. Both US and Norwegian samples of middle-aged and older adults will be assessed, because of the greater frequency of the relatively rare e4 allele among Northern Europeans. For increased sensitivity, behavioral assays of cognitive brain processes will be supplemented with event-related brain potential (ERP) measures. The research will also test the hypothesis that APOE has both a fundamental, modulatory effect as well as domain-specific effects on cognition many years before the onset of AD symptoms. The basic modulatory effect of APOE on cognition may be mediated by axonal pathways, whose integrity will be assessed using magnetic resonance imaging (MRI). Domain-specific effects will be studied by examining the interaction between APOE and neurotransmission genes recently linked to individual differences in attention and memory. The results will have significant implications for the early detection of AD as well as for an improved understanding of the neurocognitive effects of APOE. This in turn may allow for the development of prevention therapies to be provided to those at greatest risk for AD at the earliest possible time.

描述(由申请人提供)：考虑到与阿尔茨海默病相关的惊人的医疗费用，早期发现阿尔茨海默病(AD)仍然是一个重要的目标。一种主要的方法是检查那些没有痴呆，但由于载脂蛋白E(APOE)基因的e4等位基因遗传而增加了患AD的遗传风险的人。这项拟议的研究解决了几个关于载脂蛋白E-E4在导致AD的认知缺陷发展中的作用的尖锐悬而未决的问题。为了达到早期发现AD的目的，应该在中年而不是老年对个体进行研究。此外，应该使用信息处理测试，以便特定缺陷背后的认知过程可以被隔离并与大脑网络联系起来。最后，为了更好地了解与APOE相关的认知变化何时以及如何导致AD的认知缺陷，需要对中年人进行纵向研究。这项拟议的研究将通过识别对APOE-E4基因型敏感的认知和神经生物学标志物，并展示这些标志物如何在中年预测导致轻度认知障碍(MCI)和AD的后续缺陷的发展，从而推进早期发现的目标。这项纵向研究将考察APOE对两组健康成年人的注意力和记忆的影响，一组是中年(40-59岁)，另一组是老年人(60-75岁)，以及MCI患者。美国和挪威的中老年人样本都将被评估，因为相对罕见的e4等位基因在北欧人中的频率更高。为了提高灵敏度，认知脑过程的行为分析将得到事件相关脑电位(ERP)测量的补充。这项研究还将检验这一假设，即APOE在阿尔茨海默病症状出现前多年对认知具有基础性、调节性和特定领域的影响。APOE对认知的基本调节作用可能是由轴突通路介导的，其完整性将通过磁共振成像(MRI)进行评估。通过研究载脂蛋白E和神经传递基因之间的相互作用来研究特定领域的效应，这些基因最近与注意力和记忆的个体差异有关。这一结果将对AD的早期发现以及对APOE神经认知效应的更好理解具有重要意义。这反过来又可能允许尽早向AD风险最高的人提供预防治疗。