Apolipoprotein E, Attention, and Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）的早期检测仍然是一个重要的目标，考虑到与这种疾病相关的惊人的医疗费用。一个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等位基因遗传而导致AD遗传风险增加的个体。拟议的研究解决了几个严重的悬而未决的问题，APOE-E4在认知缺陷导致AD的发展中的作用。为了实现早期发现AD的目标，个体应该在中年而不是老年进行研究。此外，还应该使用信息处理测试，这样就可以将特定缺陷背后的认知过程分离出来，并与大脑网络联系起来。最后，为了更好地了解APOE相关的认知变化何时以及如何导致AD的认知缺陷，需要在中年人中进行纵向研究。这项研究将通过识别对APOE-E4基因型敏感的认知和神经生物学标志物，并显示这些标志物在中年如何预测导致轻度认知障碍（MCI）和AD的后续缺陷的发展，来推进早期检测的目标。纵向研究将检查APOE对两组健康成年人的注意力和记忆力的影响，一组在中年（40-59岁），另一组在老年（60-75岁），以及MCI患者。由于相对罕见的e4等位基因在北方欧洲人中的频率更高，因此将对美国和挪威的中年和老年人样本进行评估。为了提高灵敏度，认知大脑过程的行为分析将补充以事件相关脑电位（ERP）测量。这项研究还将检验这样一个假设，即APOE在AD症状发作前多年对认知既有基本的调节作用，也有特定领域的作用。APOE对认知的基本调节作用可能是通过轴突通路介导的，其完整性将使用磁共振成像（MRI）进行评估。通过研究APOE和神经传递基因之间的相互作用，将研究领域特异性效应，这些基因最近与注意力和记忆力的个体差异有关。这些结果将对AD的早期检测以及对APOE神经认知作用的更好理解具有重要意义。这反过来又可以允许开发预防疗法，以便在尽可能早的时间向AD风险最大的人提供。

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.