Brain Imaging, APOE & the Preclinical Course of Alzheimer's Disease

描述(由申请人提供)：我们要求对认知正常、有两个、一个或没有载脂蛋白E(APOE)？4等位基因副本的人进行五年的持续支持，载脂蛋白E？4等位基因是主要的晚发性阿尔茨海默病(AD)易感基因。这项研究利用了广泛的脑成像、体液生物标记物、认知和其他测量方法。我们的计划包括35？4个纯合子、50？4个杂合子和75？4个非携带者的队列，以允许检测、跟踪和科学研究人的临床前AD。 在三个风险级别，并为加速评估临床前AD治疗奠定了基础。它还包括来自拉丁裔社区的15？4名携带者和30？4名非携带者的队列，以帮助确定我们的发现在多大程度上与这一未被研究的少数群体相关。每个基因组中的人在人口统计上是匹配的，最初是中年晚期；他们目前的年龄是67岁(范围49-81岁)。而且，所有参与者都进行了全基因组单核苷酸多态性(SNP)基因分型。在拟议的资助期内，参与者将接受脑部局部葡萄糖代谢率(CMRgl)和纤维淀粉样蛋白沉积(A？)的PET测量、扩展磁共振成像(MRI)电池、血清和血浆样本的提取和存储，以及每两年进行一系列临床、神经心理、功能和行为测试。至少一半的人将每两年采集、储存和化验一次纵向脑脊液(CSF)样本。近二十年来，我们的首要目标一直是确定与临床前阿尔茨海默病相关的生物标记物和认知测量的特征，并为加速评估有希望的预防疗法提供基础。随着越来越多的参与者进展为轻度认知损害(MCI)和AD导致的痴呆，我们将开始表征不同的生物标记物和认知测量对随后的临床进展速度的预测程度。随着生物标志物和数据分析工具的扩展，我们将进一步表征与AD易感性有关的生物学过程。有了我们的临床前内表型和互补的数据集，我们将帮助澄清遗传风险因素和潜在的AD分离因素之间的关系。随着扩大的数据和样本共享计划，我们将提供一个可访问的全球资源，以推进临床前AD的研究。有了参与者、样本和纵向数据的基础，我们将为在认知正常的载脂蛋白E携带者中评估A？修饰剂做准备，并有助于推动AD预防研究的新纪元。

DESCRIPTION (provided by applicant): We request five years of continued support for the longitudinal study of cognitively normal persons with two, one, or no copies of the apolipoprotein E (APOE) ¿4 allele, the major late-onset Alzheimer's disease (AD) susceptibility gene. This study utilizes an extensive battery of brain imaging, fluid biomarker, cognitive, and other measurements. Our program includes a cohort of 35 ¿4 homozygotes, 50 ¿4 heterozygotes, and 75 ¿4 non-carriers to permit detection, tracking, and scientific study of preclinical AD in persons at three levels of risk and set the stage for the accelerated evaluation of preclinical AD treatments. It also includes a cohort of 15 ¿4 carriers and 30 ¿4 non-carriers from the Latino community to help establish the extent to which our findings are relevant to this understudied minority group. Persons in each genetic group were demographically matched and initially late middle-aged; their current age is 67 years (range 49-81). And, all participants have had genome-wide single nucleotide polymorphism (SNP) genotyping. During the proposed funding period participants will have PET measurements of regional cerebral metabolic rates of glucose (CMRgl) and fibrillar amyloid-¿ (A¿) deposition, an expanded magnetic resonance imaging (MRI) battery, serum and plasma samples drawn and stored, and an extensive battery of clinical, neuropsychological, functional, and behavioral tests every two years. At least half will have longitudinal cerebrospinal fluid (CSF) samples drawn, stored, and assayed every two years. For nearly two decades our overriding goals have been to characterize the biomarker and cognitive measurements associated with preclinical AD and provide a foundation for the accelerated evaluation of promising prevention therapies. With the growing number of participants progressing to mild cognitive impairment (MCI) and dementia due to AD, we will begin to characterize the extent to which different biomarker and cognitive measurements predict subsequent rates of clinical progression. With an expanded arsenal of biomarkers and data analysis tools, we will further characterize the biological processes involved in the predisposition to AD. With our preclinical endophenotypes and complementary datasets, we will help clarify relationships between genetic risk factors and potentially dissociable elements of AD. With an expanded data and sample sharing program, we will provide an accessible worldwide resource to advance the study of preclinical AD. With this foundation of participants, samples, and longitudinal data, we will prepare for the evaluation of an A¿-modifying agent in cognitively normal APOE ¿4 carriers and help to advance a new era in AD prevention research.