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

描述（由申请人提供）：我们要求对具有两个、一个或没有载脂蛋白E（APOE）<$4等位基因（主要迟发性阿尔茨海默病（AD）易感基因）拷贝的认知正常人的纵向研究提供五年的持续支持。这项研究利用了大量的脑成像，液体生物标志物，认知和其他测量。我们的项目包括35 <$4例纯合子、50 <$4例杂合子和75 <$4例非携带者，以允许检测、跟踪和科学研究临床前AD患者 在三个风险水平，并为临床前AD治疗的加速评估奠定了基础。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，以帮助确定我们的研究结果与这个未充分研究的少数群体相关的程度。每个基因组中的人在人口统计学上匹配，最初是中年晚期;他们目前的年龄是67岁（范围49-81）。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。在拟议的资助期间，参与者将接受葡萄糖（CMRgl）和纤维状淀粉样蛋白（A）沉积的局部脑代谢率的PET测量，扩展的磁共振成像（MRI）电池，血清和血浆样本提取和储存，以及每两年一次的临床，神经心理学，功能和行为测试的广泛电池。至少一半的人每两年将采集、储存和分析一次纵向脑脊液（CSF）样本。近二十年来，我们的首要目标一直是表征与临床前AD相关的生物标志物和认知测量，并为加速评估有前途的预防治疗提供基础。随着越来越多的受试者进展为轻度认知障碍（MCI）和AD所致痴呆，我们将开始描述不同生物标志物和认知测量预测随后临床进展率的程度。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AD易感性中涉及的生物学过程。通过我们的临床前内表型和补充数据集，我们将有助于澄清遗传风险因素与AD潜在分离因素之间的关系。通过扩大数据和样本共享计划，我们将提供可访问的全球资源，以推进临床前AD的研究。在参与者，样本和纵向数据的基础上，我们将准备评估认知正常的APOE <$4携带者中的A <$-修饰剂，并帮助推进AD预防研究的新时代。

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.