APOE in the Predisposition to, Protection from and Prevention of Alzheimer's Disease

项目概要/摘要 我们建议开发、使用和共享两个重要资源，用于研究认知未受损（CU）50- 由于载脂蛋白E（APOE），处于阿尔茨海默病（AD）遗传风险6个水平的90岁人群 基因型亚利桑那州APOE队列将包括300名患有APOE 2/2、2/3、3/3、2/4、3/4和4/4的CU患者 根据基因型和年龄十分位数分层，并根据性别和教育程度进行匹配。他们将提供 一个全面的纵向资源的遗传，非遗传，临床，认知和相关数据，脑成像， CSF和新出现的基于血液的淀粉样蛋白-β（Aβ）和tau病理生理学生物标志物（BBB）测量， 神经元损伤和/或神经变性和炎症（“A、T、N、I”）和CSF、血液和DNA样品。 GeneMatch将为潜在感兴趣的CU APOE基因分型人员提供异常大的资源， 参与本项目和其他研究。它将包括年龄在50-90岁之间的人， 描述六种最常见的APOE基因型，鉴定未充分研究的APOE 2和APOE 4纯合子 (HMs)，以及那些具有罕见和潜在保护性APOE变体的人，并支持他们在 Arizona APOE队列和其他纵向研究。我们将使用这些资源1）检测和跟踪不同的 A、T、N、I生物标志物; 2）确定每种APOE基因型的生物标志物上升、稳定和/或下降的年龄; 3)描述APOE 2和APOE 4等位基因剂量的差异影响，其他建议的遗传和非遗传因素 遗传因素，以及它们与我们在50-75岁参与者中的临床前A、T、N、I内表型的相互作用; 4)描述APOE 2和4等位基因剂量、其他遗传和非遗传因素的差异影响 提示参与AD的保护，以及它们对我们临床前A，T，N，I的相互作用 76-90岁的APOE 4 HM和杂合子（HT）中的内源性表型，尽管其遗传 风险; 5）进一步告知使用成像、CSF和/或 BBB终点;和6）证明有希望的BBB（包括血浆Aβ42/40、p-tau 217和 神经丝光[NfL]）在这些努力。我们将广泛分享每年更新的数据和生物信息， 样本和8）具有常见和罕见APOE基因型（包括APOE 4 HM）的有动机的研究参与者 在特别高的AD风险中，在特别低的AD风险中研究不足的APOE 2 HM，老年CU APOE 4 HM， HT，以及APOE基督城和APOE LDLR/HSPG中其他潜在保护性突变的患者 结合域; 9）以重要方式补充我们的其他队列; 10）为广泛的 一系列项目（包括计划中的“临床前APOE联盟”）。这个项目旨在调查 APOE、其他遗传和非遗传因素的作用，以及它们在检测、追踪、 AD的易感性、保护以及潜在的治疗和预防，支持广泛的 补充研究，加速预防和未来APOE修饰疗法的评估，并帮助 我们的阿尔茨海默病预防计划（API）试验在2025年之前找到有效的AD预防疗法。

PROJECT SUMMARY/ABSTRACT We propose to develop, use and share two important resources for the study of cognitively unimpaired (CU) 50- 90 year-old persons at six levels of genetic risk for Alzheimer's disease (AD) due to their apolipoprotein E (APOE) genotype. The Arizona APOE Cohort will include 300 CU persons with the APOE2/2, 2/3, 3/3, 2/4, 3/4 and 4/4 genotypes who are stratified for genotype and age decile and matched for sex and education. They will provide a comprehensive longitudinal resource of genetic, non-genetic, clinical, cognitive and related data, brain imaging, CSF and emerging blood-based biomarker (BBB) measurements of amyloid-β (Aβ) and tau pathophysiology, neuronal injury and/or neurodegeneration and inflammation (“A,T,N,I”) and CSF, blood and DNA samples. GeneMatch will provide an unusually large resource of potentially interested CU APOE-genotyped persons for enrollment in this project and other studies. It will include persons in the wider 50-90 years age range, characterize the six most common APOE genotypes, identify understudied APOE2 and APOE4 homozygotes (HMs), as well as those with rare and potentially protective APOE variants, and support their enrollment in the longitudinal Arizona APOE Cohort and other studies. We will use these resources to 1) detect and track different A,T,N,I biomarkers; 2) determine the ages at which they rise, plateau and/or decline for each APOE genotype; 3) characterize the differential impact of APOE2 and APOE4 allelic doses, other suggested genetic and non- genetic factors, and their interactions with our preclinical A,T,N,I endophenotypes in 50-75 year-old participants; 4) characterize the differential impact of APOE2 and 4 allelic dose, other genetic and non-genetic factors suggested to be involved in the protection from AD, and their interactions on our preclinical A,T,N,I endophenotypes in 76-90 year-old APOE4 HMs and heterozygotes (HT) who remained CU despite their genetic risk; 5) further inform the design and size of novel 12- and 24-month prevention trials using imaging, CSF, and/or BBB endpoints; and 6) demonstrate the value of promising BBBs (including plasma Aβ42/40, p-tau217, and neurofilament light [NfL]) in these endeavors. We will extensively share 7) annually updated data and biological samples and 8) motivated research participants with common and rare APOE genotypes, including APOE4 HMs at particularly high AD risk, understudied APOE2 HMs at particularly low AD risk, older CU APOE4 HMs and HTs, and those with APOE Christchurch and other potentially protective mutations in APOE's LDLR/HSPG binding domain; 9) complement our other cohorts in important ways; and 10) provide a foundation for a wide range of projects (including a planned “Preclinical APOE Consortium”). This project is designed to investigate the roles of APOE, other genetic and non-genetic factors, and their interactions in the detection, tracking, predisposition to, protection from, and potential treatment and prevention of AD, support a wide range of complementary studies, accelerate the evaluation of prevention and future APOE-modifying therapies, and help our Alzheimer's Prevention Initiative (API) trials find effective AD prevention therapies before 2025.