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

项目摘要/摘要 我们建议开发、使用和共享两个研究认知未受损(CU)50的重要资源-- 因载脂蛋白E(APOE)而有6种阿尔茨海默病(AD)遗传风险的90岁老人 基因分型。亚利桑那州APOE队列将包括300名APOE2/2、2/3、3/3、2/4、3/4和4/4的CU人员 按基因和年龄分层，性别和教育程度相匹配的基因类型。他们将提供 全面的遗传、非遗传、临床、认知和相关数据、脑成像、 脑脊液和新兴的基于血液的生物标记物测量淀粉样蛋白β(Aβ)和tau病理生理学， 神经元损伤和/或神经变性和炎症(“A、T、N、I”)以及脑脊液、血液和DNA样本。 GeneMatch将为以下人群提供异常大量的潜在感兴趣的CU APOE基因分型人员资源 参加这个项目和其他研究。它将包括更广泛的50-90岁年龄段的人， 确定六种最常见的载脂蛋白E基因类型，确定未被研究的载脂蛋白2和载脂蛋白4纯合子 (HMS)，以及那些具有稀有和潜在保护性APOE变体的人，并支持他们在 亚利桑那州APOE纵向队列等研究。我们将使用这些资源1)检测和跟踪不同 A、T、N、I生物标记物；2)确定每个APOE基因的上升、平稳和/或下降的年龄； 3)描述APOE2和APOE4等位基因剂量、其他建议的遗传和非遗传剂量的不同影响 遗传因素及其与我们临床前A、T、N、I内表型的相互作用； 4)描述APOE2和4等位基因剂量、其他遗传和非遗传因素的不同影响 建议参与对AD的保护，以及它们对临床前A、T、N、I的相互作用 76-90岁APOE4型HMS和杂合子(HT)的内表型，尽管他们有遗传因素，但仍保持CU 风险；5)进一步告知使用成像、脑脊液和/或 血脑屏障终点；和6)展示了有希望的血脑屏障的价值(包括血浆Aβ42/40、p-tau217和 神经丝光[NFL])。我们将广泛分享每年更新的数据和生物信息 样本和8)有动力的研究参与者具有常见和罕见的APOE基因类型，包括APOE4 HMS 在AD风险特别高的情况下，研究不足的APOE2 HMS的AD风险特别低，较旧的CU APOE4 HMS和 HTS，以及具有APOE克赖斯特彻奇和APOE LDLR/HSPG其他潜在保护性突变的患者 结合结构域；9)在重要方面补充我们的其他同龄人；以及10)为广泛的 一系列项目(包括一个计划中的“临床前APOE联盟”)。该项目旨在调查 载脂蛋白E、其他遗传和非遗传因素及其相互作用在检测、跟踪、 对阿尔茨海默病的易感性、防护以及潜在的治疗和预防，支持广泛的 补充研究，加快对预防和未来APOE修饰疗法的评估，并帮助 我们的阿尔茨海默氏症预防倡议(API)试验发现，在2025年前，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.