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- 90 岁老人因载脂蛋白 E (APOE) 存在六级阿尔茨海默病 (AD) 遗传风险 基因型。亚利桑那州 APOE 队列将包括 300 名具有 APOE2/2、2/3、3/3、2/4、3/4 和 4/4 的 CU 人员 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的基因型。他们将提供 遗传、非遗传、临床、认知和相关数据、脑成像、 CSF 和新兴的基于血液的生物标志物 (BBB) 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 将提供异常庞大的可能对 CU APOE 基因分型感兴趣的人的资源 参加该项目和其他研究。它将包括 50-90 岁年龄段的人， 表征六种最常见的 APOE 基因型，识别尚未研究的 APOE2 和 APOE4 纯合子 （HM），以及那些具有罕见和潜在保护性 APOE 变体的人，并支持他们加入 纵向亚利桑那州 APOE 队列和其他研究。我们将使用这些资源来 1）检测和跟踪不同的 A、T、N、I 生物标志物； 2) 确定每种 APOE 基因型上升、稳定和/或下降的年龄； 3) 描述 APOE2 和 APOE4 等位基因剂量的差异影响，其他建议的遗传和非遗传因素 遗传因素及其与 50-75 岁参与者的临床前 A、T、N、I 内表型的相互作用； 4) 表征 APOE2 和 4 等位基因剂量、其他遗传和非遗传因素的差异影响 建议参与 AD 保护，以及它们在我们的临床前 A、T、N、I 上的相互作用 76-90 岁 APOE4 HM 和杂合子 (HT) 的内表型，尽管他们的遗传基因仍然是 CU 风险； 5) 进一步告知使用影像、脑脊液和/或的新型 12 个月和 24 个月预防试验的设计和规模 BBB 端点； 6) 证明有前景的 BBB 的价值（包括血浆 Aβ42/40、p-tau217 和 神经丝光[NfL]）在这些努力中。我们将广泛分享7）每年更新的数据和生物 样本和 8) 具有常见和罕见 APOE 基因型（包括 APOE4 HM）的积极研究参与者 AD 风险特别高、AD 风险特别低、未充分研究的 APOE2 HM、较旧的 CU APOE4 HM 和 HT、APOE 基督城患者和 APOE LDLR/HSPG 中其他潜在保护性突变的患者 结合域； 9）在重要方面补充我们的其他群体； 10）为广泛的 一系列项目（包括计划中的“临床前 APOE 联盟”）。该项目旨在调查 APOE、其他遗传和非遗传因素的作用及其在检测、跟踪、 AD 的易感性、预防性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 年之前找到了有效的 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.