Temporal Trends, Novel Imaging and Molecular Characterization of Preclinical and Clinical Alzheimer's Disease in the Framingham Cohorts

FHS是一项前瞻性、基于社区的3代研究， 参与者年龄在20-50岁之间，每2-4年检查一次，以收集广泛的生活方式， 血管，生物标志物数据; 9300人患有GWAS。这个队列中包含1036个多代家庭。 AD痴呆（和MCI）的监测已经持续了40多年。我们已经确认了1421号 AD事件，1767例MCI，800多例参与脑捐赠计划，获得7000+ 1.5T脑MRI， 反复的详细的神经心理学评估我们最近获得了广泛的组学在~6000 (gene表达、甲基化、miRNA、代谢组学和蛋白质组学）和基因组学（50倍全基因组 4197个序列[WGS]，基于家系插补至6554）通过NHLBI资助的SABRe CVD （组学）和TOPMed（WGS）计划。我们寻求利用这些丰富的资源（> 2 500万美元）。我们提出 这些具体目标：目的1是检查和解释临床AD痴呆的时间趋势， FHS队列。在过去的40年中，FHS中痴呆的年龄特异性发病率有所下降 与会者（新闻稿中）。然而，这一下降的原因仍不清楚。因此，我们建议继续 通过强化监测跟踪AD痴呆和MCI的时间趋势， 尸检我们假设，更好的教育，一些血管因素的治疗和保护性的生活方式， 变化（饮食、活动、社会参与）可以部分解释这些趋势。目标2是确定 FHS家族中临床前AD的模式和预测因子，通过获得（i）一种新的循环生物标志物 （8000多人的血浆tau蛋白，使用5-15年前收集的样本，并在450人中重复测定）， 补充1000+生物标志物已经可用，和（ii）脑成像与tau-和淀粉样蛋白- PET，3 TMRI， 包括评估450名无痴呆和中风的患者的功能连接性、纤维束成像和血流， 年龄在35-75岁之间的FHS参与者，我们（a）直接验证了家族认知和AD痴呆状态 (both父母和所有4个祖父母都是FHS参与者），并且（B）具有WGS和组学数据。AIM 3 是利用现有的WGS和广泛的“组学”数据对AD进行深入的分子表型分析。我们 将对AD痴呆和临床前AD内表型进行传统的基于家庭的WGS分析 和新的高维（共表达，网络，基于系统）分析与博士合作。 DeJager（加速医学合作伙伴-AD的PI，拥有1200个大脑的组学数据），维滕（获奖 数学家在应用图形分析组学）和利维（PI的SABRe-CVD在FHS）。我们将验证 我们在无关和多种族（Omni）FHS参与者中的发现，通过与其他队列的合作， 并通过dbGaP和BioLINCC共享所有数据以供其他人分析。我们希望能发现新的生物 AD的途径、药物靶点和生物标志物，特别是适用于AD临床前阶段的那些， 那些解释AD风险的有希望的趋势;这些途径应该被证明对AD预防最有用。

The Framingham Heart Study (FHS) is a prospective, community-based 3-generational study that enrolled participants between ages 20-50 and has examined them every 2-4 years to collect extensive lifestyle, vascular, biomarker data; 9300 have GWAS. Embedded in this cohort are 1036 multigenerational families. Surveillance for AD dementia (and MCI) has been ongoing for over 4 decades. We have identified 1421 incident AD, 1767 MCI, enrolled 800+ in a brain donation program, obtained 7000+ 1.5T brain MRI, and repeated, detailed neuropsychological assessments. We have recently obtained extensive omics in ~6000 (gene expression, methylation, miRNA, metabolomics and proteomics) and genomics (50X whole genome sequences [WGS] in 4197 with pedigree-based imputation to 6554) through the NHLBI funded SABRe CVD (omics) and TOPMed (WGS) programs. We seek to leverage these rich resources (>$25 million). We propose these specific aims: AIM 1 is to examine and explain temporal trends in clinical AD dementia in the FHS cohorts. The age-specific incidence of dementia has declined over the past 4 decades among FHS participants (in press). However, the reasons for this decline remain unclear. We thus propose to continue tracking temporal trends in AD dementia and MCI through intensive surveillance, and verifying diagnoses at autopsy. We hypothesize that better education, treatment of some vascular factors and protective lifestyle changes (diet, activity, social engagement) may partially explain these trends. AIM 2 is to identify the patterns and predictors of preclinical AD within FHS families by obtaining (i) a novel circulating biomarker (plasma tau on 8000+ persons, using samples collected 5-15 years ago and repeat assay in 450) to supplement 1000+ biomarkers already available, and (ii) brain imaging with tau- and amyloid- PET, 3TMRI, including assessment of functional connectivity, tractography and blood flow, in 450 dementia- and stroke-free, FHS participants age 35-75 on whom we have (a) directly verified familial cognition and AD dementia status (both parents and all 4 grandparents were FHS participants), and also (b) have WGS and omics data. AIM 3 is to utilize the available WGS and extensive `omics' data for deep molecular phenotyping of AD. We will undertake conventional family-based WGS analyses of AD dementia and preclinical AD endophenotypes and novel high dimensional (co-expression, network, systems-based) analyses in collaboration with Drs. DeJager (PI of Accelerated Medicine Partnerships-AD, with omics data in 1200 brains), Witten (award-winning mathematician in applying graphical analysis to omics) and Levy (PI of SABRe-CVD at FHS). We will validate our findings in unrelated and multi-ethnic (Omni) FHS participants, through collaborations with other cohorts, and share all data through dbGaP and BioLINCC for analyses by others. We expect to identify new biologic pathways, drug targets and biomarkers for AD, especially those applicable to the preclinical stage of AD and those explaining promising trends in AD risk; such pathways should prove most useful for AD prevention.