Plasma Proteome and Risk of Alzheimer Dementia and Related Endophenotypes in the Framingham Study

联系PD/PI：Ramachandran，Vasan S 摘要 随着美国老龄化，认知障碍和阿尔茨海默病(AD)的负担迅速增加 人口。因此，确定长期症状前阶段的分子特征是至关重要的。 以识别和定位其临床静止期。临床前阿尔茨海默病的结构和分子应用新标准 成像(MRI和PET)和脑脊液(CSF)分析，这是昂贵的、有创的和不可扩展的 进行基于人群的筛查。因此，有一种对症状前阶段的血液生物标志物的探索， 轻度认知障碍(MCI)和痴呆症，可以(I)阐明正常脑老化的生物学，AD 和AD相关痴呆(ADRD)，(2)改进AD的风险预测，以及(3)允许风险分层和 早期临床前疾病靶向临床试验的入选对象选择。 AD是一种典型的蛋白质病，以蛋白质错误折叠和形成神经毒性蛋白为特征 集合体。受损的大脑蛋白质会泄漏到脑脊液中，并进入血液。因此，超敏感 蛋白质组学已被用于识别痴呆前期和AD的血液生物标记物。然而，初步研究 由于设计不够理想，以及缺乏分析验证和复制，因此一直规模较小。 我们将在两个关键时间点(中年和中年)表征血浆蛋白质组(1310 SomaScan蛋白质) 老年人)在1874年弗雷明翰后代研究(FOS)中的中老年个体 正常认知和异常认知的光谱。参与者有一系列的神经认知和脑成像数据 (包括子集的正电子发射计算机断层扫描)，并正在监测AD。我们假设血浆 蛋白质组随着年龄的增长和认知的早期变化而变化。我们假设纵向的图案 血液生物标记物可以区分正常衰老与合并症、痴呆前期、MCI和AD。 我们的具体目标是：目的1.分析1874名老年FOS参与者的血浆蛋白质组 第十次检查(2019-2021年)，将蛋白质组与危险因素、生活方式和药物横截面联系起来； 躯体系统的功能和合并症；以及AD的结构/认知内表型。目标2.评估 血浆蛋白随年龄增长的纵向变化超过25年的随访期(第5至第10年) 检查；使用以前的现有蛋白质数据)，并将蛋白质变化与 神经认知和脑成像测量。目的3.在检查10中联系血浆蛋白质组(和变化 两次考试之间)对认知功能下降、中风和阿尔茨海默病的发生率。目标4.将顶部联系起来 在PET扫描中，AIMS 1-3中的蛋白质组发现大脑淀粉样蛋白和tau蛋白。我们将验证我们的发现 并在独立的队列中复制它们。我们的多学科团队将确定 AD和ADRD新的纵向蛋白质组特征；构建与以下相关的生物蛋白质网络 AD可作为预防中年及以后认知功能减退和AD的临床试验的靶点。

Contact PD/PI: Ramachandran, Vasan S Abstract The burden of cognitive impairment and Alzheimer disease (AD) is increasing rapidly with the aging of the US population. Accordingly, it is critical to identify molecular signatures of the long pre-symptomatic phase of AD to identify and target its clinically silent phase. New criteria of preclinical AD use structural and molecular imaging (MRI and PET) and cerebrospinal fluid (CSF) assays, which are expensive, invasive and not scalable for population-based screening. Hence, there is a quest for blood biomarkers of pre-symptomatic stages, mild cognitive impairment (MCI), and dementia that could (i) elucidate the biology of ‘normal’ brain aging, AD and AD-related dementias (ADRD), (ii) improve risk prediction of AD, and iii) permit risk stratification and subject selection for enrollment in targeted clinical trials of early preclinical disease. AD is an archetypal proteinopathy characterized by protein misfolding and formation of neurotoxic protein aggregates. Damaged cerebral proteins leak into the CSF and can enter the blood. Therefore, ultra-sensitive proteomic profiling has been used to identify blood biomarkers of pre-dementia and AD. Yet, initial studies have been small, limited by suboptimal designs, and an absence of analytical validation and replication. We will characterize the plasma proteome (1310 SomaScan proteins) at two critical time points (mid-life and older age) in 1874 middle-aged-to-elderly individuals in the Framingham Offspring Study (FOS) spanning the spectrum of normal and abnormal cognition. Participants have serial neurocognitive and brain imaging data (including PET scans in a subset) and are under surveillance for AD. We hypothesize that the plasma proteome changes with the aging and with early changes in cognition. We posit that longitudinal patterns of blood biomarkers can distinguish normal aging from presence of comorbidities, pre-dementia, MCI and AD. Our specific aims are: Aim 1. Characterize the plasma proteome in 1874 elderly FOS participants at their tenth exam (2019-2021), and relate the proteome cross-sectionally to risk factors, lifestyle and medications; function of body systems and comorbidities; and structural/cognitive endophenotypes of AD. Aim 2. Evaluate longitudinal changes in plasma proteins with aging over a 25-yr follow-up period (between the 5th and 10th exams; using extant protein data at former), and relate protein changes to longitudinal trajectories of neurocognitive and brain imaging measures. Aim 3. Relate the plasma proteome at exam 10 (and changes between exams) to the incidence of cognitive decline, stroke and AD prospectively. Aim 4. Relate the top proteomic findings in Aims 1-3 to brain amyloid and tau on PET scans in a subset. We will validate our findings with mass spectrometry, and replicate them in independent cohorts. Our multidisciplinary team will identify novel longitudinal proteomic signatures of AD and ADRD; construct biological protein networks associated with AD that may be targeted in clinical trials for preventing cognitive decline and AD in middle age and beyond.