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

摘要 随着美国人口的老龄化，认知障碍和阿尔茨海默病（AD）的负担正在迅速增加 人口因此，识别长的症状前阶段的分子特征是至关重要的 以识别和靶向其临床沉默期。临床前AD使用结构和分子的新标准 成像（MRI和PET）和脑脊液（CSF）检测，这些检测昂贵、侵入性且不可扩展 进行人口筛查因此，存在对症状前阶段的血液生物标志物的探索， 轻度认知功能障碍（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），（ii）改善AD的风险预测，和iii）允许风险分层， 早期临床前疾病的靶向临床试验招募受试者的选择。 AD是一种典型的蛋白质病，其特征是蛋白质错误折叠和神经毒性蛋白的形成 集料.受损的大脑蛋白质会泄漏到CSF中，并可能进入血液。因此，超敏感 蛋白质组学分析已用于鉴定痴呆前期和AD的血液生物标志物。然而，最初的研究 规模小，受次优设计的限制，缺乏分析验证和复制。 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）。 在1874名中年至老年人中进行的FOS研究中， 正常和异常认知的光谱。参与者有一系列的神经认知和大脑成像数据 （包括子集中的PET扫描），并接受AD监测。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。我们认为，纵向模式的 血液生物标志物可以区分正常衰老与合并症、痴呆前期、MCI和AD的存在。 我们的具体目标是：目标1。描述1874名老年FOS参与者的血浆蛋白质组， 第十次考试（2019-2021），并将蛋白质组与风险因素，生活方式和药物进行横断面联系; 身体系统和共病的功能;以及AD的结构/认知内表型。目标2.评价 在25年的随访期内（第5和第10年之间），血浆蛋白随年龄的纵向变化 考试;使用现有的蛋白质数据在以前），并与蛋白质的变化纵向轨迹 神经认知和脑成像测量。目标3。将检查10时的血浆蛋白质组（和变化 检查之间）与认知能力下降、卒中和AD的发生率的关系。目标4。联系顶部 目标1-3中的蛋白质组学发现，在PET扫描的子集中针对脑淀粉样蛋白和tau蛋白。我们会验证我们的发现 用质谱分析法，在独立的群体中复制它们。我们的多学科团队将确定 AD和ADRD的新纵向蛋白质组特征;构建与AD和ADRD相关的生物蛋白质网络 AD可能是临床试验的目标，用于预防中年及以后的认知能力下降和AD。

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.