Plasma Proteomic Signatures for Alzheimer's Disease and Related Dementias

为了更好地了解阿尔茨海默病（AD）的病理生理，在临床前阶段发现AD，以及寻找新的治疗靶点，迫切需要确定AD的分子特征。血浆蛋白质组是鉴定分子特征的理想资源，因为蛋白质具有基本的生物学功能，是直接的治疗靶点，并揭示疾病机制。我们的初步数据确定了几种与认知障碍和ad相关脑萎缩相关的血浆蛋白质组学生物标志物。我们还发现，通过我们验证的衰老蛋白质组学特征（称为“蛋白质组学时钟”）测量，相对于实际年龄，加速的生物（即蛋白质组学）衰老与多种与年龄相关的疾病（包括认知障碍）的风险较高有关。然而，对AD前蛋白质组学变化的研究仍处于早期阶段。本研究的目的是通过利用种族多样化的妇女健康倡议记忆研究（WHIMS）中2,836名妇女的嵌套病例队列，提高对AD和相关痴呆（ADRD）的蛋白质组学的理解。WHIMS包含纵向认知和神经影像学测量；在26年的随访中，严格确定了1336例MCI和ADRD病例；丰富的表型数据；和保存的生物标本。SOMAscan是最全面的蛋白质组学平台，可测量多种生物学途径中7,000种临床相关的人类蛋白质，将用于从基线和14-18年后收集的血液样本中纵向表征蛋白质组。我们还将从这些样本中获得阿尔茨海默病病理的纵向血浆生物标志物。我们的中心假设是：(i)加速的蛋白质组学衰老将与MCI/ADRD的高风险和认知健康长寿的可能性降低有关；（ii）含有7000个蛋白质的SOMAscan将能够鉴定新的蛋白质组学生物标志物、特征和MCI/ADRD及相关内表型的生物学途径。我们的目标是：目的1)确定经过验证的衰老蛋白质组时钟与MCI/ADRD事件和认知健康寿命（即存活至90岁无认知障碍）之间的关联；目的2)确定基线血浆蛋白质组和14-18年蛋白质组变化与MCI/ADRD事件和认知健康寿命的关系；目标3)将Aim 2中发现的衰老和adrd相关蛋白的蛋白质组学时钟与AD病理的神经影像学测量和血浆生物标志物联系起来；目标4)确定预测MCI/ADRD、认知健康寿命和AD病理血浆生物标志物的新多蛋白特征。关键蛋白将在单独的平台（ELISA）上进行验证，并在外部队列中进行复制。本研究将进一步了解ADRD发病机制和衰老认知功能障碍的异质性机制，确定ADRD的风险和保护性蛋白质组学因子，并提出ADRD病理生理靶向干预的候选蛋白。新的蛋白质组学数据将为更广泛的科学界识别新的蛋白质组学生物标志物提供丰富而有价值的资源，从而具有持久的影响。

There is a great need to determine molecular signatures of Alzheimer’s disease (AD) to better understand AD pathophysiology, to detect AD in the preclinical stage, and to identify novel therapeutic targets. The plasma proteome is an ideal resource in which to identify molecular signatures, as proteins perform essential biological functions, are direct therapeutic targets, and shed light on disease mechanisms. Our preliminary data identified several plasma proteomic biomarkers associated with cognitive impairment and AD-related brain atrophy. We also found that accelerated biological (i.e., proteomic) aging relative to chronological age, as measured by our validated proteomic signature of aging (known as a ‘proteomic clock’), was associated with higher risk of multiple age-related conditions, including cognitive impairment. Yet, study of the proteomic changes preceding AD is still in its early stages. The objective of this study is to improve understanding of the proteomics of AD and related dementias (ADRD) by leveraging a nested case-cohort of 2,836 women in the racially diverse Women’s Health Initiative Memory Study (WHIMS). WHIMS contains longitudinal cognitive and neuroimaging measures; 1,336 incident cases of MCI and ADRD rigorously ascertained during 26 years of follow-up; rich phenotypic data; and preserved biospecimens. SOMAscan, the most comprehensive proteomics platform measuring 7,000 clinically relevant human proteins across numerous biological pathways, will be used to characterize the proteome longitudinally from blood samples collected at baseline and 14-18 years later. We will also obtain longitudinal plasma biomarkers of AD pathology from these samples. Our central hypotheses are that: (i) accelerated proteomic aging will be associated with higher risk of MCI/ADRD and lower likelihood of cognitively healthy longevity; and (ii) the 7,000-protein SOMAscan will enable identification of novel proteomic biomarkers, signatures, and biological pathways for MCI/ADRD and related endophenotypes. Our Aims are: Aim 1) Determine associations of validated proteomic clocks of aging with incident MCI/ADRD and cognitively healthy longevity (i.e., survival to age 90 without cognitive impairment); Aim 2) Determine associations of the plasma proteome at baseline, and 14-18-year changes in the proteome, with incident MCI/ADRD and cognitively healthy longevity; Aim 3) Relate proteomic clocks of aging and ADRD-associated proteins identified in Aim 2 to neuroimaging measures and plasma biomarkers of AD pathology; and Aim 4) Identify novel multi-protein signatures that predict MCI/ADRD, cognitively healthy longevity, and plasma biomarkers of AD pathology. Key proteins will be validated on a separate platform (ELISA) and replicated in external cohorts. This study will advance understanding of the heterogeneous mechanisms of ADRD pathogenesis and cognitive impairment in aging, identify risk and protective proteomic factors, and suggest candidate proteins for pathophysiology-targeted interventions in ADRD. The novel proteomic data will be a rich and valuable resource for the broader scientific community to identify novel proteomic biomarkers for a wealth of phenotypes, thus having an enduring impact.