通过蛋白质组学分析确定晚年痴呆风险的蛋白质标志物

阿尔茨海默病(AD)的病理变化早于认知功能缺陷的发生数十年，但研究人员对其了解并不透彻。在最新的研究中，Walker及其同事利用蛋白质组学和基因组学对中年成人队列进行了纵向随访，并确定了可增加25年后痴呆风险的通路特异性血浆蛋白。这些蛋白的信号通路特征是在痴呆发病前10年左右的早期临床前阶段失调的免疫信号和蛋白稳态，以及异常的凝血和补体信号。这项研究表明，不同的生物学机制可能与AD的早期和晚期临床前阶段相关。

实验过程：

使用大规模蛋白质组学平台在10981名中年人中研究了4877种血浆蛋白质与25年痴呆风险之间的关联。发现了32种与痴呆相关的血浆蛋白，它们参与了蛋白稳态、免疫、突触功能和细胞外基质组织。

然后，研究人员在两个独立队列中重复了其中15种蛋白质与临床相关神经认知结局之间的关联。证明了这32个痴呆相关蛋白中的12个与AD、神经变性或神经炎症的脑脊液(CSF)生物标志物相关。 

研究发现：

分析发现这些候选蛋白标志物中的8个在AD患者的人类死后脑组织中异常表达，尽管一些与痴呆风险相关性最强的蛋白，如GDF15，在这些脑组织样本中未检测到。通过网络分析，发现了一个与痴呆风险相关的蛋白质标签，其特征是在痴呆发病前20年到中年的成年人中，特异性免疫和蛋白酶稳态/自噬通路的失调，以及在痴呆发病前10年到痴呆发病前的凝血和补体信号异常。双向双样本孟德尔随机化遗传学验证了研究人员的9个候选蛋白作为中年AD的标志物，并推断了SERPINA3在AD发病机制中的因果关系。

原文：

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer’s disease (AD) and related dementias.  However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease.  Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults.  We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization.  We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts.  We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation.  We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples.  Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset.  Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis.  Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

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