Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21210, USA.
Sci Transl Med. 2023 Jul 19;15(705):eadf5681. doi: 10.1126/scitranslmed.adf5681.
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.
多种生物学过程已被牵涉到阿尔茨海默病（AD）及相关痴呆症的病理生理学中。然而，对于疾病早期相关的外周生物学机制的了解有限。在这里，我们使用了一个大规模的蛋白质组学平台，研究了 10981 名中年成年人中 4877 种血浆蛋白与 25 年痴呆风险的关联。我们发现了 32 种与痴呆相关的血浆蛋白，它们涉及蛋白质稳态、免疫、突触功能和细胞外基质组织。然后，我们在两个独立的队列中复制了这些蛋白中的 15 种与临床相关的神经认知结果之间的关联。我们证明了这 32 种与痴呆相关的蛋白中的 12 种与 AD、神经退行性变或神经炎症的脑脊液（CSF）生物标志物相关。我们发现，这些候选蛋白标志物中的 8 种与 AD 患者的人死后脑组织中的 CSF 标志物相关，尽管与痴呆风险最密切相关的一些蛋白，如 GDF15，在这些脑组织样本中未被检测到。使用网络分析，我们发现了一个痴呆风险的蛋白质特征，其特征是中年人在痴呆发病前约 20 年特定免疫和蛋白质稳态/自噬途径的失调，以及痴呆发病前约 10 年异常的凝血和补体信号。双向两样本孟德尔随机化遗传验证了我们的 9 种候选蛋白作为中年人 AD 的标志物，并推断了 SERPINA3 在 AD 发病机制中的因果关系。最后，我们为中年人 AD 和痴呆风险预测确定了一组候选标志物。
