Frick Elisabet A, Emilsson Valur, Jonmundsson Thorarinn, Steindorsdottir Anna E, Johnson Erik C B, Puerta Raquel, Dammer Eric B, Shantaraman Anantharaman, Cano Amanda, Boada Mercè, Valero Sergi, García-González Pablo, Gudmundsson Elias F, Gudjonsson Alexander, Loureiro Joseph J, Orth Anthony P, Seyfried Nicholas T, Levey Allan I, Ruiz Agustin, Aspelund Thor, Jennings Lori L, Launer Lenore J, Gudmundsdottir Valborg, Gudnason Vilmundur
Icelandic Heart Association, Kopavogur, 200, Iceland.
Faculty of Medicine, University of Iceland, Reykjavik, 101, Iceland.
medRxiv. 2023 Nov 9:2023.11.08.23298251. doi: 10.1101/2023.11.08.23298251.
The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD of -ε carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly on -ε carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by -ε yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon -ε genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on -ε. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.
当前对晚发性阿尔茨海默病（LOAD）进行早期干预、预防和治疗的需求，促使人们更深入地了解可能有助于生物标志物和药物靶点发现的潜在分子过程。我们利用来自一个基于人群的前瞻性老年队列（n = 5294）血清中的高通量蛋白质组测量，鉴定出303种与LOAD发病相关的独特蛋白质（中位随访时间12.8年）。其中超过40%的蛋白质与ε4等位基因携带者状态的LOAD相关。这些蛋白质参与神经元过程，并且与LOAD在大脑和脑脊液中的蛋白质特征重叠。我们发现17种蛋白质与LOAD的关联强烈依赖于ε4等位基因携带者状态。它们中的大多数在脑脊液中与LOAD表现出一致的关联，并且三分之一具有脑特异性基因表达。值得注意的是，在双向孟德尔随机化分析中确定，该组中的四种蛋白质（TBCA、ARL2、S100A13和IRF6）在携带ε4等位基因时下调，但在LOAD发病时上调，反映了对疾病发作的潜在反应。因此，在调整ε4基因型后，这些蛋白质与LOAD的直接关联发生了逆转，这一发现我们在一个外部队列（n = 719）中得到了重复验证。我们的研究结果为可能导致LOAD发生和早期检测的失调通路提供了见解，包括那些独立于或依赖于ε4等位基因的通路。重要的是，我们在循环中发现的许多与LOAD相关的蛋白质已被发现在脑组织中表达，并且与AD有直接联系。因此，这里鉴定出的蛋白质及其上游调节通路，为LOAD提供了新的循环生物标志物和治疗靶点候选来源。
