Wang Xifeng, Yang Huayu, Zhan Dengcheng, Sun Haiying, Huang Qiang, Zhang Yiping, Lin Yue, Wei Gen, Hua Fuzhou, Liu Li, Chen Shibiao
Department of Anesthesiology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006, 17# Yong Wai Zheng Street, Nanchang City, Jiangxi Province, PR China.
Department of Neuroscience, Tat Chee Avenue City University of Hong Kong, 999077, Hong Kong City, PR China.
Heliyon. 2024 Oct 5;10(20):e39013. doi: 10.1016/j.heliyon.2024.e39013. eCollection 2024 Oct 30.
Alzheimer's disease (AD) is a gradual neurodegenerative ailment that lacks any disease-modifying intervention. Our objective was to pinpoint pharmacological targets with a focus on amyloid beta (Aβ) and tau to treat and prevent AD in the European population. A proteome-wide Mendelian randomization (MR) analysis was carried out to estimate the associations between proteins and cerebrospinal fluid (CSF) Aβ-42 and phosphorylated Tau (p-Tau). We utilized colocalization and MR analysis to investigate whether the identified proteins were associated with the risk of AD. Additionally, we expanded our investigation to include non-AD phenotypes by conducting a phenome-wide MR analysis of 1646 disease traits based on the FinnGen and UK Biobank databases to explore potential side effects. We identified 11 proteins that were genetically associated with both CSF Aβ-42 and p-Tau levels. The genetically predicted levels of three proteins, GAL3ST2, POLR1C, and BIN1, were found to be associated with an increased risk of AD with high colocalization. In the phenome-wide MR analysis, two out of the three biomarkers were associated with at least one disease, except for GAL3ST2, which was not associated with any disease under the threshold of FDR <0.1. POLR1C was found to be associated with the most disease traits, and all disease associations with genetically inhibited BIN1 were protective. The proteome-wide MR investigation revealed 11 proteins that were associated with the level of CSF Aβ-42 and p-Tau. Among them, GAL3ST2, POLR1C, and BIN1 were identified as potential therapeutic targets for AD and warrant further investigation.
阿尔茨海默病（AD）是一种渐进性神经退行性疾病，目前尚无任何疾病修饰干预措施。我们的目标是确定以淀粉样β蛋白（Aβ）和tau蛋白为重点的药理学靶点，用于治疗和预防欧洲人群中的AD。我们进行了全蛋白质组孟德尔随机化（MR）分析，以估计蛋白质与脑脊液（CSF）Aβ-42和磷酸化tau蛋白（p-Tau）之间的关联。我们利用共定位和MR分析来研究已鉴定的蛋白质是否与AD风险相关。此外，我们通过基于芬兰基因库（FinnGen）和英国生物银行（UK Biobank）数据库对1646种疾病特征进行全表型MR分析，将研究扩展到非AD表型，以探索潜在的副作用。我们鉴定出11种与CSF Aβ-42和p-Tau水平均存在遗传关联的蛋白质。发现三种蛋白质GAL3ST2、POLR1C和BIN1的遗传预测水平与AD风险增加相关，且共定位程度较高。在全表型MR分析中，除GAL3ST2在错误发现率（FDR）<0.1的阈值下与任何疾病均无关联外，这三种生物标志物中的两种与至少一种疾病相关。发现POLR1C与最多的疾病特征相关，并且所有与基因抑制的BIN1相关的疾病关联均具有保护作用。全蛋白质组MR研究揭示了11种与CSF Aβ-42和p-Tau水平相关的蛋白质。其中，GAL3ST2、POLR1C和BIN1被确定为AD的潜在治疗靶点，值得进一步研究。
