Zhan Hui, Cammann Davis, Cummings Jeffrey L, Dong Xianjun, Chen Jingchun
Interdisciplinary Neuroscience Program, University of Nevada, Las Vegas (UNLV), Las Vegas, NV, USA.
Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas (UNLV), Las Vegas, NV, USA.
J Transl Med. 2025 Mar 6;23(1):278. doi: 10.1186/s12967-025-06317-5.
Alzheimer's disease (AD) is the main cause of dementia with few effective therapies. We aimed to identify potential plasma biomarkers or drug targets for AD by investigating the causal association between plasma proteins and AD by integrating comprehensive Mendelian randomization (MR) and multi-omics data.
Using two-sample MR, cis protein quantitative trait loci (cis-pQTLs) for 1,916 plasma proteins were used as an exposure to infer their causal effect on AD liability in individuals of European ancestry, with two large-scale AD genome-wide association study (GWAS) datasets as the outcome for discovery and replication. Significant causal relationships were validated by sensitivity analyses, reverse MR analysis, and Bayesian colocalization analysis. Additionally, we investigated the causal associations at the transcriptional level with cis gene expression quantitative trait loci (cis-eQTLs) data across brain tissues and blood in European ancestry populations, as well as causal plasma proteins in African ancestry populations.
In those of European ancestry, the genetically predicted levels of five plasma proteins (BLNK, CD2AP, GRN, PILRA, and PILRB) were causally associated with AD. Among these five proteins, GRN was protective against AD, while the rest were risk factors. Consistent causal effects were found in the brain for cis-eQTLs of GRN, BLNK, and CD2AP, while the same was true for PILRA in the blood. None of the plasma proteins were significantly associated with AD in persons of African ancestry.
Comprehensive MR analyses with multi-omics data identified five plasma proteins that had causal effects on AD, highlighting potential biomarkers or drug targets for better diagnosis and treatment for AD.
阿尔茨海默病（AD）是痴呆的主要病因，有效治疗方法很少。我们旨在通过整合综合孟德尔随机化（MR）和多组学数据，研究血浆蛋白与AD之间的因果关系，以确定AD潜在的血浆生物标志物或药物靶点。
使用两样本MR，将1916种血浆蛋白的顺式蛋白质定量性状位点（cis-pQTLs）作为暴露因素，推断其对欧洲血统个体患AD易感性的因果效应，以两个大规模AD全基因组关联研究（GWAS）数据集作为发现和重复验证的结果。通过敏感性分析、反向MR分析和贝叶斯共定位分析验证显著的因果关系。此外，我们还利用欧洲血统人群脑组织和血液中的顺式基因表达定量性状位点（cis-eQTLs）数据，以及非洲血统人群中的因果血浆蛋白，研究了转录水平上的因果关联。
在欧洲血统个体中，五种血浆蛋白（BLNK、CD2AP、GRN、PILRA和PILRB）的遗传预测水平与AD存在因果关系。在这五种蛋白质中，GRN对AD有保护作用，而其他几种是危险因素。在大脑中发现GRN、BLNK和CD2AP的顺式eQTL具有一致的因果效应，在血液中PILRA也是如此。在非洲血统个体中，没有一种血浆蛋白与AD显著相关。
综合多组学数据的MR分析确定了五种对AD有因果效应的血浆蛋白，突出了用于AD更好诊断和治疗的潜在生物标志物或药物靶点。
