Zhang Erdong, Chen Tingting, Chen Yanqin, Long Chenxiang, Tao Ling, Shen Xiangchun, Dai Fengqiu
The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, Guizhou, China.
The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, Guizhou, China.
Front Aging Neurosci. 2024 Jul 15;16:1433691. doi: 10.3389/fnagi.2024.1433691. eCollection 2024.
Alzheimer's disease (AD) is a leading cause of dementia, characterized by the accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau proteins, leading to neuroinflammation and neuronal damage. The role of the immune system in AD pathogenesis is increasingly recognized, prompting an exploration of the causal relationship between immune cells and AD by using Mendelian randomization (MR) approaches.
Utilizing genome-wide association study (GWAS) data from European cohorts, we conducted an MR study to investigate the causal links between immune cell phenotypes and AD. We selected single nucleotide polymorphisms (SNPs) associated with immune cell traits at a genome-wide significance threshold and applied various MR methods, including MR Egger, Weighted median, and inverse variance weighted analysis, to assess the causality between 731 immune phenotypes and AD.
Our MR analysis identified 15 immune cell types with significant causal relationships to AD pathogenesis. Notably, the absolute count of CD28CD4CD8 T cells and the expression of HLA DR on B cells were linked to a protective effect against AD, while 13 other immune phenotypes were identified as contributing to the risk factors for the disease. The causal effects of AD on immunophenotypic traits are predominantly negative, implying that AD may impair the functionality of immune cells. Validation through independent datasets, such as FinnGen and GCST90027158, confirmed the causal association between six specific immune cells and AD.
This comprehensive MR study elucidates the intricate network of causal relationships between diverse immunophenotypic traits and AD, providing novel insights into the immunopathogenesis of AD. The findings suggest potential immunological targets that could be leveraged for early diagnosis, disease monitoring, and therapeutic intervention.
阿尔茨海默病（AD）是痴呆症的主要病因，其特征是β-淀粉样蛋白（Aβ）和过度磷酸化的tau蛋白积累，导致神经炎症和神经元损伤。免疫系统在AD发病机制中的作用日益受到认可，促使人们通过孟德尔随机化（MR）方法探索免疫细胞与AD之间的因果关系。
利用来自欧洲队列的全基因组关联研究（GWAS）数据，我们进行了一项MR研究，以调查免疫细胞表型与AD之间的因果联系。我们在全基因组显著性阈值下选择与免疫细胞特征相关的单核苷酸多态性（SNP），并应用各种MR方法，包括MR Egger、加权中位数和逆方差加权分析，来评估731种免疫表型与AD之间的因果关系。
我们的MR分析确定了15种免疫细胞类型与AD发病机制存在显著因果关系。值得注意的是，CD28CD4CD8 T细胞的绝对计数和B细胞上HLA DR的表达与对AD的保护作用相关，而其他13种免疫表型被确定为该疾病的危险因素。AD对免疫表型特征的因果效应主要为阴性，这意味着AD可能损害免疫细胞的功能。通过独立数据集（如FinnGen和GCST90027158）进行的验证证实了六种特定免疫细胞与AD之间的因果关联。
这项全面的MR研究阐明了多种免疫表型特征与AD之间复杂的因果关系网络，为AD的免疫发病机制提供了新的见解。研究结果表明了潜在的免疫靶点，可用于早期诊断、疾病监测和治疗干预。
