Zhang Erdong, Dai Fengqiu, Tao Ling, Chen Yanqin, Chen Tingting, Shen Xiangchun
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.
J Alzheimers Dis. 2025 Feb;103(4):1277-1288. doi: 10.1177/13872877241313140. Epub 2025 Jan 29.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that predominantly affects elderly individuals across the globe. While genetic, environmental, and lifestyle factors are known to influence the onset of AD, the underlying mechanisms remain unclear.
To elucidate the intricate interplay between metabolites and immune cell activation in the ethology of AD, and to determine their collective impact on AD risk.
We conducted a comprehensive analysis of genome-wide association studies data to examine the relationships between metabolites, immune cell phenotypes, and the risk of AD. Our study encompassed a comprehensive examination involving 731 distinct immune cell types, 1400 metabolites, and a large cohort comprising10,520 AD cases with 401,661 controls. We employed univariate Mendelian randomization to assess bidirectional relationships between metabolites and AD, metabolites and immune cells, as well as immune cells and AD. Subsequently, multivariate Mendelian randomization was then applied to evaluate the potential mediating role of immune cells on the relationship between metabolites and AD.
Specific metabolites, the histidine/pyruvate ratio and homoarginine, were positively associated with the risk of AD, mediated by immune cells. Conversely, 4-hydroxycoumarin and glycolithocholate sulfate showed protective associations against AD. Immune cell markers, CD64 on monocytes and HLA DR on CD14 CD16 monocytes were linked to higher AD risk, while CD33 HLA DR CD11b myeloid cells and HLA DR on CD8 T cells were protective.
This study highlights the critical role of immune cells in the pathogenesis of AD, demonstrating how their interaction with specific metabolites influences disease risk.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，主要影响全球老年人。虽然已知遗传、环境和生活方式因素会影响AD的发病，但潜在机制仍不清楚。
阐明代谢物与免疫细胞激活在AD病因学中的复杂相互作用，并确定它们对AD风险的共同影响。
我们对全基因组关联研究数据进行了全面分析，以研究代谢物、免疫细胞表型与AD风险之间的关系。我们的研究包括对731种不同免疫细胞类型、1400种代谢物以及一个由10520例AD病例和401661例对照组成的大型队列进行全面检查。我们采用单变量孟德尔随机化来评估代谢物与AD、代谢物与免疫细胞以及免疫细胞与AD之间的双向关系。随后，应用多变量孟德尔随机化来评估免疫细胞在代谢物与AD关系中的潜在中介作用。
特定代谢物，即组氨酸/丙酮酸比值和高精氨酸，与AD风险呈正相关，由免疫细胞介导。相反，4-羟基香豆素和硫酸甘氨石胆酸显示出对AD的保护作用。免疫细胞标志物，单核细胞上的CD64和CD14 CD16单核细胞上的HLA DR与较高的AD风险相关，而CD33 HLA DR CD11b髓样细胞和CD8 T细胞上的HLA DR具有保护作用。
本研究强调了免疫细胞在AD发病机制中的关键作用，证明了它们与特定代谢物的相互作用如何影响疾病风险。
