血脑屏障生物标志物调节外周免疫与阿尔茨海默病之间的关联。

Blood-brain barrier biomarkers modulate the associations of peripheral immunity with Alzheimer's disease.

作者信息

Hou Jia-Hui, Jiang De-Ming, Chu Min, Wu Li-Yong

机构信息

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.

出版信息

Transl Psychiatry. 2025 Apr 10;15(1):138. doi: 10.1038/s41398-025-03347-x.

DOI:10.1038/s41398-025-03347-x

PMID:40210862

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11986039/

Abstract

The association between peripheral immunity and Alzheimer's disease (AD) has been increasingly recognized, but the underlying mechanisms are still unclear. We used multiple linear regression models to explore the association between peripheral immune biomarkers / blood-brain barrier (BBB)-related biomarkers and AD biomarkers. And we used causal mediation analysis with 10,000 bootstrapped iterations to investigate the functions of BBB-related biomarkers in mediating the associations between peripheral immune biomarkers and AD pathology, cerebral atrophy degree, as well as cognitive function. A total of 543 participants (38.7% female, mean age of 74.8 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were involved. Neutrophils percent (NEU%), lymphocytes percent (LYM%), neutrophils / lymphocytes (NLR), and chemotactic factor-3 (CCL26) were significantly associated with cerebrospinal fluid (CSF) β-amyloid-42 (Aβ-42), phosphorylated-tau (P-tau), total tau (T-tau)/Aβ-42 and P-tau/Aβ-42, the associations of NEU% with AD pathology were mediated by CCL26 (proportion: 18-24%; p < 0.05). NEU%, LYM%, NLR, CCL26, CD40 and matrix metalloproteinase-10 (MMP10) were significantly associated with whole brain, hippocampal volume, middle temporal lobe (MTL) volume, and entorhinal cortex (EC) thickness, the associations of peripheral immune biomarkers with cerebral atrophy degree were mediated by BBB-related biomarkers (proportion: 7-17%; p < 0.05). NEU%, LYM%, NLR, CCL26, CD40 and MMP10 were significantly associated with global cognition, executive function, memory function, immediate recall, and delayed recall, the associations of peripheral immune biomarkers with cognitive function were mediated by BBB-related biomarkers (proportion: 9-24%; p < 0.05). This study suggests that peripheral immunity may influence AD through influencing BBB function, providing a more robust and comprehensive evidence chain for the potential role of inflammation in AD.

摘要

外周免疫与阿尔茨海默病（AD）之间的关联已得到越来越多的认识，但其潜在机制仍不清楚。我们使用多元线性回归模型来探索外周免疫生物标志物/血脑屏障（BBB）相关生物标志物与AD生物标志物之间的关联。并且我们使用具有10000次自抽样迭代的因果中介分析来研究BBB相关生物标志物在介导外周免疫生物标志物与AD病理学、脑萎缩程度以及认知功能之间关联中的作用。来自阿尔茨海默病神经影像倡议（ADNI）的总共543名参与者（女性占38.7%，平均年龄74.8岁）被纳入研究。中性粒细胞百分比（NEU%）、淋巴细胞百分比（LYM%）、中性粒细胞/淋巴细胞（NLR）和趋化因子-3（CCL26）与脑脊液（CSF）β淀粉样蛋白-42（Aβ-42）、磷酸化tau蛋白（P-tau）、总tau蛋白（T-tau）/Aβ-42以及P-tau/Aβ-42显著相关，NEU%与AD病理学之间的关联由CCL26介导（比例：18-24%；p<0.05）。NEU%、LYM%、NLR、CCL26、CD40和基质金属蛋白酶-10（MMP10）与全脑、海马体积、颞中回（MTL）体积以及内嗅皮质（EC）厚度显著相关，外周免疫生物标志物与脑萎缩程度之间的关联由BBB相关生物标志物介导（比例：7-17%；p<0.05）。NEU%、LYM%、NLR、CCL26、CD40和MMP10与整体认知、执行功能、记忆功能、即时回忆和延迟回忆显著相关，外周免疫生物标志物与认知功能之间的关联由BBB相关生物标志物介导（比例：9-24%；p<0.05）。本研究表明外周免疫可能通过影响BBB功能来影响AD，为炎症在AD中的潜在作用提供了更有力和全面的证据链。