Lan Guoyu, Li Anqi, Gonzalez-Ortiz Fernando, Lv Jieqin, Ran Wenqing, Cai Yue, Sun Pan, Liu Lin, Yang Jie, Zhang Laihong, He Zhengbo, Fang Lili, Zhou Xin, Zhu Yalin, Liu Zhen, Fan Xiang, Chen Xuhui, Xu Linsen, Wang Qingyong, Wang Xinlu, Sun Kun, Cheng Guanxun, Han Ying, Blennow Kaj, Wang Lu, Ran Pengcheng, Guo Tengfei
Institute of Neurological and Psychiatric Disorders, Shenzhen Bay Laboratory, Shenzhen, 518132, China.
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, China.
Mol Psychiatry. 2025 Apr 1. doi: 10.1038/s41380-025-02976-4.
Loss-of-function mutation of triggering receptor expressed on myeloid cell 2 (TREM2) is associated with increased risks for Alzheimer's disease (AD). Recent animal studies reveal that the activation of peripheral TREM2 signaling may affect cerebral β-amyloid (Aβ) and tau aggregates. However, the underlying relationship between peripheral TREM2 and brain AD pathology has not yet been well-elucidated in the aging population. In this study, we collected 318 Chinese older adults with Aβ PET and plasma biomarker measures, including soluble TREM2 (sTREM2) and glial fibrillary acidic protein (GFAP), a proxy for astrocyte reactivity. Additionally, 129 participants underwent tau PET scans. We explored the association between plasma sTREM2, GFAP, and primary AD pathology. Plasma sTREM2 was negatively associated with reduced temporal tau PET burden in participants with abnormal Aβ and tau pathology. Higher plasma sTREM2 was related to the weaker association of Aβ pathology and plasma phosphorylated tau with tau PET increases. In contrast, elevated plasma GFAP was related to greater Aβ and tau PET burden along with stronger Aβ-related tau accumulation. Finally, higher plasma sTREM2 was linked to attenuated strength of the association between plasma GFAP and tau PET increases at both pre-defined regions of interest and voxel levels. Altogether, our findings suggest distinct relationships between plasma sTREM2 and GFAP with cerebral tau pathology, providing novel insights into the roles of peripheral TREM2 signaling and astrocytic reactivity in AD neuropathological development. This study has important implications, such as targeting the peripheral TREM2 signature, which may be a potential strategy for future AD therapies.
髓样细胞2（TREM2）上表达的触发受体功能丧失突变与阿尔茨海默病（AD）风险增加有关。最近的动物研究表明，外周TREM2信号的激活可能会影响脑内β-淀粉样蛋白（Aβ）和tau蛋白聚集物。然而，在老年人群中，外周TREM2与脑AD病理学之间的潜在关系尚未得到充分阐明。在本研究中，我们收集了318名有Aβ正电子发射断层扫描（PET）和血浆生物标志物测量结果的中国老年人，这些生物标志物包括可溶性TREM2（sTREM2）和胶质纤维酸性蛋白（GFAP，一种星形胶质细胞反应性的替代指标）。此外，129名参与者接受了tau蛋白PET扫描。我们探讨了血浆sTREM2、GFAP与原发性AD病理学之间的关联。在Aβ和tau病理学异常的参与者中，血浆sTREM2与颞叶tau蛋白PET负荷降低呈负相关。较高的血浆sTREM2与Aβ病理学和血浆磷酸化tau蛋白与tau蛋白PET增加之间的关联较弱有关。相比之下，血浆GFAP升高与更大的Aβ和tau蛋白PET负荷以及更强的Aβ相关tau蛋白积累有关。最后，在预先定义的感兴趣区域和体素水平上，较高的血浆sTREM2与血浆GFAP和tau蛋白PET增加之间的关联强度减弱有关。总之，我们的研究结果表明血浆sTREM2和GFAP与脑tau病理学之间存在不同的关系，为外周TREM2信号和星形胶质细胞反应性在AD神经病理发展中的作用提供了新的见解。这项研究具有重要意义，例如针对外周TREM2特征，这可能是未来AD治疗的一种潜在策略。
