Higher plasma soluble TREM2 correlates with reduced cerebral tau accumulation in Alzheimer's disease

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.