Cerebrospinal Fluid sTREM2 in Alzheimer's Disease Is Associated with Both Amyloid and Tau Pathologies but not with Cognitive Status

Background: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is considered a biomarker of microglial activation. The relationships between CSF sTREM2 levels and Alzheimer's disease (AD) CSF core biomarkers, cognitive status, and neurodegeneration remain unclear. Objective: To assess the association between CSF sTREM2 levels and AD progression and other AD hallmarks. Methods: Using the Alzheimer's Disease Neuroimaging Initiative database, we investigated 1,035 participants, including 310 cognitively normal controls, 527 patients with mild cognitive impairment, and 198 patients with dementia. They were grouped according to CSF pathology (A/T profile) severity. CSF sTREM2 levels were compared between the groups, and linear regression analysis was performed to evaluate the factors affecting sTREM2 levels. The predictive effectiveness of sTREM2 levels was tested, and the correlation with other indicators was explored. The increase rate was assessed using linear mixed-effects models. Results: Higher CSF sTREM2 levels were associated with older age as well as higher CSF p-tau or t-tau and amyloid-beta levels (all p < 0.001), but not with cognitive status. sTREM2 levels were not correlated with the baseline or longitudinal scale and neuroimaging result changes, and could not predict clinical conversion, but were correlated with multiple non-amyloid-beta and non-tau CSF cytokines related to inflammation and neurodegeneration (p < 0.0001). The increased sTREM2 expression rate did not change among groups. Conclusion: CSF sTREM2 levels were jointly determined by age, amyloid-beta, and tau pathologies, leading to complex AD cognitive continuum changes. Although sTREM2 levels could not predict cognitive deterioration and neurodegeneration, they could reflect the microglial state as a non-specific biomarker.