The role of sTREM2 in Alzheimer’s continuum

Abstract

BACKGROUND Neuroinflammation has emerged as a vital player in the Alzheimer’s disease (AD) pathogenesis. Microglial activation is considered the center of this theory. Triggering receptors expressed on myeloid cells 2 (TREM2) are known to increase the risk of AD and are related to other neurodegenerative diseases, implicating microglia and the innate immune system in the CNS as pivotal factors in the pathogenesis of AD. The soluble fragment of TREM2 (sTREM2) serves as a marker of microglial activation and changes dynamically during AD. sTREM2 is released into the cerebrospinal fluid (CSF) and plasma after proteolytic processes via shedding by ADAM proteases in the ectodomain of TREM2. CSF sTREM2 is selectively expressed in microglia. Plasma sTREM2 is thought to originate from peripheral blood mononuclear cells (PBMCs). OBJECTIVES We aimed to elucidate the roles of cerebrospinal fluid (CSF) and plasma sTREM2 in the AD continuum by analyzing their relationships with conventional AD biomarkers. Therefore, we investigated the potential of CSF and plasma sTREM2 levels as biomarkers of AD. METHODS Participants were consecutively recruited from Asan Medical Center from 2018 to 2020. The participants were stratified according to amyloid positivity and clinical status. Along with other AD biomarkers, sTREM2 levels were measured in plasma and CSF. RESULTS CSF sTREM2 levels were positively correlated with pTau-181 levels (ρ = 0.25, P = 0.019). In contrast, plasma sTREM2 showed an inverse relationship and were negatively correlated with pTau-181 (ρ = ─ 0.33, P = 0.002). Plasma sTREM2 were negatively correlated with amyloid deposition in basal ganglia (ρ = ─ 0.35, P = 0.01, in AD continuum). Neither CSF nor plasma sTREM2 predicted amyloid positivity in the brain compared to plasma pTau-181. However, plasma sTREM2 were negatively correlated with basal ganglia amyloid deposition (ρ = ─ 0.33, P = 0.028) in AD continuum. In terms of cognitive decline, the combination of plasma sTREM2 and Aβ42/Aβ40 ratio (AUC = 0.761, P < 0.001) showed statistical significance. CONCLUSION The CSF sTREM2, in line with previous studies, was found to be related to tau biomarkers rather than amyloid. Plasma sTREM2 is a prognostic marker for predicting cognitive decline and reflects amyloid deposition in the basal ganglia in the AD continuum. In clinical practice, these findings might facilitate biomarker-supported diagnosis and prediction of fast decliners in patients with AD.