Plasma soluble TREM2 is associated with plasma pTau-181 and pTau-231 in cognitively normal older adults at risk of Alzheimer's disease

ABSTRACT Background CSF and blood soluble TREM2 (sTREM2) levels have been found to increase at early stage of Alzheimer’s Disease (AD). The relationships between sTREM2, AD-related biomarkers, and other neuroinflammation biomarkers remain unclear. Moreover, the impact of rare variants in TREM2 gene (R47H/R62H), which are associated with increased risk of AD, on plasma sTREM2 has not been elucidated. Objective Investigate the association of plasma sTREM2 levels with brain Aβ load and AD-related blood biomarkers such as phosphorylated tau (pTau)-181, pTau-231, GFAP, NFL, and other neuroinflammation and peripheral inflammation markers in cognitively normal (CN) older adults at risk of AD (CN Aβ+) compared to CN Aβ-, including the effect of AD-linked TREM2 rare variants. Methods Plasma sTREM2 concentrations were measured by MesoScale Discovery (MSD) assay from the KARVIAH cohort. Participants underwent cognitive tests and PET amyloid imaging. Genetic data and blood biomarkers were included for correlation analysis. Associations with plasma sTREM2 were investigated upon stratification by PET-Aβ load SUVR ((CN Aβ- (n=65) and CN Aβ+ (n=35)) as the main analysis. A subgroup analysis based on the TREM2 R47H genotype was carried out as exploratory analysis. Results Plasma sTREM2 positively correlated with plasma pTau181, and pTau231 in CN Aβ+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain Aβ load were higher in R47H TREM2 carriers compared to non-carriers. Conclusions Plasma sTREM2, a marker of microglia activation, is associated with plasma pTau181 and 231 in cognitively normal older adults at risk of AD, with higher plasma sTREM2 levels in R47H TREM2 carriers.