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

Background:CSF and blood soluble TREM2 (sTREM2) levels have been found to increase at early stage of Alzheimers Disease (AD), albeit plasma levels have been inconclusive. Alterations to AD-related blood biomarkers and brain amyloid beta (Abeta) load remain unclear. How R47H/R62H rare variants in TREM2 gene associated with increased risk of AD may affect plasma sTREM2 has not been reported. Objective:Investigate the association of plasma sTREM2 levels with brain Abeta load and AD-related blood biomarkers such as phosphorylated tau (pTau)-181, pTau-231, GFAP, and NFL in cognitively normal (CN) older adults at risk of AD (CN Abeta+) compared to CN Abeta-, 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 positron emission tomography (PET)-Abeta load SUVR ((CN Abeta- (n=65) and CN Abeta+ (n=35)) as 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 Abeta+ group. Plasma sTREM2 positively correlated with serum microglial kynurenine pathway metabolites. Plasma sTREM2 and brain Abeta 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.