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 amyloid-β (Aβ) load and AD-related blood biomarkers, i.e., 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 and R62H genotype was conducted 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 Our findings suggest plasma sTREM2 relates to downstream tau processes in amyloid-positive individuals, providing novel insights into the roles of peripheral TREM2 signaling that reflects microglial activity in early AD neuropathological development.

Affiliated Institutions

• University of Gothenburg SE
• University of Wisconsin–Madison US
• The University of Melbourne AU
• Sorbonne Université FR
• King's College London GB
• Curtin University AU
• Monash University AU
• University College London GB
• Hornsby Ku-ring-gai Hospital AU
• UK Dementia Research Institute GB
• Centre for Mental Health GB
• Edith Cowan University AU
• Macquarie University AU
• Banner Health US
• University of Science and Technology of China CN
• University of Pittsburgh US
• Duke Medical Center US
• Stavanger University Hospital
• Australian Alzheimer’s Research Foundation AU
• IPB University ID
• Sahlgrenska University Hospital SE
• Florey Institute of Neuroscience and Mental Health AU
• KaRaMinds AU
• Pitié-Salpêtrière Hospital FR
• Murdoch University AU
• Eli Lilly (United States) US
• Institut du Cerveau FR

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