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

BackgroundCSF 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.ObjectiveInvestigate 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.MethodsPlasma 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 <i>TREM2 R47H</i> and <i>R62H</i> genotype was conducted as exploratory analysis.ResultsPlasma 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.ConclusionsOur 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.

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Publication Details

Journal
Journal of Alzheimer s Disease
Published
2025-12-09
DOI
https://doi.org/10.1177/13872877251400780
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
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article

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

Chai K. Lim, Kathryn Goozee, Kaj Blennow, Hamid R. Sohrabi et al.
Journal of Alzheimer s Disease
Neuroinflammation and Neurodegeneration Mechanisms
article

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

Chai K. Lim, Kathryn Goozee, Kaj Blennow, Hamid R. Sohrabi, Steve Pedrini, Kevin Taddei, Pratishtha Chatterjee, Colin Louis Masters, Thomas K. Karikari, Cameron W. Morris, Stephanie Ruth Rainey‐Smith, Ralph N. Martins, Prita R. Asih, Gilles J. Guillemin, Simon Matthew Laws, Hong Wang, Nicholas J. Ashton, Henrik Zetterberg
article en

Abstract

BackgroundCSF 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.ObjectiveInvestigate 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.MethodsPlasma 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 <i>TREM2 R47H</i> and <i>R62H</i> genotype was conducted as exploratory analysis.ResultsPlasma 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.ConclusionsOur 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.

Journal of Alzheimer s DiseaseVol. 109(2)
Edith Cowan University (AU), University of Science and Technology of China (CN), University of Wisconsin–Madison (US), The University of Melbourne (AU), Eli Lilly (United States) (US), University of Pittsburgh (US), Murdoch University (AU), King's College London (GB), Curtin University (AU), IPB University (ID), Florey Institute of Neuroscience and Mental Health (AU), Stavanger University Hospital (NO), Hornsby Ku-ring-gai Hospital (AU), Sahlgrenska University Hospital (SE), Banner Health (US), Centre for Mental Health (GB), Sorbonne Université (FR), Pitié-Salpêtrière Hospital (FR), Duke Medical Center (US), UK Dementia Research Institute (GB), KaRaMinds (AU), Australian Alzheimer’s Research Foundation (AU), Institut du Cerveau (FR), Dementia Australia (AU), University College London (GB), Monash University (AU), University of Gothenburg (SE), Macquarie University (AU)
Openalex Percentile: Top 54%
Neuroinflammation and Neurodegeneration Mechanisms
DOISourceOpenAlex
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