The relationship of soluble TREM2 to other biomarkers of sporadic Alzheimer’s disease

Abstract

Microglial activation is a central player in the pathophysiology of Alzheimer’s disease (AD). The soluble fragment of triggering receptor expressed on myeloid cells 2 (sTREM2) can serve as a marker for microglial activation and has been shown to be overexpressed in AD. However, the relationship of sTREM2 with other AD biomarkers has not been extensively studied. We investigated the relationship between cerebrospinal fluid (CSF) sTREM2 and other AD biomarkers and examined the correlation of plasma sTREM2 with CSF sTREM2 in a cohort of individuals with AD and without AD. Participants were consecutively recruited from Asan Medical Center from 2018 to 2020. Subjects were stratified by their amyloid positivity and clinical status. Along with other AD biomarkers, sTREM2 level was measured in the plasma as well as CSF. In 101 patients with either amyloid-positive or negative status, CSF sTREM2 was closely associated with CSF T-tau and P-tau and not with Abeta42. CSF sTREM2 levels were found to be strongly correlated with CSF neurofilament light chain. The comparison of CSF and plasma sTREM2 levels tended to have an inverse correlation. Plasma sTREM2 and P-tau levels were oppositely influenced by age. Our results suggest that neuroinflammation may be closely associated with tau-induced neurodegeneration.

Reactive astrogliosis: A friend or foe in the pathogenesis of Alzheimer’s disease

“…A very thorough analysis of the Dominantly Inherited Alzheimer Network (DIAN) cohort corroborates these findings, indicating that longitudinal increase in CSF sTREM2 is associated with slower deposition of Aβ (Christian et al, 2021). Whether plasma sTREM2 levels are expressed differently in AD patients must be further explored, and the influence of different sTREM2 variants (e.g., the R47H TREM2 variant) should be considered (Ashton et al, 2019; Park et al, 2021; Vilalta et al, 2021). In fact, it seems that microglial activation could display a biphasic profile, in which different phenotypes (either beneficial or detrimental) might distinctly respond to the core pathology of AD, a behaviour very similar to astrocytes.…”

Alzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint

“…Therefore, it is possible that as the disease progresses, there is a failure of microglial function, particularly in phagocytosing Aβ plaques, and hence reduced TREM2 activity. Alternatively, TREM2 may be a marker of Aβ-induced tau pathology and neurodegeneration in AD ( Park et al, 2021 ), supporting the notion that microglial activation may drive tau pathology ( Pascoal et al, 2021 ).…”

“…Furthermore, plasma sTREM2 concentrations do not correlate with CSF t-tau, p-tau, or Aβ 1–42 ( Piccio et al, 2016 ; Bekris et al, 2018 ). Interestingly, Bekris et al (2018) observed a significant positive correlation between plasma and CSF sTREM2, whilst Piccio et al (2016) observed a non-significant positive correlation between plasma and CSF sTREM2 concentrations, and Park et al (2021) observed a negative correlation between plasma and CSF sTREM2. The cause of the differing results between these studies is not clear but may be due to differences in cohort sizes or methodological factors.…”

“…This is particularly important as the serum concentration of proteins involved in AD are thought to range from 10 –16 to 10 –12 M ( Galasko, 2005 ; Jong et al, 2007 ). Simoa measurements of Aβ, glial fibrillary acidic protein (GFAP), phosphorylated tau (p-tau) and neurofilament light chain (NfL), but not the soluble fragment of triggering receptor expressed on myeloid cells 2 (sTREM2), in both CSF and plasma are now well-established ( Janelidze et al, 2016 ; Hendricks et al, 2019 ; Vergallo et al, 2019 ; Benedet et al, 2021 ; Blennow, 2021 ; Park et al, 2021 ). However, as we move into the era of disease-modifying therapies for AD targeting Aβ pathology, there is a need for more sensitive and robust techniques to measure changes in these proteins in trial participants.…”

Association of daily sleep duration with the incident dementia by serum soluble TREM2 in a community

“…28 Increased sTREM2 levels in the plasma have been shown to be a marker of activation of microglia, neuroinflammation, and neuronal injury. 8,29,30 We previously showed a clear association between increased serum sTREM2 levels and elevated risk of developing dementia. 7 The present study also showed a U-shaped association between daily sleep duration and dementia risk in subjects with high sTREM2 levels, but not in subjects with low sTREM2 levels.…”