Neuroimaging biomarkers and CSF sTREM2 levels in Alzheimer's disease: a longitudinal study

Abstract

Understanding the exact pathophysiological mechanisms underlying the involvement of triggering receptor expressed on myeloid cells 2 (TREM2) related microglia activation is crucial for the development of clinical trials targeting microglia activation at different stages of Alzheimer's disease (AD). Given the contradictory findings in the literature, it is imperative to investigate the longitudinal alterations in cerebrospinal fluid (CSF) soluble TREM2 (sTREM2) levels as a marker for microglia activation, and its potential association with AD biomarkers, in order to address the current knowledge gap. In this study, we aimed to assess the longitudinal changes in CSF sTREM2 levels within the framework of the A/T/N classification system for AD biomarkers and to explore potential associations with AD pathological features, including the presence of amyloid-beta (Aβ) plaques and tau aggregates. The baseline and longitudinal (any available follow-up visit) CSF sTREM2 levels and processed tau-PET and Aβ-PET data of 1001 subjects were recruited from the ADNI database. The participants were classified into four groups based on the A/T/N framework: A+ /TN+ , A+ /TN- , A- /TN+ , and A- /TN- . Linear regression analyses were conducted to assess the relationship between CSF sTREM2 with cognitive performance, tau and Aβ-PET adjusting for age, gender, education, and APOE ε4 status. Based on our analysis there was a significant difference in baseline and rate of change of CSF sTREM2 between ATN groups. While there was no association between baseline CSF sTREM2 and cognitive performance (ADNI-mem), we found that the rate of change of CSF sTREM2 is significantly associated with cognitive performance in the entire cohort but not the ATN groups. We found that the baseline CSF sTREM2 is significantly associated with baseline tau-PET and Aβ-PET rate of change only in the A+ /TN+ group. A significant association was found between the rate of change of CSF sTREM2 and the tau- and Aβ-PET rate of change only in the A+ /TN- group. Our study suggests that the TREM2-related microglia activation and their relations with AD markers and cognitive performance vary the in presence or absence of Aβ and tau pathology. Furthermore, our findings revealed that a faster increase in the level of CSF sTREM2 might attenuate future Aβ plaque formation and tau aggregate accumulation only in the presence of Aβ pathology.

Keywords: Alzheimer’s disease; Amyloid βeta; Microglia; TREM2; Tau.

Figure 1

(A) Baseline level of CSF sTREM2 were compared between groups and (B) longitudinal trajectories of CSF sTREM2 and (C) rate of change of CSF sTREM2.

Figure 2

(A) Association between cognitive performance (ADNI-mem) and baseline level of CSF sTREM2, (B) rate of change of CSF sTREM2 (slope) in ATN groups, and (C) all participants.

Figure 3

(A) Association between baseline CSF sTREM2 and tau and Aβ-PET rate of change, (B) association between baseline CSF sTREM2 and baseline tau and Aβ-PET.

Figure 4

(A) Association between rate of change of CSF sTREM2 and tau and Aβ-PET rate of change, (B) association between rate of change of CSF sTREM2 and baseline tau and Aβ-PET.

Figure 5

Overview of the CSF sTREM2 levels within the ATN framework.