Dynamic changes of CSF sTREM2 in preclinical Alzheimer’s disease: the CABLE study

Abstract

Background: Loss of function of triggering receptor expressed on myeloid cell 2 (TREM2), a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). Whether TREM2 levels are pathologically altered during the preclinical phase, and whether cerebrospinal fluid (CSF) soluble TREM2 protein (sTREM2) has a relationship with major pathological processes including Aβ and tau deposition are still unclear.Methods: According to the NIA-AA criteria, 659 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups, stage 0 (normal Aβ 1-42 , T-tau and P-tau), stage 1 (low Aβ 1-42 , normal T-tau and P-tau), stage 2 (low Aβ 1-42 and high T-tau or P-tau), and suspected non-AD pathology (SNAP) (normal Aβ 1-42 and high T-tau or P-tau), to examine changes of CSF sTREM2 in the preclinical AD. Biomarker cut-off was based on the assumption that one-third of adults with normal cognition have AD pathology.Results: The level of CSF sTREM2 in the stage 1 decreased compared with the stage 0 (P < 0.001), and then increased in the stage 2 (P = 0.008). SNAP individuals also had significantly increased CSF sTREM2 (P < 0.001). Results of multiple linear regressions also showed positive correlations of CSF sTREM2 with Aβ 1-42 (β = 0.192, P < 0.001), T-tau (β = 0.215, P < 0.001) and P-tau (β = 0.123, P < 0.001).Conclusion: CSF sTREM2 levels are dynamic in preclinical AD. Aβ pathology is associated with a decrease in CSF sTREM2 in the absence of tau deposition and neurodegeneration. However, tau pathology and neurodegeneration are associated with an increase in CSF sTREM2.

Association between methylation of BIN1 promoter in peripheral blood and preclinical Alzheimer’s disease

“…Therefore, in this study, CSF biomarker positive participants were defined as having CSF Aβ42 levels in the lower one-third of the distribution of participants (A+: ≤120.71 pg/mL) or having p-tau (T+: ≥39.15 pg/mL) or t-tau ( N +: ≥184.19 pg/mL) levels in the upper one-third of the distribution. This method for establishing cut-offs was also used in previous studies, yielding reasonable results 22 , 32 .…”

“…The CABLE database is an ongoing large independent cohort study initiated in 2017. It aimed to determine the genetic and environmental modifiers of AD biomarkers and their utility in early diagnosis in the northern Chinese Han population 21 , 22 . All participants in CABLE were enrolled at Qingdao Municipal Hospital, Shandong Province, China.…”

The Relationship of Soluble TREM2 to Other Biomarkers of Sporadic Alzheimer’s Disease

“…Why CSF sTREM2 was not signi cantly associated with Aβ 42 in our sample is unknown. Given the early appearance of Aβ 42 and its plateau in the prodromal stage of AD, giving way to the increase in P-tau, sTREM2 may be closely linked with Aβ-triggered tau phosphorylation occurring after Aβ 42 accumulation [11,28] . Tau aggregations might affect the microglial activation state, suppressing Aβ clearance and producing neurodegeneration [29,30] .…”

Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, while the Alzheimer’s R47H mutant does the opposite

“…Third, in transgenic mouse models overproducing Aβ the knockout of TREM2 expression accelerates amyloid plaque seeding 17 and the plaques have increased protofibrillar halos and hotspots 3,16,18 , indicating that either TREM2 or sTREM2 inhibit plaque formation. Fourth, in the earliest pre-symptomatic stages of AD, at the time of Aβ deposition, sTREM2 levels in cerebrospinal fluid (CSF) are lower than in healthy controls 10,19 , consistent with sTREM2 being an endogenous inhibitor of Aβ deposition. However, the CSF Aβ levels rise in the early symptomatic stages of AD, and then decline again at later stages of AD 11,12 .…”