The dynamic functional role of triggering receptor expressed on myeloid cells 2 (TREM2) assessed with cerebrospinal fluid and positron emission tomography measures

Abstract

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) regulates several microglial activities and is essential for microglia to switch to an activated state. The role of TREM2 in the pathogenesis of Alzheimer’s disease (AD) is unclear, however. Following its role in microglial activity, the ectodomain of TREM2 is cleaved into the soluble proteolytic end product of TREM2 (sTREM2), which is released from the transmembrane domain into the cerebrospinal fluid (CSF) and, therefore, CSF sTREM2 is considered a biomarker of TREM2 activity.MethodTo examine the role of TREM2, we explored the relationships between CSF sTREM2, amyloid‐beta (Aβ42), phosphorylated tau‐181 (p‐tau‐181), and total‐tau (t‐tau) in a cohort of 495 participants (100 patients with AD, 257 patients with MCI, and 138 controls) whose data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Associations between CSF sTREM2 and 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET), 18F‐florbetapir (18F‐AV45) PET, and grey matter volume (GMV) were also investigated.ResultCSF sTREM2 levels were stable across AD, MCI and cognitively normal subgroups. In the whole cohort, CSF sTREM2 positively correlated with age (r = 0.214,p<0.001), CSF Aβ42 (r = 0.118,p = 0.009), CSF t‐tau (r = 0.423,p<0.001), and CSF p‐tau‐181 (r = 0.396,p<0.001), and negatively correlated with MMSE score (r = ‐0.105,p = 0.019). CSF sTREM2, t‐tau and p‐tau‐181 could significantly predict CSF Aβ42 levels, while CSF sTREM2 and Aβ42 could significantly predict CSF p‐tau‐181 and t‐tau levels. Higher CSF sTREM2 was associated with greater amyloid load, decreased glucose metabolism, and reduced GMV in MCI, but not in AD, in certain brain regions.ConclusionCSF sTREM2 levels were comparable across clinical groups, and with CSF sTREM2 correlating with markers of AD and neuronal damage, we predict that changes in neuropathological processes occurring in relation to changes in CSF sTREM2 levels are a result of alterations in TREM2 function, rather than quantity. Taken together with the relationships between CSF sTREM2 and imaging findings, these results suggest that sTREM2 appears early on in the AD trajectory, probably in response to early microglial activation in MCI in response to evolving pathological processes.