CSF sTREM2 predicts markers of blood brain barrier integrity and amyloid beta metabolism independent of APOE‐ε4 status

Abstract

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor commonly studied for its roles in microglial regulation and amyloid beta deposition in Alzheimer’s disease (AD). Its soluble form, sTREM2, measurable in cerebrospinal fluid (CSF) is a novel biomarker of microglial activity. CSF sTREM2 has been associated with AD progression and biomarkers of neurodegeneration (for which tau is one), while associations with amyloid‐β biomarkers have been inconclusive. Furthermore, cerebrovascular injury commonly co‐occurs with AD, contributes to clinical progression, and drives microglial activation through independent signaling cascades. However, sTREM2 associations with cerebrovascular pathology have been largely unexplored.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6.33 , male=67%, mild cognitive impairment=47%), associations between baseline CSF sTREM2 concentrations (measured using an in‐house immunoassay) and CSF AD biomarkers (Aβx‐42, Aβ1‐42, Aβx‐40, total tau, and phosphorylated tau) and cerebrovascular injury (CSF/plasma albumin ratio) were assessed using linear regression. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status.ResultHigher baseline CSF sTREM2 concentrations predicted an increased CSF/plasma albumin ratio, indicative of compartmental blood brain barrier (BBB) permeability (p=1.36e‐07). Additionally, higher levels of sTREM2 predicted increased CSF protein levels of Aβx‐40 (p=1.53e‐09), and Aβx‐42 (p=7.73e‐03), but not Aβ1‐42 (p=0.26) levels, indicating a possible role for the TREM2 axis in regulating or responding to amyloid beta species composition. We also replicated previous associations between higher CSF sTREM2 and higher CSF tau (p=6.14e‐07) and p‐tau (p=1.82e‐08).ConclusionWe report a novel association between sTREM2 and a marker of BBB integrity, highlighting opportunities for further investigation of the TREM2 axis with cerebrovascular injury. We also report a novel association between sTREM2 and amyloid‐β abundance that does not seem to reflect amyloid burden in the brain, and we replicate an sTREM2 association with markers of neurodegeneration. Future work will seek to better characterize the timing of sTREM2 changes relative to markers of BBB dysfunction and AD pathogenesis.