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Background: Cerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer's disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. We previously found a novel association between high Aβ40 (but not Aβ42) and high sTREM2 levels at baseline and replicated additional associations between a fluid biomarker of blood‐brain barrier (BBB) integrity and CSF biomarkers of neurodegeneration. Therefore, we sought to determine the relative contributions of these biological correlates to CSF sTREM2 levels during the prodromal stages of AD. Additionally we investigated whether the residual variance in sTREM2 level correlated with each biomarker predicted future cognitive performance. Method: Leveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6, male=67%, mild cognitive impairment=47%), previously established associations between baseline CSF sTREM2 concentrations and CSF AD biomarkers (Aβx‐40, total tau, phosphorylated tau, and neurofilament light) and BBB integrity (CSF/plasma albumin ratio) were examined via hierarchical linear regression using sTREM2 as an outcome variable. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status. Baseline CSF sTREM2 levels and corresponding residual components when adjusting for other biomarker levels in independent models were used in longitudinal mixed effects models predicting an episodic memory composite calculated as a z‐score from independent tests. Participants had up to five visits (mean±sd=2.63±1.30 visits). Result: High baseline CSF sTREM2 levels predicted slower longitudinal memory decline in VMAP (β=1.442e‐05, p=0.035). Additionally, the component of sTREM2 signal correlated with Aβx‐40 best predicted future memory performance (β=2.217e‐05, p=0.007). Together, Aβx‐40, phosphorylated tau, and the CSF/plasma albumin ratio jointly explained 36% of variance in sTREM2 levels. Aβx‐40 levels and the CSF/plasma albumin ratio explained sTREM2 signal above and beyond established associations with tau (R2=0.21; R2=0.21; and R2=0.17, respectively). Conclusion: We highlight potential contributions of Aβ homeostasis and BBB integrity to elevations in CSF sTREM2, underscoring novel biomarker associations relevant to disease progression. Results suggest that the tight correlation between baseline CSF sTREM2 and Aβx‐40 levels may have notable importance to cognitive trajectory in an aged cohort enriched for mild cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Triggering 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. Method: Leveraging 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. Result: Higher 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). Conclusion: We 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. [ABSTRACT FROM AUTHOR]