Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes.

Jagan A Pillai,James Bena,Maria Khrestian,James B Leverenz,Lynn M Bekris

doi:10.3389/fnagi.2021.676744

Abstract

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.

Highlights

Genome-wide association studies in Alzheimer’s disease (AD) have noted multiple susceptibility loci for late-onset AD related to the innate immune system (Lambert et al, 2013; Van Cauwenberghe et al, 2016)
Between A+T+ cognitively normal (CN), mild cognitive impairment (MCI) and dementia groups in Alzheimer’s Disease Neuroimaging Initiative (ADNI), only cerebrospinal fluid (CSF) Aβ levels differed between them (F = 3.91, p = 0.023) but not CSF t-tau, p-tau, sTREM2 and soluble tumor necrosis factor receptor 2 (sTNFR2) analytes (Supplementary Figure 1)
Among the MCI and AD dementia A+ T+ participants in the ADNI cohort, univariate analysis demonstrated that sTNFR2 and sTREM2 were significantly correlated with each other and with CSF t-tau and p-tau but not with Aβ42

Summary

Introduction

Genome-wide association studies in Alzheimer’s disease (AD) have noted multiple susceptibility loci for late-onset AD related to the innate immune system (Lambert et al, 2013; Van Cauwenberghe et al, 2016) Among these susceptibility loci, the presence of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to increase the risk of AD development by 2–3-fold (Guerreiro et al., 2013; Jonsson et al, 2013). TREM2 is thought to enhance the rate of phagocytosis and to modulate inflammatory signaling (Gratuze et al, 2018) These results, amongst animal and in vitro models, have prompted researchers to evaluate how TREM2 may mediate clinical outcomes of interest in AD. Other studies have found that CSF sTREM2 has a dynamic response in the tracking of AD progression (Suárez-Calvet et al, 2016c, 2019; Ma et al, 2020), and a study in patients with MCI or AD dementia who had A+ and T+ biomarkers found that higher concentrations of sTREM2 in CSF were associated with reduced memory decline, lower CSF p-tau levels, and hippocampal shrinkage (Ewers et al, 2019)

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