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

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.

TREM2 is associated with tumor immunity and implies poor prognosis in glioma

“…Meanwhile, most studies have shown that TREM2 is a negative regulator of inflammation, which can inhibit the secretion of cytokines, regulate the development and function of dendritic cells, microglia and osteoclasts, regulate phagocytosis, eliminate bacteria, promote anti-inflammatory effects, and protect the body ( 30 , 31 ). However, some studies have shown that TREM-2 plays a dual role in inflammatory-related diseases, causing adverse effects on the body ( 32 , 33 ). In summary, more and more evidence show that TREM-2 participates in the regulation of inflammatory response and plays a key role in the immune response.…”

Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-1

“…Regarding the time course of the changes in AD-related markers, it has been hypothesized that CSF sTREM2 levels do not begin to increase before the elevation of CSF Aβ levels, rather they begin increasing prior to the onset of clinical symptoms from cognitively normal stages to preclinical AD ( 13 ). Nevertheless, although the pathological significance of serum sTREM2 levels in the continuum of cognitive impairment in type 2 diabetes remains unclear, an in vitro study showed that high levels of glucose activated microglia to up-regulate TREM2 expression and induce an inflammatory response ( 36 ).…”

“…A remarkable characteristic of TREM2 is its ability to release its ectodomain as a soluble form (sTREM2) into the extracellular space upon proteolytic cleavage ( 7 – 9 ). Elevation of sTREM2 in cerebrospinal fluid (CSF) has been suggested to reflect microglial activation ( 10 – 12 ) and associated with faster cognitive decline in individuals at the preclinical stage of Alzheimer’s disease (AD) ( 13 ). In addition, sTREM2 levels in serum were also negatively associated with cognitive function in patients with AD ( 14 ).…”

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…Higher levels of baseline CSF sTREM2 were associated with lower regional atrophy and WM damage in A+T+ MCI participants but with increased regional WM damage in A+T+ AD participants 177 . The action of CSF sTREM2 at different disease stages may be further modulated by interaction with CSF tumor necrosis receptor 2 178 …”