Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status

Abstract

Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured solubleTREM2 (sTREM2) in the CSF of a large AD case-control dataset (n=180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r=0.35, p<1×10-4; r=0.40, p<1×10-4 respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P=0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; p=1×10-3). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P=6×10-3), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P=5.45×10-07) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.

TREM2, Microglia, and Neurodegenerative Diseases

“…Under normal conditions, the actual shedding of TREM2 might help to explain why TREM2 protein is not readily detected on adult microglia despite the abundant expression of TREM2 mRNA [51,56]. When considering the potential of sTREM2 as a biomarker for neurodegeneration, it is known that sTREM2 is normally found in human cerebrospinal fluid (CSF) at $0.2-4 ng/ml, and its concentration increases with age [108][109][110]. Of note, sTREM2 levels are higher in males than in females [109].…”

“…When considering the potential of sTREM2 as a biomarker for neurodegeneration, it is known that sTREM2 is normally found in human cerebrospinal fluid (CSF) at $0.2-4 ng/ml, and its concentration increases with age [108][109][110]. Of note, sTREM2 levels are higher in males than in females [109]. Compared to healthy controls, CSF levels of sTREM2 have been shown to be elevated in subjects with multiple sclerosis (MS) [111,112], AD [56,[108][109][110], [ 5 6 4 _ T D $ D I F F ] and FTD [109].…”

A Novel TREM2-Mediated Link between Diabetes and Cognitive Impairment: Recent Findings and Future Perspectives

“…TREM2 is assumed to exhibit anti-inflammatory roles, mainly based on in vitro analyses; however, recent growing evidence highlights the pro-inflammatory roles of TREM2 in in vivo disease settings [12] and suggest pathological implications of TREM2-expressing microglia in neuroinflammation and concomitant neurodegeneration, with a shift in microglial phenotypes from homeostasis to disease states. sTREM2 is detected in human blood and cerebrospinal fluid (CSF), and CSF sTREM2 levels are elevated in patients with neurodegenerative diseases compared to healthy controls [18,[26][27][28][29][30]. Whereas CSF sTREM2 is a topic of great interest as a potential marker for neurodegenerative diseases, the pathophysiological significance of serum blood sTREM2 remains unclear.…”

“…Whereas CSF sTREM2 is a topic of great interest as a potential marker for neurodegenerative diseases, the pathophysiological significance of serum blood sTREM2 remains unclear. Additionally, the function of sTREM2 has not been elucidated, although elevated sTREM2 levels in CSF have been suggested to reflect microglial activation in response to neuronal degeneration [27][28][29][30][31]. In this respect, recent studies uncovered sTREM2 as not just an inactive end-product but also a signaling molecule [15] that promotes macrophage survival by preventing apoptosis [32] and activates microglia to ultimately trigger inflammatory responses and prolong survival [33].…”

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

“…In addition, the effect of the 5XFAD transgene significantly altered the expression of genes known to be misregulated in AD, particularly Bin1, Cd33, Clu (Karch et al, 2012), Trem2 (Piccio et al, 2016), and C1qa (Hong et al, 2016), Figure 1F. However, the impact of causal FAD mutations on cognitive performance and risk gene expression varied widely depending on the specific background strain evaluated.…”