Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C, Alzheimer’s Disease Neuroimaging Initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease. Sci Transl Med. 2019 Aug 28;11(507) PubMed.

AlzBiomarker Database

Meta-Analysis

Curated Study Data

Biomarker
(Source)		 Cohort
(N)		 Measurement
Mean ± SD		 Method;
Assay Name;
Manufacturer		 Diagnostic
Criteria
sTREM2
(CSF)		 AD
(66)		 4608 ± 2201
pg/mL		 Electrochemiluminescence;
Other/Not Specified;
In-house		 McKhann et al., 1984
sTREM2
(CSF)		 CTRL-
CNC
(100)		 3762 ± 1841
pg/mL		 Electrochemiluminescence;
Other/Not Specified;
In-house

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Comments

  1. The roles of TREM2 in AD pathogenesis have commanded substantial attention following from the recognition that TREM2 variants are associated with dramatically elevated AD risk. Previous work from this group reported that soluble forms of TREM2 were found at elevated levels in the CSF of AD patients and those with mild cognitive impairment (MCI). Soluble TREM2 (sTREM2) increases were associated with phospho-tau levels in CSF. TREM2 is cleaved at the microglial cell surface by ADAM proteinases, releasing the extracellular soluble domain into the interstitial space, eventually appearing in the CSF. It has been tacitly assumed that release of sTREM2 was reflective of the microglial activation that accompanies disease pathogenesis. Subsequently, elevated CSF sTREM2 was reported to be linked to higher gray-matter volume (Gispert et al., 2016), and disease-associated SNPs at the MS4A locus (Deming et al., 2019). 

    In the present study, Ewers et al. report that subjects who are biomarker-positive (Aβ42 and p-tau) have higher CSF sTREM2 at baseline and exhibit slower disease progression, as evidenced by memory and cognition scores. Indeed, individuals with higher ratios of CSF sTREM2 to phospho-tau were less likely to convert to AD and had slower rates of cognitive loss. These data argue that sTREM2 has salutary actions on disease pathogenesis.

    These findings highlight our ignorance of TREM2 biology in the brain. The concentrations of sTREM2 in the CSF generally have been interpreted as reflective of microglial “activation.” The Ewers study raises the question more broadly of whether increased microglial “activation” favors disease exacerbation or attenuation. The answer is likely to be nuanced.

    First and foremost, there are questions about how sTREM2 is generated. It is clear that the full-length, membrane-associated receptor is shed from the membrane by ADAM10/17, releasing the extracellular domain. It is unclear whether ADAM-mediated cleavage is constitutive or regulated, since ADAM activity is subject to physiological regulation. Existing data suggest that the normal cleavage of TREM2 is quantitatively significant, resulting in reducing overall receptor levels. It also has been postulated that TREM2 cleavage is ligand-stimulated, which would serve to preferentially inactivate the active forms of the receptor. However, the TREM2 gene is alternatively spliced, yielding TREM2 species that do not possess a transmembrane domain and are predicted to be secreted. Del-Aguila et al. reported that up to 25 percent of sTREM2 in the CSF could arise from these transcripts, but this has yet to be demonstrated (Del-Aguila et al., 2019). 

    A provocative study by Zhong and colleagues forces a reevaluation of the significance of sTREM2. These authors report that sTREM2 has cell-autonomous actions through autocrine signaling on microglia whereby the sTREM2 binds to an unknown entity on the microglial cell surface and elicits a broad range of disease-attenuating effects as well as improved behavior (Zhong et al., 2019). 

    Overall, there are more questions than answers.

    References:

    Gispert JD, Suárez-Calvet M, Monté GC, Tucholka A, Falcon C, Rojas S, Rami L, Sánchez-Valle R, Lladó A, Kleinberger G, Haass C, Molinuevo JL. Cerebrospinal fluid sTREM2 levels are associated with gray matter volume increases and reduced diffusivity in early Alzheimer's disease. Alzheimers Dement. 2016 Dec;12(12):1259-1272. Epub 2016 Jul 14 PubMed.

    Del-Aguila JL, Benitez BA, Li Z, Dube U, Mihindukulasuriya KA, Budde JP, Farias FH, Fernández MV, Ibanez L, Jiang S, Perrin RJ, Cairns NJ, Morris JC, Harari O, Cruchaga C. TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers. Mol Neurodegener. 2019 May 8;14(1):18. PubMed.

    Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, Wang D, Gao Y, Zhu Y, Sheng X, Chen K, Wang N, Zhu L, Can D, Marten Y, Shinohara M, Liu CC, Du D, Sun H, Wen L, Xu H, Bu G, Chen XF. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model. Nat Commun. 2019 Mar 25;10(1):1365. PubMed.

    View all comments by Gary Landreth

  2. The findings of Ewers et al. provide a valuable advance for understanding how measurements of the biomarker CSF sTREM2 relate to the rate of disease progression around the early symptomatic stages of Alzheimer’s. What the data imply, as far as TREM2 and microglial activity in AD progression go, is still uncertain because we don’t really know what CSF sTREM2 is telling us biologically. The authors favor the idea that elevated CSF sTREM2 reflects increased TREM2 surface levels and TREM2 signaling activity in brain microglia, which could be true. A second possibility is that CSF sTREM2 is a benign reflection of microglial cell number. In either case, the correlation between elevated sTREM2 and attenuated cognitive decline would suggest that a more robust microglial response to AD pathology would be helpful at this stage (Hamelin et al., 2016; Focke et al., 2018). 

    However, a third possibility is that microglial TREM2 contributes to neurodegeneration at this disease stage (Leyns et al., 2017), and that increased shedding of sTREM2 is a protective mechanism. Relating CSF sTREM2 measurements to biomarkers of microglial abundance and active TREM2 signaling will help resolve these uncertainties.

    References:

    Hamelin L, Lagarde J, Dorothée G, Leroy C, Labit M, Comley RA, de Souza LC, Corne H, Dauphinot L, Bertoux M, Dubois B, Gervais P, Colliot O, Potier MC, Bottlaender M, Sarazin M, Clinical IMABio3 team. Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016 Apr;139(Pt 4):1252-64. Epub 2016 Mar 15 PubMed.

    Focke C, Blume T, Zott B, Shi Y, Deussing M, Peters F, Schmidt C, Kleinberger G, Lindner S, Gildehaus FJ, Beyer L, von Ungern-Sternberg B, Bartenstein P, Ozmen L, Baumann K, Dorostkar MM, Haass C, Adelsberger H, Herms J, Rominger A, Brendel M. Early and longitudinal microglial activation but not amyloid accumulation predict cognitive outcome in PS2APP mice. J Nucl Med. 2018 Sep 27; PubMed.

    Leyns CE, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, Robinson GO, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11524-11529. Epub 2017 Oct 9 PubMed.

    View all comments by David Hansen

  3. We want to clarify an important point. The goal of our study was not to finally determine if sTREM2 or full-length TREM2 exert a protective function, or which variant needs to be therapeutically modified. Rather, we wanted to find out whether TREM2 is protective in AD patients or not. The only way to do this at the moment is by measuring sTREM2 in CSF and correlating its levels with longitudinal cognitive/clinical scores. Because there are major efforts in the pharmaceutical industry to design therapeutic strategies capable of modulating TREM2 activity, one should better know early on if modulating TREM2 expression/function is beneficial or not.

    It is also important to note that we do not find significant amounts of sTREM2 in CSF derived from alternatively spliced TREM2.  We analyzed a set of human CSF samples using a novel antibody that detects selectively ADAM10-cleaved sTREM2, in comparison with an antibody that detects all forms of sTREM2. This revealed that almost all sTREM2 in CSF is derived by proteolytic shedding from the full-length protein. 

    View all comments by Michael Ewers

  4. These findings fit quite elegantly with our recent findings and hypothesis that innate immune activity modulates development of presymptomatic AD, and that markers of immune activation are generally beneficial (Meyer et al., 2019). For various reasons we could not include sTREM2 among the CSF immune markers analyzed. A critical feature of both the cited publication and our analyses is that the apparent "effect" of immune activating cytokines and chemokines is not necessarily on progression of AD pathology, but rather on the symptomatic expression of a given degree of such pathology. These "effects" appear to modify not only cross-sectional cognitive performance (ADAS-Cog-11 in our analyses) and four-year cognitive decline, but even clinical diagnosis itself.

    References:

    Meyer PF, Savard M, Poirier J, Morgan D, Breitner J, Alzheimer's Disease Neuroimaging Initiative. Hypothesis: cerebrospinal fluid protein markers suggest a pathway toward symptomatic resilience to AD pathology. Alzheimers Dement. 2019 Sep;15(9):1160-1171. Epub 2019 Aug 9 PubMed.

    View all comments by John Breitner

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