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. 2019 Jan 10;14(1):1.
doi: 10.1186/s13024-018-0301-5.

Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology

Marc Suárez-Calvet  1   2   3 , Estrella Morenas-Rodríguez  4   5 , Gernot Kleinberger  6   7 , Kai Schlepckow  4 , Miguel Ángel Araque Caballero  8 , Nicolai Franzmeier  8 , Anja Capell  6 , Katrin Fellerer  6 , Brigitte Nuscher  6 , Erden Eren  6   9   10 , Johannes Levin  4   11 , Yuetiva Deming  12 , Laura Piccio  13   14 , Celeste M Karch  12   14   15 , Carlos Cruchaga  12   14   15 , Leslie M Shaw  16   17 , John Q Trojanowski  16   17 , Michael Weiner  18 , Michael Ewers  8 , Christian Haass  19   20   21 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Early increase of CSF sTREM2 in Alzheimer's disease is associated with tau related-neurodegeneration but not with amyloid-β pathology

Marc Suárez-Calvet et al. Mol Neurodegener. .

Abstract

Background: TREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.

Methods: A cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.

Results: CSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.

Conclusions: Aβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.

Keywords: Alzheimer’s disease; Biomarkers; Microglia; Neurodegeneration; Neuroinflammation; Shedding; TREM2.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the Ludwig-Maximilians Universität München institutional review board (IRB), as well as the IRB of all participating centers in ADNI.

Consent for publication

Not applicable.

Competing interests

CH collaborates with DENALI Therapeutics and received speakers honoraria from Novartis and Roche. KS collaborates with DENALI. JL reports to receive consulting fees from Aesku, Axon Neuroscience and Ionis Pharmaceuticals, speakers’ fees from Bayer Vital and the Willi Gross and non-financial support from Abbvie, outside the submitted work. CC receives research support from Biogen, EISAI, Alector and Parabon, and is a member of the advisory board of ADx Healthcare. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The remaining authors declare that they have no competing of interest.

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Figures

Fig. 1
Fig. 1
CSF sTREM2 in ADNI participants carrying a TREM2 rare variant. Scatter plot representing the levels of CSF sTREM2 in carriers of a TREM2 rare variant, compared to the non-carriers ADNI participants. Solid bars represent the mean and the standard deviation (SD). P-values were assessed by a one-way ANCOVA adjusted for age, followed by Bonferroni corrected post hoc pairwise comparisons between the TREM2 variants carriers’ groups and the non-carriers. We did not include in the comparison those rare variants with only one subject (p.R62H/p.D87N and p.H157Y).
Fig. 2
Fig. 2
CSF sTREM2 in the A/T/N framework. Scatter plot depicting the levels of CSF sTREM2 for each of the four biomarker profiles, as defined by the A/T/N framework, coupled with clinical staging, as defined by CDR. The biomarkers groups T (tau pathology) and N (neurodegeneration) were merged in order to reduce the number of groups to compare. The CDR = 1 stage includes some biomarker profiles will low number of subjects, which precludes performing statistical analysis. They are still shown in the figure for sake of completeness. Each biomarker category is represented in a different colour: healthy controls are depicted in blue, Alzheimer’s continuum category in red, SNAP category in green, and purple depicts biomarker profiles not assigned in a specific category in the present study. The analysis reported in the main text was conducted excluding the TREM2 rare variants carriers, the P-values are reported in bold, and the number of individuals (n) per group indicated. Including these carriers (depicted in yellow) rendered similar results (P-values reported between brackets). Solid bars represent the mean and the standard deviation (SD). P-values were assessed by a one-way ANCOVA adjusted for age, followed by Bonferroni corrected post hoc pairwise comparisons. Abbreviations: A: Aβ pathology biomarker status; AD: Alzheimer’s disease; CDR: clinical dementia rating; CSF: cerebrospinal fluid; N: neurodegeneration biomarker status; SNAP: suspected non-Alzheimer’s pathology; T: tau pathology biomarker status.
Fig. 3
Fig. 3
CSF sTREM2 across the Alzheimer’s continuum. Scatter plot showing the levels of CSF sTREM2 in healthy controls (depicted in blue) and the different stages of the Alzheimer’s continuum (depicted in red). The main analysis was conducted excluding the TREM2 rare variants carriers, the P-values are reported in bold, and the number of individuals (n) per group indicated. Including these carriers (depicted in yellow) rendered similar results (P-values reported between brackets) P-values were assessed by a one-way ANCOVA adjusted for age, followed by Bonferroni corrected post hoc pairwise comparisons. Abbreviations: A: Aβ pathology biomarker status; AD: Alzheimer’s disease; CDR: clinical dementia rating; CSF: cerebrospinal fluid; N: neurodegeneration biomarker status; SNAP: suspected non-Alzheimer’s pathophysiology; T: tau pathology biomarker status.
Fig 4.
Fig 4.
Association of CSF sTREM2 and AD core CSF biomarkers. Scatter plots representing the associations of CSF sTREM2 with each of the AD CSF core biomarkers: T-tau (a), P-tau181P (b), and Aβ1-42 (c) in three different groups defined by the biomarker profile: healthy controls (blue), Alzheimer’s continuum (red) and SNAP groups (green). The solid lines indicate the regression line and the 95% confidence interval for each of the groups. The standardized regression coefficients (β) and the P-values are shown and were computed using a linear model adjusting for age, and are conducted excluding the outliers values. Including them, did not change the conclusions (see Additional file 1: Table S2). We also performed the analysis including the participants carrying a TREM2 rare variant (depicted in yellow) and the results were similar (see Additional file 1: Table S3). Abbreviations: Aβ1-42: amyloid-beta 42; T-tau: total tau; P-tau: tau phosphorylated at Threonine 181; SNAP: suspected non-Alzheimer’s pathology.
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