Research ArticleAlzheimer’s Disease

Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease

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Science Translational Medicine  28 Aug 2019:
Vol. 11, Issue 507, eaav6221
DOI: 10.1126/scitranslmed.aav6221
  • Fig. 1 Baseline values of CSF sTREM2 concentrations and CSF sTREM2–to–p-tau181 ratio.

    Box plots show CSF sTREM2 concentrations (A) and the ratio of concentrations of CSF sTREM2 to p-tau181 (B). CSF samples were obtained from 100 cognitively normal control subjects (CN), who were negative for CSF Aβ1–42 and CSF p-tau181 (A−T−). CSF samples were also obtained from 285 subjects who were positive for CSF Aβ1–42 and CSF p-tau181 (A+T+), including those who were cognitively normal or who had MCI or AD dementia. For both measurements, the group differences tested by ANCOVA were statistically significant, which remained after removal of the three outliers from the A+T+ group. Outliers were defined according to the Tukey criterion (66). *P < 0.01.

  • Fig. 2 Effect of CSF sTREM2– and CSF sTREM2–to–p-tau181 ratio on changes in cognition.

    Regression plots show the change in episodic memory (A and C) and global cognition (B and D) as a function of CSF sTREM2 concentrations (top) or the CSF sTREM2top-tau181 ratio (bottom) at different time points during cognitive follow-up in all subjects who were positive for CSF Aβ1–42 and CSF p-tau181 (A+T+). For illustration purposes, the regression lines are shown for subjects with high versus low values of CSF sTREM2 or the CSF sTREMtop-tau181 ratio (split at the median). In all regression analyses, CSF sTREM2 concentrations and CSF sTREM2top-tau181 ratios were included as continuous measures. The full regression models included the interaction term of CSF sTREM2 (or CSF sTREM2top-tau181 ratio) × time, controlled for CSF p-tau181 × time, and CSF Aβ1–42 × time interactions among other potentially confounding variables.

  • Fig. 3 Effect sizes for CSF sTREM2 and CSF p-tau181.

    Bars show the effect size (Cohen’s d value) of the association between CSF sTREM2 concentrations (blue) or CSF p-tau181 concentrations (orange) on the rate of change in episodic memory (assessed by the ADNI-MEM score; solid bars) or global cognition (assessed by the ADAS13 score; striped bars). The effect sizes derived from linear mixed-effects analyses are shown for all subjects who were positive for CSF Aβ1–42 and CSF p-tau181 (A+T+) at different clinical stages (MCI, n = 184; AD dementia, n = 66) and after the data were pooled (n = 285). A positive d value means that higher CSF concentrations were associated with slower cognitive decline (less decrease in the ADNI MEM score and less increase in the ADAS13 score). A negative d value means that higher CSF concentrations were associated with worse cognitive decline as determined by mixed-effects regression analyses. *P < 0.05.

  • Fig. 4 Effect of CSF sTREM2– and CSF sTREM2–to–p-tau181 ratio on changes in hippocampal volume.

    Regression plot shows the change in bilateral hippocampal volume measured by MRI as a function of CSF sTREM2 concentrations at different time points during follow-up (A) and CSF sTREM2top-tau181 ratios (B) for subjects who were positive for CSF Aβ1–42 and CSF p-tau181 (A+T+) and for whom longitudinal hippocampal volume data were available (n = 285). For illustration purposes, the regression lines are shown for subjects with high versus low values for CSF sTREM2 or CSF sTREMtop-tau181 ratios (split at the median). All regression analyses included the interaction term of time × CSF sTREM2 concentrations (or CSF sTREM2top-tau181 ratios) as continuous measures and controlled for the interactions of CSF p-tau181 × time and CSF Aβ1–42 × time among other potentially confounding variables.

  • Fig. 5 Survival plot for conversion to MCI or AD dementia.

    (Top) The Cox regression–derived survival plot shows that a higher ratio of the concentrations of CSF sTREM2 to p-tau181 (split by median) was associated with a higher probability of remaining clinically stable over time in the A+T+ group. (Bottom) The table indicates the number of subjects in the high and low CSF sTREM2–to–p-tau181 ratio subgroups at successive follow-up time points.

  • Table 1 Subject characteristics for each group.

    Values are shown as mean, with SD in parentheses.

    CN A−T−All A+T+MCI A+T+AD dementia A+T+
    Number10028518466
    Age in years72.8 (5.36)73.53 (7.39)72.9 (7.11)73.6 (8.51)
    Gender (F/M)45/55126/15977/10732/34
    Years of education16.1 (2.80)15.91 (2.88)16.1 (2.81)15.2 (3.11)*
    Clinical follow-up in years4.82 (2.40)3.69 (2.00)*4.05 (1.94)*2.18 (0.473)*
    ADNI-MEM score1.11 (0.58)−0.15 (0.74)*−0.07 (0.57)*−0.89 (0.5)*
    ADAS13 score9.1 (4.32)20.19 (8.53)*18.67 (6.32)*29.66 (6.83)*
    1–42 (pg/ml)1527 (311)639.62 (172.89)*657 (167)*552 (166)*
    p-tau181 (pg/ml)16.4 (2.95)37.76 (13.12)*38.0 (13.5)*39.9 (13.5)*
    Total tau (pg/ml)186.6 (33.3)370.9 (115.2)*374.6 (120.1)*386.9 (113.5)*
    CSF sTREM2 (pg/ml)3762 (1841)4540 (2422)*4452 (2518)*4608 (2201)*

    *Significantly (P < 0.05) different from cognitively normal controls (CN A−T−) via post hoc Tukey test.

    • Table 2 Regression analyses for the effects of CSF sTREM2 concentrations on the rate of change in the ADNI-MEM and ADAS-cog scores and in hippocampal volume.

      All models are controlled for age, gender, education, CSF p-tau181 × time, CSF-Aβ1–42 × time, CSF sTREM2, CSF Aβ1–42, CSF p-tau181 (fixed effects) plus random slope (time) and intercept. Regular P values were assessed using Satterthwaite’s method. For nonparametric confirmation of results, P values were further assessed using permutation testing with 1000 iterations (P-perm.). B, regression coefficient; CI, confidence interval; T value, t test statistic; Cohen’s d, effect size d; P-perm., P value from permutation test.

      ADNI-MEMInteraction termB (SE)95% CIT valueCohen’s dPP-perm.
      CN A−T−CSF sTREM2 × time0.036 (0.046)−0.052–0.125<1NA0.4290.395
      CSF sTREM2/p-tau × time0.043 (0.043)−0.042–0.127<1NA0.3310.312
      All A+T+CSF sTREM2 × time0.071 (0.022)0.028–0.1133.2580.430.0010.020
      CSF sTREM2/p-tau × time0.088 (0.020)0.049–0.1284.3540.55<0.001<0.001
      MCI A+T+CSF sTREM2 × time0.071 (0.028)0.017–0.1252.5810.410.0110.046
      CSF sTREM2/p-tau × time0.092 (0.025)0.043–0.1413.6630.57<0.0010.004
      AD dementia
      A+T+
      CSF sTREM2 × time0.050 (0.023)0.006–0.0942.1940.620.0330.027
      CSF sTREM2/p-tau × time0.059 (0.022)0.016–0.1032.6710.730.0090.006
      ADAS13Interaction termB (SE)95% CIT valueCohen’s dPP-perm.
      CN A−T−CSF sTREM2 × time0.087 (0.047)−0.006–0.1791.849NA0.0740.084
      CSF sTREM2/p-tau × time0.070 (0.043)−0.015–0.1571.626NA0.1150.151
      All A+T+CSF sTREM2 × time−0.076 (0.035)−0.145–−0.007−2.1370.280.0340.045
      CSF sTREM2/p-tau × time−0.102 (0.033)−0.167–−0.037−3.0780.380.0020.023
      MCI A+T+CSF sTREM2 × time−0.076 (0.046)−0.165–0.013−1.672NA0.0960.205
      CSF sTREM2/p-tau × time−0.105 (0.042)−0.186–−0.024−2.5300.390.0120.033
      AD dementia
      A+T+
      CSF sTREM2 × time−0.047 (0.054)−0.151–0.056<1NA0.3840.352
      CSF sTREM2/p-tau × time−0.076 (0.054)−0.181–0.029−1.402NA0.1660.137
      Hippocampal volumeInteraction termB (SE)95% CIT valueCohen’s dPP-perm.
      CN A−T−CSF sTREM2 × time−0.010 (0.013)−0.046–0.016<1NA0.4450.382
      CSF sTREM2/p-tau × time−0.007 (0.013)−0.032–0.018<1NA0.6060.552
      All A+T+CSF sTREM2 × time0.023 (0.010)0.004–0.0432.3180.390.0220.024
      CSF sTREM2/p-tau × time0.023 (0.009)0.005–0.0412.5330.410.0120.024
      MCI A+T+CSF sTREM2 × time0.034 (0.013)0.008–0.0602.5630.490.0120.010
      CSF sTREM2/p-tau × time0.030 (0.012)0.007–0.0532.5800.490.0110.010
      AD dementia
      A+T+
      CSF sTREM2 × time−0.004 (0.023)−0.047–0.040−0.159NA0.8740.888
      CSF sTREM2/p-tau × time0.0001 (0.001)−0.0001–0.0003<1NA0.9990.999

    Supplementary Materials

    • stm.sciencemag.org/cgi/content/full/11/507/eaav6221/DC1

      Fig. S1. CSF sTREM2 and CSF sTREM2 to p-tau181 ratio per group.

      Fig. S2. Selection of the final subject group.

      Fig. S3. Effect of CSF sTREM2 on changes in cognition in clinical subgroups.

      Fig. S4. Effect of CSF sTREM2 measurements on hippocampal changes in MCI A+T+.

      Table S1. Regression analyses with additional control for CSF total tau.

      Table S2. Regression analyses with additional control for hippocampus volume.

    • This PDF file includes:

      • Fig. S1. CSF sTREM2 and CSF sTREM2 to p-tau181 ratio per group.
      • Fig. S2. Selection of the final subject group.
      • Fig. S3. Effect of CSF sTREM2 on changes in cognition in clinical subgroups.
      • Fig. S4. Effect of CSF sTREM2 measurements on hippocampal changes in MCI A+T+.
      • Table S1. Regression analyses with additional control for CSF total tau.
      • Table S2. Regression analyses with additional control for hippocampus volume.

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