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

Abstract

Loss of function of TREM2, a key receptor selectively expressed by microglia in the brain, contributes to the development of Alzheimer's disease (AD). We therefore examined whether soluble TREM2 (sTREM2) concentrations in cerebrospinal fluid (CSF) were associated with reduced rates of cognitive decline and clinical progression in subjects with AD or mild cognitive impairment (MCI). We measured sTREM2 in CSF samples from 385 elderly subjects, including cognitively normal controls, individuals with MCI, and subjects with AD dementia (follow-up period: mean, 4 years; range 1.5 to 11.5 years). In subjects with AD defined by evidence of CSF Aβ_1-42 (amyloid β-peptide 1 to 42; A+) and CSF p-tau₁₈₁ (tau phosphorylated on amino acid residue 181; T+), higher sTREM2 concentrations in CSF at baseline were associated with attenuated decline in memory and cognition. When analyzed in clinical subgroups, an association between higher CSF sTREM2 concentrations and subsequent reduced memory decline was consistently observed in individuals with MCI or AD dementia, who were positive for CSF Aβ_1-42 and CSF p-tau₁₈₁ (A+T+). Regarding clinical progression, a higher ratio of CSF sTREM2 to CSF p-tau₁₈₁ concentrations predicted slower conversion from cognitively normal to symptomatic stages or from MCI to AD dementia in the subjects who were positive for CSF Aβ_1-42 and CSF p-tau_181. These results suggest that sTREM2 is associated with attenuated cognitive and clinical decline, a finding with important implications for future clinical trials targeting the innate immune response in AD.

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 Aβ_1–42 and CSF p-tau₁₈₁ (A−T−). CSF samples were also obtained from 285 subjects who were positive for CSF Aβ_1–42 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 sTREM2–to–p-tau₁₈₁ ratio (bottom) at different time points during cognitive follow-up in all subjects who were positive for CSF Aβ_1–42 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 sTREM–to–p-tau₁₈₁ ratio (split at the median). In all regression analyses, CSF sTREM2 concentrations and CSF sTREM2–to–p-tau₁₈₁ ratios were included as continuous measures. The full regression models included the interaction term of CSF sTREM2 (or CSF sTREM2–to–p-tau₁₈₁ ratio) × time, controlled for CSF p-tau₁₈₁ × time, and CSF Aβ_1–42 × 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 Aβ_1–42 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 sTREM2–to–p-tau₁₈₁ ratios (B) for subjects who were positive for CSF Aβ_1–42 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 sTREM–to–p-tau₁₈₁ ratios (split at the median). All regression analyses included the interaction term of time × CSF sTREM2 concentrations (or CSF sTREM2–to–p-tau₁₈₁ ratios) as continuous measures and controlled for the interactions of CSF p-tau₁₈₁ × time and CSF Aβ_1–42 × 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.