Cerebrospinal fluid sTREM2 mediates the associations of α-synuclein with tau pathology in older adults without dementia: two population-based study

Abstract

Background: The role of microglial activation by α-synuclein in Alzheimer’s disease (AD) remains unclear. This study aimed to evaluate the role of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in regulating the relationship between α-synuclein and tau pathology in cerebrospinal fluid (CSF).

Methods: A total of 989 participants were included in the CABLE (Chinese Alzheimer’s Biomarker and LifestylE) study. Multiple linear regression analyses were performed to assess the associations of CSF α-synuclein and sTREM2 with tau pathology. Causal mediation analyses with 10,000 bootstrap iterations were conducted to investigate the mediating effect of sTREM2 on the relationship between α-synuclein and tau pathology. Additionally, subgroup analyses were performed based on APOE ε4 carrier status. The same analytical method was applied to the ADNI (Alzheimer’s Disease Neuroimaging Initiative) cohort for validation. Furthermore, Cox proportional hazards models were employed to evaluate the longitudinal association between α-synuclein levels and the risk of AD in the ADNI cohort. Causal mediation analysis further evaluated the mediating role of tau pathology in the relationship between α-synuclein and the risk of AD.

Results: In CABLE, elevated levels of α-synuclein were significantly associated with increased levels of sTREM2 (p < 0.001), p-tau₁₈₁ (p < 0.001), and T-tau (p < 0.001). The relationship between α-synuclein and tau pathology was partially mediated by sTREM2, with mediation rates of 4.8% and 6.3%, respectively. Further subgroup analysis revealed that this mediating relationship was present only in APOE ε4 non-carriers. The CABLE findings were validated in the ADNI, with the proportion of mediators ranging from 17.1 to 18.8%. Additionally, higher levels of α-synuclein were linked to an increased risk of AD (hazard ratio = 2. 137, p = 0.006). The relationship between α-synuclein levels and the risk of AD was mediated by p-tau₁₈₁ but not T-tau, with a mediation rate of 67.6%.

Conclusions: Overall, activated microglia partially mediate the α-synuclein-tau pathology association, while p-tau₁₈₁ further mediates the relationship between α-synuclein and AD risk. Thus, targeting the CSF α-synuclein-microglia-tau pathological pathway provides new insights into the prevention and treatment of AD.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12967-025-06729-3.

Keywords: APOE ε4; Alzheimer’s disease; Cerebrospinal fluid; Microglia; Tau pathology; sTREM2; Α-synuclein.

Fig. 1

Association of CSF α-synuclein with CSF sTREM2 and tau pathology. In the CABLE cohort, multiple linear regression models showed a positive association between CSF α-synuclein and CSF sTREM2 (A), p-tau₁₈₁ (B), and T-tau (C) after adjusting for age, sex, education, and APOE ε4 genotype. In addition, CSF sTREM2 was positively correlated with CSF p-tau₁₈₁ (D) and T-tau (E). The above findings were validated in the ADNI cohort (F-J). Abbreviations: APOE apolipoprotein gene; CSF cerebrospinal fluid; sTREM2 soluble triggering receptor expressed on myeloid cells 2; P-tau phosphorylated tau; T-tau total tau; CABLE Chinese Alzheimer’s Biomarker and LifestylE; ADNI Alzheimer’s Disease Neuroimaging Initiative

Fig. 2

CSF sTREM2 modulates the association of α-synuclein with tau pathology. In the CABLE cohort, the relationship between CSF α-synuclein and tau pathology (A-B) was mediated by CSF sTREM2. These findings were replicated in the ADNI cohort (C-D). Abbreviations: CSF cerebrospinal fluid; sTREM2 soluble triggering receptor expressed on myeloid cells 2; P-tau phosphorylated tau; T-tau total tau; CABLE Chinese Alzheimer’s Biomarker and LifestylE; ADNI Alzheimer’s Disease Neuroimaging Initiative; IE indirect effect

Fig. 3

The Impact of the APOE ε4 gene on mediating effects. In the CABLE cohort, the mediating effect of CSF sTREM2 on the relationship between CSF α-synuclein and tau pathology was observed exclusively in participants who were negative for the APOE ε4 allele (A-B). These findings were corroborated in the ADNI cohort (C-D). Abbreviations: APOE apolipoprotein gene; CSF cerebrospinal fluid; sTREM2 soluble triggering receptor expressed on myeloid cells 2; P-tau phosphorylated tau; T-tau total tau; CABLE Chinese Alzheimer’s Biomarker and LifestylE; ADNI Alzheimer’s Disease Neuroimaging Initiative; IE indirect effect

Fig. 4

Higher levels of α-synuclein increase incident AD risk. There was a linear relationship between CSF α-synuclein levels and the risk of AD (A). The surv_cutpoint function was employed to determine the optimal cut-off value, resulting in the division of the population into the α-synuclein-High group and the α-synuclein-Low group (B). The α-synuclein-High group exhibited a higher rate of progression from CN or MCI to dementia (C). The relationship between α-synuclein levels and the risk of AD was completely mediated by p-tau₁₈₁ (D). Categorical variables, rather than continuous ones, were employed for α-synuclein. Survival-time: the follow-up time from baseline to the AD event. Abbreviations: AD Alzheimer’s disease; HR hazard ratio. CN Cognitively normal; CSF Cerebrospinal fluid; MCI Mild cognitive impairment; P-tau phosphorylated tau; T-tau total tau

Fig. 5

Schematic representation of the effect of α-synuclein-microglia activation on the pathogenesis of AD among the total participants. Neuronal synapses secrete α-synuclein, which activates microglia to release sTREM2 and promotes the development of tau pathology. p-tau181, but not T-tau, further mediates the relationship between α-synuclein and the risk of AD. *P < 0.05, **P < 0.01 and *P < 0.001. Abbreviations: CSF cerebrospinal fluid; sTREM2 soluble triggering receptor expressed on myeloid cells 2; P-tau phosphorylated tau; T-tau total tau