sTREM2 and GFAP mediated the association of cerebrospinal fluid GLP-1R with tau pathology in alzheimer’s disease

Glucagon-like peptide-1 receptor (GLP-1R) is involved in metabolic regulation and has also been implicated in neuroprotection and the modulation of neuroinflammatory processes in the central nervous system. GLP-1R has therefore emerged as a potential therapeutic target for Alzheimer’s disease (AD). However, the relationships between cerebrospinal fluid (CSF) GLP-1R, AD core biomarkers, and glial response biomarkers remain unclear. CSF GLP-1R, glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), amyloid-β1−42(Aβ 42 ), and phosphorylated-tau (P-tau), total tau (T-tau) data for 689 participants were extracted from the AD Neuroimaging Initiative (ADNI) database. Associations between CSF GLP-1R and AD biomarkers were examined using multivariable linear regression and linear mixed-effects models. Moreover, 132 cognitively normal participants from the Parkinson’s Progression Markers Initiative (PPMI) were included to explore associations. The causal mediation analyses (10,000 bootstraps) were employed to investigate the underlying associations between CSF GLP-1R and CSF biomarkers. In ADNI, lower CSF GLP-1R levels were significantly associated with increased sTREM2, GFAP, Aβ 42 , P-tau and T-tau concentrations (all P < 0.001). Mediation analysis in further revealed that the associations between CSF GLP-1R and tau pathology were partially mediated by sTREM2 (proportion: 43.9%-45.5%, P < 0.001) and GFAP (proportion: 39.7%-40.9%, P < 0.001). However, these mediation effects were not observed for Aβ 42 . In the PPMI cohort, CSF GLP-1R showed consistent inverse associations with P-tau, T-tau, sTREM2, and GFAP (all P < 0.05). CSF GLP-1R was associated with sTREM2, GFAP, and tau pathology. sTREM2 and GFAP partly mediate the associations between CSF GLP-1R and tau biomarkers. These findings identify associations of CSF GLP-1R with tau pathology and glial response biomarkers in AD, although the biological significance of these relationships requires further investigation.