The association of enlarged perivascular space with microglia-related inflammation and Alzheimer's pathology in cognitively normal elderly

Background: Glymphatic dysfunction may contribute to the accumulation of Alzheimer's disease (AD) pathol-ogies. Conversely, AD pathologic change might also cause neuroinflammation and aggravate glymphatic dysfunction, forming a loop that accelerates AD progression. In vivo validations are needed to confirm their relationships. Methods: In this study, we included 144 cognitively normal participants with AD pathological biomarker data (baseline CSF A beta 1-42, T-Tau, P-Tau181; plasma P-Tau181 at baseline and at least one follow-up) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Each subject had completed structural MRI scans. Among them, 117 subjects have available neuroinflammatory biomarker (soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and 123 subjects have completed two times [F-18]-florbetapir PET. The enlarged PVS (EPVS) visual rating scores in basal ganglia (BG) and centrum semiovale (CS) were assessed on T1-weighted images to reflect glymphatic dysfunction. Intracranial volume and white matter hyperintensities (WMH) volume were also calculated for further analysis. We performed stepwise linear regression models and mediation analyses to estimate the association between EPVS severity, sTREM2, and AD biomarkers. Results: CS-EPVS degree was associated with CSF sTREM2, annual change of plasma P-tau181 and total WMH volume, whereas BG-EPVS severity was associated with age, gender and intracranial volume. The sTREM2 mediated the association between CSF P-tau181 and CS-EPVS. Conclusion: Impaired glymphatic dysfunction could contribute to the accumulation of pathological tau protein. The association between tauopathy and glymphatic dysfunction was mediated by the microglia inflammatory process. These findings may provide evidence for novel treatment strategies of anti-neuroinflammation therapy in the early stage.