In vivo multimodal PET/MRI imaging and plasma biomarkers implicate glymphatic dysfunction linking neuroinflammation to tau pathology in the early Alzheimer’s disease continuum

Purpose: Neuroinflammation is a key factor contributing to cognitive decline in Alzheimer’s disease (AD). This study aims to investigate the mechanistic associations among neuroinflammation, glymphatic dysfunction, tau pathology, and cognitive decline in AD spectrum. Methods: The study included 355 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and a supportive cohort of 59 individuals from Wuhan Union Hospital (WHUH). Tau pathology was quantified using 18F-AV1451 positron emission tomography (PET). Glymphatic function was estimated through diffusion tensor image analysis along the perivascular space (DTI-ALPS). Neuroinflammation was assessed via plasma glial fibrillary acidic protein (GFAP) in two cohorts and translocator protein (TSPO) PET imaging with 18F-DPA-714 in supportive cohort. Correlation analyses and mediation models were employed to evaluate the directional relationships among tau deposition, inflammation, glymphatic function, and cognition. Results: Higher levels of inflammation were significantly associated with lower DTI-ALPS index (β = −0.171, P = 0.046), which in turn was associated with higher tau burden (β = 0.162, P = 0.010). Path analysis revealed significant indirect associations linking neuroinflammation to cognitive performance through glymphatic dysfunction and tau pathology, with total indirect effects of − 0.165 (95% CI, − 0.266 to − 0.105) in ADNI and − 0.143 (95% CI, − 0.386 to − 0.013) in WHUH. These findings support a hypothesized inflammation–glymphatic–tau pathway rather than a definitive causal cascade. Conclusion: Our findings are consistent with a hypothesized inflammation–glymphatic–tau association in which greater neuroinflammation is linked to reduced glymphatic function and higher regional tau burden, particularly in preclinical and prodromal stages. Chinese clinical trial registry: This study obtained ethical approval from the Institutional Review Committee of Nanjing Drum Tower Hospital (ChiCTR-BRC-17011316, date:20170506; ChiCTR1900022526, date:20190415).