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

Authors

Xinru Xu, Dongming Liu, Xun Sun, Kaichen Yang, Pin Lv, Jiaming Lu, Weiwei Ruan, Xiaotian Xia, Jiu Chen, Yingxin Chen, Haocheng Wang, Xi Wu, Danni Ge, Biao Yang, Mengyu Wan, Hengyan Liang, Xiaoli Lan, Yongkang Gai, Bing Zhang

Published in

European journal of nuclear medicine and molecular imaging. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

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.
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.
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.
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.
This study obtained ethical approval from the Institutional Review Committee of Nanjing Drum Tower Hospital (ChiCTR-BRC-17011316, date:20170506; ChiCTR1900022526, date:20190415).

PMID:
42463967
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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