Multimodal imaging and plasma biomarkers link neuroinflammation, glymphatic dysfunction, and tau pathology in early Alzheimer's disease.

In early Alzheimer's disease, greater neuroinflammation was linked to reduced glymphatic function and higher tau burden; total indirect effect on cognition was -0.165 (95% CI -0.266 to -0.105) in ADNI and -0.143 in a replication cohort.

• Neuroinflammation (plasma GFAP, TSPO PET) was associated with lower DTI-ALPS index (β=-0.171, p=0.046), and lower DTI-ALPS was associated with higher tau burden (β=0.162, p=0.010).
• Indirect effect linking inflammation to cognitive performance via glymphatic dysfunction and tau pathology was -0.165 (95% CI -0.266 to -0.105) in ADNI and -0.143 (95% CI -0.386 to -0.013) in WHUH.
• Cross-sectional design limits causal inference; findings support a hypothesized inflammation-glymphatic-tau pathway rather than a definitive cascade.

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