Disentangling tau, glymphatic dysfunction and astrocytic activation in amyloid-positive Alzheimer's disease

Alzheimer’s disease (AD) features tau pathology, neurodegeneration, and cognitive decline. Dysfunction of the glymphatic system, which clears pathological proteins, and astrocytic activation may exacerbate neurodegeneration. We investigated the interplay among tau accumulation, glymphatic dysfunction, and astrocytic activation in amyloid PET-positive AD patients using diffusion tensor image analysis along the perivascular space (DTI-ALPS) as a glymphatic biomarker. Our cohort comprised 157 AD patients and 117 cognitively unimpaired controls. We measured DTI-ALPS, plasma GFAP, hippocampal volume, and cognitive scores at two time points. [F18]Florzolotau PET quantified tau burden. Regression analyses assessed associations between biomarkers and cognitive decline, and mediation analysis tested GFAP’s role in tau-driven neurodegeneration. We also compared topographical distributions of DTI-ALPS and GFAP using tau PET and gray matter images. Tau burden emerged as the strongest predictor of cognitive decline, while DTI-ALPS showed no significant cognitive association. GFAP mediated the link between tau burden and hippocampal atrophy, implicating astrocytic activation in tau-driven neurodegeneration. Regional analyses revealed GFAP associations in anterior cingulate and medial temporal areas, contrasting with DTI-ALPS patterns in parasagittal and lateral prefrontal regions. These findings underscore tau burden as the driver of cognitive decline, with astrocytic activation mediating neurodegeneration; glymphatic dysfunction minimally impacts cognition.