Choroid plexus remodeling linked to impaired CSF‐mediated clearance and Alzheimer's disease progression

INTRODUCTION: Impaired cerebrospinal fluid (CSF) -mediated clearance has been implicated in Alzheimer's disease (AD), but how choroid plexus (ChP) remodeling relates to these processes in vivo remains incompletely understood. METHODS: In a large ADNI cohort, we integrated structural magnetic resonance imaging (MRI), amyloid/tau positron emission tomography (PET), and diffusion tensor imaging (DTI) -derived analysis along the perivascular space (ALPS) to characterize ChP changes and their associations with ventricular measures, glymphatic marker, CSF biomarkers, and cognition across diagnostic stages. Our experiments in APP/PS1 mice complemented human analyses. RESULTS: ChP volume increased with disease stage, while PET signal decreased. Larger ChP volume was associated with ventricular enlargement, a lower ALPS index, higher cortical amyloid/tau burden, and worse cognitive performance. Glymphatic impairment partially mediated ChP effects on cognition and pathology. APP/PS1 mice recapitulated the key ChP and glymphatic MRI phenotypes observed in humans, alongside altered expression and localization of key proteins. DISCUSSION: ChP remodeling linked to impaired CSF-mediated clearance, highlighting its role as an early diagnostic and therapeutic target.