Choroid plexus free‐water correlates with glymphatic function in Alzheimer's disease

Abstract INTRODUCTION Free‐water imaging of the choroid plexus (CP) may improve the evaluation of Alzheimer's disease (AD). METHODS Our study investigated the role of free‐water fraction (FWf) of CP in AD among 216 participants (133 Aβ+ participants and 83 Aβ– controls) enrolled in the NeuroBank‐Dementia cohort at Ruijin Hospital (RJNB‐D). The Alzheimer's Disease Neuroimaging Initiative dataset was used for external validation. RESULTS At baseline, Aβ+ participants showed higher CP FWf, increased white matter hyperintensity (WMH) volume, and decreased diffusion tensor image analysis along the perivascular space (DTI‐ALPS). In Aβ+ participants, DTI‐ALPS mediated the association between CP FWf and periventricular WMH. CP FWf was associated with cortical tau accumulation, synaptic loss, hippocampal and cortical atrophy, and cognitive performance. During follow‐up, CP FWf increased faster in Aβ+ participants than controls. DISCUSSION Elevated CP FWf indicated impaired glymphatic function and AD neurodegeneration, and can be a sensitive biomarker for AD progression. The study was registered on ClinicalTrials.gov (NCT05623124). Highlights This cohort study found higher free‐water fraction (FWf) of the choroid plexus (CP) in amyloid beta (Aβ)+ participants. CP FWf was related to glymphatic function, brain atrophy, tau burden, synaptic loss, and cognition. Aβ+ participants showed faster growth of CP FWf than Aβ– controls during follow‐up. The growth rate of CP FWf exceeded that of white matter lesion and tau accumulation in Aβ+ participants. CP FWf can serve as a sensitive imaging marker of glymphatic function and Alzheimer's disease progression.