Choroid Plexus Free-Water Correlates with Glymphatic function and Neurodegeneration in Alzheimer’s Disease

Free-water imaging of the choroid plexus (CP) is an index revealing components of the CP, which may improve the evaluation of Alzheimer's disease (AD). Our study evaluated free water fraction (FWf) of CP in 216 participants (133 Aβ+ participants and 83 Aβ- controls) continuously enrolled in the Ruijin NeuroBank of Alzheimer's Disease and Dementia (RJNB-D) cohort. The ADNI dataset was used for external validation. Assessments of AD neurodegeneration included Aβ-PET, Tau-PET, synaptic vesicle glycoprotein 2A-PET scans, and blood biomarkers included glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), neurogranin (NRGN), and Tumor Necrosis Factor-α (TNF-α). The CP FWf and diffusion tensor image analysis along the perivascular space (DTI-ALPS) index were independently associated with Aβ positivity in both RJNB-D and ADNI datasets. Within the Aβ+ group, the negative correlation between CP FWf and DTI-ALPS was validated by two datasets. Furthermore, we observed a partial mediation effect of DTI-ALPS between CP FWf and periventricular white matter hyperintensity (pWMH). Elevated CP FWf was linked to worse Mini-Mental State Examination, increased Tau accumulation, reduced synaptic density, and elevated levels of NFL, GFAP, NRGN, and TNF-α. Longitudinally, CP FWf increased faster in Aβ+ participants than Aβ- controls (time × group interaction effect p = 0.046). The growth of CP FWf was associated with a reduction in DTI-ALPS (ρ = -0.42, p = 0.006), and the growth rate of CP FWf surpassed that of pWMH, Tau, and GFAP. Overall, our findings suggest that elevated CP FWf indicates impaired glymphatic function and AD neurodegeneration. Trial registration The study is registered on ClinicalTrials.gov (NCT05623124).