Choroid plexus–glymphatic axis disruption in Alzheimer's disease: Cerebrospinal fluid expansion as a mediator of metabolic dysfunction and cognitive decline

BackgroundThe choroid plexus (ChP) and glymphatic system are crucial for cerebrospinal fluid (CSF) homeostasis and brain waste clearance. While their individual roles in Alzheimer's disease (AD) are recognized, the mechanisms linking ChP structural changes, glymphatic dysfunction, and CSF dynamics to metabolic and cognitive decline remain unclear.ObjectiveWe aimed to investigate the interrelationships among ChP volume, glymphatic function, CSF volumetric changes, cerebral glucose metabolism, and cognitive status across the AD spectrum.MethodsThis cross-sectional study included 142 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, categorized as cognitively normal (NC, n = 38), early mild cognitive impairment (EMCI, n = 31), late mild cognitive impairment (LMCI, n = 31), and AD (n = 42). We analyzed multimodal neuroimaging data, including normalized ChP volume (nChP), CSF sub-volumes, the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, and [18F]-FDG-PET standardized uptake value ratios. Partial correlation and mediation analyses were performed, adjusting for covariates.ResultsIncreased nChP correlated with larger CSF (nTotal-CSF: r = 0.324, FDR-p = 0.004), lower DTI-ALPS, and reduced FDG. nChP drove cognitive decline via two paths: "nChP→nTotal-CSF→ Mini-Mental State Examination (MMSE)" (44.1% total effect) and "nChP→DTI-ALPS→FDG→MMSE" (9.9%, p < 0.001). CSF showed spatial mediation: nCSF-LV (66.20% on metabolism) outperformed external CSF (38.90%); DTI-ALPS negatively correlated with nCSF-LV (r = -0.406, FDR-p < 0.01).ConclusionsOur findings demonstrate that ChP enlargement is linked to cognitive impairment through pathways involving CSF dynamics and glymphatic function, with cerebral hypometabolism as a key downstream effector. This study posits a "CSF dynamics imbalance" cascade in AD, highlighting the potential of targeting Choroid Plexus-CSF-glymphatic axis for early diagnosis and intervention.