Choroid plexus enlargement is negatively associated with cognitive performance in a DTI-ALPS–dependent manner

Abstract

Background Disturbances in brain fluid homeostasis are increasingly implicated in neurodegeneration. Imaging measures of structural alterations of the choroid plexus (CP) and impaired glymphatic transport have each been associated with cognitive decline, yet their potential interaction in humans remains poorly understood. Methods We investigated the relationship between CP volume, glymphatic diffusion, and cognitive performance in 100 memory clinic patients. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was used as an imaging proxy of glymphatic diffusion, and CP volume and WMH volume were derived from structural MRI using FastSurfer segmentation. Multivariable linear regression models examined associations between CP volume, ALPS index, and global cognitive performance measured by the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Models were adjusted for age, sex, education, APOE ε4 status, WMH burden and plasma phosphorylated tau (pTau217). Interaction terms tested whether CP structure and glymphatic diffusion jointly influenced cognition. Results Larger CP volume was associated with lower ALPS index after adjustment for demographic and molecular covariates (β = −282.19, p = 0.015). CP volume and ALPS index were not independently associated with MoCA scores; however, a significant interaction between CP volume and ALPS index was observed (β = −13,299.09, p = 0.036). The association between CP volume and cognitive performance depended on DTI-ALPS, such that larger CP volumes were associated with poorer MoCA scores at higher ALPS values, whereas CP volume showed little association with cognition at lower ALPS values. This interaction improved model fit compared with main-effects models (R2 = 0.31). The findings remained significant after adjusting for CSF volume and were replicated using MMSE as the outcome. Plasma pTau217 levels were strongly associated with worse cognition but did not significantly modify the CP-ALPS interaction. Conclusion CP enlargement is associated with glymphatic diffusion, and its relationship with cognitive performance varies across DTI-ALPS index values. These findings suggest that interactions between CSF regulatory systems may correlate with cognitive performance in a state-dependent manner. Notably, higher ALPS values in individuals with enlarged CP may reflect compensatory or altered perivascular fluid dynamics rather than preserved glymphatic function, highlighting the complexity of interpreting diffusion-based markers of brain clearance.