A Multi-omic Atlas of Human Choroid Plexus in Alzheimer’s Disease

The choroid plexus (CP) regulates barrier integrity, cerebrospinal-fluid (CSF) dynamics, and immune surveillance, yet its role in Alzheimer’s disease (AD) remains poorly defined. We performed snRNA-seq on CP samples from 69 ROSMAP participants spanning normal cognition, mild cognitive impairment, and AD dementia, and integrated these data with spatial transcriptomics, snATAC-seq, and proteomics from CP tissue and CSF. We identified 17 CP cell states and uncovered widespread disease-associated transitions that converged into three major phenotypic axes. Along the inflammatory axis, epithelial cells and border-associated macrophages (BAMs) showed progressive immune activation, with BAMs shifting from inflammatory to stress-dominant states. In the barrier axis, epithelial cells, fibroblasts, and endothelial cells exhibited reduced junction-related gene expression and broad alterations in transport pathways. Epithelial cells also showed late-stage cilia loss and CSF-regulatory pathway impairment, indicating a breakdown in epithelial polarity and CSF sensing, consistent with abnormal CSF proteomic signatures. Along the remodeling axis, fibroblasts showed bidirectional ECM alterations, while epithelial and stromal cells demonstrated aberrant cell–matrix adhesion pathways. Spatial neighborhood analysis revealed a multicellular signaling hub, with epithelial-rich niches showing the strongest dysregulation in AD. Together, these findings define a unified model of CP dysfunction in AD and position the CP as an active, multicellular contributor to AD pathophysiology.