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

Philippe, T.; Avey, D. R.; Vasco, N. K.; Vyas, H.; Tissera, S. D.; Xu, J.; Ng, B.; Saunders, D. M.; Lagrimas, A. K.; Duong, D.; Seyfried, N. T.; Bennett, D. A.; Wang, Y.

doi:10.1101/2025.11.23.690014

bioRxiv · 10.1101/2025.11.23.690014

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

Philippe, T.·Avey, D. R.·Vasco, N. K.·Vyas, H.·Tissera, S. D.·Xu, J.·Ng, B.·Saunders, D. M.·Lagrimas, A. K.·Duong, D.·Seyfried, N. T.·Bennett, D. A.·Wang, Y.

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Abstract

The choroid plexus (CP) regulates barrier integrity, cerebrospinal-fluid (CSF) dynamics, and immune surveillance, yet its role in Alzheimers 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 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.

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Philippe, T., Avey, D. R., Vasco, N. K., Vyas, H., Tissera, S. D., Xu, J., Ng, B., Saunders, D. M., Lagrimas, A. K., Duong, D., Seyfried, N. T., Bennett, D. A., Wang, Y.. 2025-11-25. A Multi-omic Atlas of Human Choroid Plexus in Alzheimer's Disease. https://doi.org/10.1101/2025.11.23.690014

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