TTN+ macrophages are enriched in the human choroid plexus in Alzheimer's disease.

The choroid plexus (ChP) regulates cerebrospinal fluid homeostasis and immune surveillance, but its cellular organization and response to Alzheimer's disease (AD) remain incompletely defined. Here, we integrate single-nucleus RNA sequencing with spatial transcriptomics to generate a high-resolution atlas of the adult human ChP. We identify all major epithelial, stromal, and immune populations and resolve heterogeneity within macrophages, including a distinct subset expressing the giant protein TTN. These TTN+ macrophages exhibit coordinated cytoskeletal, stress-response, and phagocytic gene programs and localize to perivascular and stromal niches. In AD, we observe broad, cell type-specific transcriptional remodeling across epithelial, endothelial, mesenchymal, and immune compartments, with expansion of TTN+ macrophages and increased senescence signatures. Spatial and ligand-receptor analyses reveal altered tissue organization and macrophage interaction patterns with neighboring cells. Combined with in situ validations, these findings provide evidence of TTN expression by macrophages, and reveal a broader AD-associated contextual shift in human ChP immune function in which TTN+ macrophages are enriched.