A spatial multi-omics framework maps meningeal–hippocampal communication and nominates translational targets in Alzheimer’s disease

Background Alzheimer's disease (AD) exhibits spatial heterogeneity, yet the mechanisms by which immune-active meninges communicate with vulnerable brain regions during disease progression remain unclear. This study aimed to investigate meninges-hippocampus crosstalk and map the communication patterns during AD pathology development. Methods We employed 5xFAD transgenic mouse models and integrated bulk RNA sequencing, proteomics, and spatial transcriptomics across time-course analyses to distinguish AD pathology from normal aging processes. Transcription factor activity inference was coupled with ligand-receptor dynamics analysis to examine regulatory modules in homeostatic and disease-associated microglia. Results We identified structure-specific disease genes, including a robust 19-gene hippocampal signature that demonstrated reproducibility in an independent cohort and validation at the protein level. Spatial analysis defined a disease progression axis and revealed meningeal ligand programs that align with hippocampal receptor activation. We nominated a set of ligand-receptor pairs that track pathology gradients and uncovered shared and state-specific regulatory modules in both homeostatic and disease-associated microglia. Conclusions Our multi-omics spatial framework establishes the meninges as an active interface that shapes hippocampal pathology in AD. This work provides candidate communication and regulatory targets for therapeutic intervention, offering new insights into the spatial heterogeneity mechanisms underlying disease progression and potential avenues for treatment development.