Multi‑omics profiling reveals shared blood-brain barrier stress signatures and disease-specific vascular remodelingin capillary cerebral amyloid angiopathy and GRN-associated frontotemporal dementia

Frontotemporal dementia caused by progranulin mutations (FTD-GRN) and capillary cerebral amyloid angiopathy (capCAA) are neurodegenerative disorders marked by protein aggregation, neuronal loss, and neuroinflammation. Although their etiologies differ, both exhibit blood–brain barrier (BBB) perturbations, implicating vascular dysfunction as contributing to neuropathology. Here, we aimed to identify the shared and disease-specific changes in BBB properties that can be therapeutical targets in neurodegeneration. We performed mass-spectrometry–based proteomics on cortical capillaries isolated from post-mortem capCAA, FTD-GRN, and non-demented control brains. Parallel single-nucleus RNA sequencing, enriched for vascular and glial populations, enabled multi-omics comparisons. This analysis revealed pronounced vascular remodelling in capCAA, epithelial–mesenchymal transition (EMT), angiogenesis, and complement activation. In contrast, FTD-GRN exhibited transcriptional stress responses, involving E2F and MYC targets, mTORC1 and interferon-associated signaling. Importantly, both shared BBB-associated stress signatures, characterized by metabolic dysfunction, extracellular matrix remodeling, and activation of stress pathways. Together, our study highlights the role of shared BBB stress programs in neurodegeneration and underscores the importance of vascular dysfunction as a common component across distinct dementia etiologies.