APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction
Year: 2026
Type: preprint
Abstract: Cerebral amyloid angiopathy (CAA), characterized by cerebrovascular amyloid deposition, is strongly associated with Alzheimer’s disease, ischemic injury, and lobar hemorrhages. APOE4 is the strongest known genetic risk factor for CAA, yet the cellular sources of APOE4 that drive pathogenic vascular amyloid deposition remain poorly defined. Here, we identify vascular-associated fibroblasts (VAFs) as a key source of APOE4 that mediates CAA and cerebrovascular dysfunction. In post-mortem brain tissue from APOE4/E4 patients with confirmed CAA, APOE colocalizes with COL6⁺ VAFs around Aβ-laden vessels. Therefore, to study the contribution of APOE4 derived from VAFs in CAA, independently of parenchymal sources, we used 5xFAD mice in which the endogenous mouse Apoe coding exons are replaced with floxed human APOE4 sequences. This enables selective suppression of APOE4 expression in VAFs upon tamoxifen induction of Col1a2-CreERT + . APOE4 reduction in VAFs markedly reduced CAA, with the strongest effects observed in leptomeningeal vessels. Additionally, Aβ40, which preferentially associates with vascular amyloid, was significantly reduced in the vascular fraction. VAF APOE4 depletion resulted in fewer small microbleeds and an approximately 50% reduction in parenchymal border macrophages within the leptomeningeal compartment, whereas astrocytic reactivity remained unchanged. Functional assessment using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries. Together, these findings establish VAF-derived APOE4 as a compartment-specific driver of CAA and cerebrovascular dysfunction. One Sentence Summary Vascular-associated fibroblasts are a major source of pathogenic APOE4 that drives vascular dysfunction in cerebral amyloid angiopathy.
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Alzheimer's Association, Alvin J. Siteman Cancer Center, Hope Center for Neurological Disorders, National Institutes of Health, Center for Cellular Imaging, Washington University, National Institute on Aging, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Center for Research Resources
Awards: G1114310655, How Do Meningeal Lymphatics Affect Cerebral Amyloid Angiopathy?, G299873027, G4158561821, Arizona Alzheimer's Disease Core Center, National Brain and Tissue Resource for Parkinson's Disease and Related Disorders, WHOLE SLIDE IMAGING SYSTEM FOR TRANSLATIONAL NEUROSCIENCE, Neuroimmunology of AD and CAA with focus on innate immunity and lymphatics, Cancer Center Support Grant
OpenAlex ID: W7219914920