Spatially resolved transcriptomic profiling identifies distinct signatures in parenchymal and vascular microenvironments in Alzheimer's Disease with Cerebral Amyloid Angiopathy

INTRODUCTION Alzheimer's disease (AD) pathology frequently coexists with cerebral amyloid angiopathy (CAA), in which amyloid beta (Aβ) deposits in cerebral blood vessels. Although anti‐Aβ immunotherapies can reduce parenchymal plaques, they often exacerbate vascular pathology. This study investigates compartment‐specific microenvironmental responses to parenchymal versus vascular amyloid deposition. METHODS We performed spatial whole‐transcriptomic profiling on postmortem brain tissue from individuals with mixed AD/CAA pathology. Gene expression signatures were compared between parenchymal and vascular compartments to identify microenvironment‐specific responses to amyloid deposition. RESULTS Analysis revealed that the vascular amyloid microenvironment is distinct from that of parenchymal amyloid, particularly in how shared pathways are differentially upregulated. Notably, although elements of the matrisome were activated in both contexts, they exhibited distinct expression patterns depending on the microenvironment. DISCUSSION These findings highlight the dynamic and context‐dependent nature of the microenvironment in AD/CAA. Our results emphasize the need for compartment‐specific therapeutic strategies to mitigate amyloid pathology and reduce treatment‐related complications.