WSB. APP/PS1 mice develop age‐dependent cerebral amyloid angiopathy, cerebrovascular dysfunction, and white matter deficits

INTRODUCTION Cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimer's disease (AD) pathogenesis. Here, we characterize the susceptibility of the WSB/EiJ genetic context to human AD‐relevant cerebrovascular phenotypes. METHODS CAA and parenchymal plaque analysis and in vivo neurovascular imaging were performed on WSB. APP/PS1 brains. Transcriptomics was performed on WSB. APP/PS1 and B6. APP/PS1 brains. B6 and WSB cerebrovascular reactivity was assayed ex vivo . Additional CAA and parenchymal plaque analysis was performed on WSB. APP/PS1 mice with APOE 2 , APOE 3 , or APOE 4 alleles. RESULTS WSB. APP/PS1 brains exhibited plaque deposition, CAA, transcriptomic overlap with human AD, myelin deficits, cerebrovascular/metabolic uncoupling, and altered cerebrovascular morphology. Aged WSB vasculature retained vasoreactivity but exhibited increased stiffness. Compared to WSB. APOE 2/2 APP/PS1 , WSB. APOE 4/4 APP/PS1 mice had increased CAA and plaque‐associated microglial area. DISCUSSION These data illustrate the utility of the WSB genetic context to model CAA and uncover vascular contributions to AD.