WSB.APP/PS1 mice develop age-dependent cerebral amyloid angiopathy, cerebrovascular deficits, and white matter damage, which are modified by humanized APOE alleles.

Vascular contributions are now widely accepted to play a key role in many cases of dementia, including Alzheimer's disease (AD), that commonly manifest as cerebral small vessel diseases, including cerebral amyloid angiopathy (CAA). However, the mechanisms by which vascular contributions such as CAA contribute dementias such as AD are not well understood. This is due in part to the lack mouse models that develop robust CAA, hampering our ability to develop therapies that target vascular deficits. To address this, we have explored the use of distinct genetic contexts to enhance the face validity of mouse models for AD. We have previously identified the WSB/EiJ (WSB) strain as a model that shows increased susceptibility to CAA in the presence of the APP/PS1 amyloid driver, compared to the commonly used C57BL/6J (B6) strain. Here, we now perform an in-depth characterization of WSB.APP/PS1 and its WSB wild type (WT) counterpart, assessing male and female mice, at 4, 8, and 12 months of age (M). We show that WSB.APP/PS1 mice show mild CAA at 8M, with robust CAA being apparent at 14M. Transcriptional profiling showed strong correlation to AMP-AD gene expression modules highlighting the human relevance of WSB.APP/PS1 mice and predicted white matter deficits at 14M that was confirmed by immunofluorescence. PET/CT showed blood flow and metabolic deficits, and modifications in small vessel morphology in 8M WSB.APP/PS1 compared to WSB WT mice. We tested whether cerebrovascular reactivity deficits in WSB WT mice may underly the susceptibility to CAA, but interestingly, they did not show age-dependent decline in reactivity that was observed in B6 mice. Finally, using an allelic series of humanized apolipoprotein E (APOE), we show that APOE4 increased the extent of CAA in WSB.APP/PS1 mice, compared to APOE2 and APOE3, but in a sex-dependent manner. Collectively, these data show the utility of the WSB strain to uncover mechanisms of vascular contributions to Alzheimer's disease and related dementias.