Our work shows that in contrast to the B6.APP/PS1 strain that has been widely used historically, CAST.APP/PS1, WSB.APP/PS1 and PWK.APP/PS1 represent models that provide a new lens to understanding central features of human AD including amyloid-induced neurodegeneration, neuroinflammation, cerebrovascular integrity and cerebral amyloid angiopathy. Here, CAST is linked to Alzheimer disease.