In Alzheimer disease, cerebral amyloid angiopathy (CAA), which disrupts blood–brain barrier (BBB) function, is especially prevalent in carriers of the E4 variant of APOE. Here, human induced pluripotent stem cells containing different combinations of APOE variants were used to generate a 3D culture that recapitulated many BBB features. 3D cultures containing APOE4-containing pericyte-like cells showed more CAA than those in which other APOE combinations were present in pericytes or other cell types. This CAA was linked to an upregulation of APOE driven by increased calcineurin–NFAT signalling. Dysregulated NFAT and APOE were also seen in human hippocampal APOE4-containing pericytes, suggesting this pathway as a possible therapeutic target for reducing CAA.