Updated project metadata. Apolipoprotein E4 (APOE4), the main susceptibly gene for Alzheimer’s disease1–5, exerts cerebrovascular toxicity6 leading to blood-brain barrier (BBB) breakdown in humans7–9 and APOE4 transgenic mice10–13. Moreover, an early BBB dysfunction predicts cognitive decline in humans7. However, the comprehensive large-scale analysis of cell-specific mechanisms underlying APOE4 cerebrovascular disorder and how it relates to neuronal disorder is lacking. Using single-nucleus RNA-sequencing, phosphoproteome and proteome analysis14–17 here we show that APOE4 compared to APOE3 leads to early disruption of the BBB transcriptome in 2-3-month old APOE4 knock-in mice18 followed by dysregulation in protein signaling networks. This includes proteins regulating cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, and transcription and RNA-splicing suggestive of DNA damage in pericytes. Changes in the BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes starting at 2-3 months of age. The BBB breakdown preceded loss of neurites, post-synaptic interactome dysregulation, and behavioral deficits that developed 2-5 months later, and was associated with astrocyte and microglia response protecting BBB integrity. Thus, disruption of the BBB cell-specific signaling mechanisms could be an initial central contributor to APOE4-mediated neuronal disorder, and possibly a major target to correct APOE4-related cognitive deficits.