APOE4-APP interactions exert early influences on cerebrovascular structure and function: implications for Alzheimer's disease.

BACKGROUND: APOE4 and APP are two of the main genetic risk factors for Alzheimer's disease (AD). Although there have been suggestions that these two factors interact, most of the in vivo evidence for such interactions comes from transgenic mouse models that suffer from complications associated with protein overexpression. Our goal was to examine the consequences of interactions between APOE4 and APP on brain function while avoiding the use of transgenic mice. METHODS: We generated and characterized double-mutant knock-in mice incorporating familial APP mutations and humanized APOE4. RESULTS: In the brains of 3-month-old double-mutant mice there were significant alterations in vascular remodeling genes, vascular structure and blood-brain barrier permeability. These changes were not observed in either APOE4 or APP single-mutant mice and, thus, were caused by interactions between the two genes. These interaction effects were transient, because they were absent in 8-month-old double-mutant mice. CONCLUSION: These findings indicate that early vascular changes, driven by the interaction of APP and APOE4, may influence the progression of AD. Our work highlights the need to focus on the synergistic vascular actions of APOE4 and APP, particularly at younger ages.