APOE 𝜀4‐related blood–brain barrier breakdown is associated with microstructural abnormalities

Abstract INTRODUCTION Blood–brain barrier (BBB) dysfunction occurs in Alzheimer's disease (AD). Yet, the stage at which it appears along the AD time course and whether it contributes to neurodegeneration remain unclear. METHODS Older adults (61 to 90 years) from cognitively normal (CN) to mildly cognitively impaired (CI), enriched for APOE 𝜀4 and amyloid positivity, underwent dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) and diffusion MRI to measure BBB permeability and brain microstructure. Analysis of variance compared BBB permeability according to cognitive status, amyloid beta (Aβ), and APOE4 . Linear regressions assessed associations of BBB permeability with brain microstructure and interactions with Aβ and APOE4 . RESULTS BBB permeability was elevated for APOE4 carriers across the cortical gray matter, with the strongest differences among CN amyloid‐negative individuals. Associations between entorhinal BBB permeability and microstructure interacted with Aβ and APOE4 , with the strongest relationships in amyloid‐positive individuals and APOE4 carriers. DISCUSSION APOE4 may drive widespread BBB dysfunction in preclinical AD, which may contribute to neurodegenerative changes early along the AD cascade. Highlights Gray matter blood–brain barrier (BBB) permeability is elevated for APOE4 carriers. APOE4‐related BBB breakdown appears in the absence of cognitive decline or amyloid. BBB leakage correlates with entorhinal cortex microstructural injury. Associations with microstructure are strongest for amyloid‐positive APOE4 carriers.