Blood-brain barrier permeability varies by brain region and APOE4 status and correlates with brain microstructure among high-AD risk groups.

BACKGROUND

Although strong evidence exists for blood-brain barrier (BBB) disruption in Alzheimer's disease (AD), substantial uncertainty remains regarding its role. We address gaps and inconsistencies in the literature by examining regional variation in BBB permeability among cognitively normal older adults enriched for AD risk, the influence of genetic risk and its interactions with amyloid-β and sex, and the relationships between BBB breakdown and brain microstructure. Additionally, we compare two methods of quantifying BBB permeability.

METHODS

Dynamic contrast-enhanced magnetic resonance imaging and restriction spectrum imaging were performed on 48 cognitively normal older adults. We examined differences in whole-brain regional BBB permeability between APOE4 carriers and non-carriers, as well as associations with brain microstructure. Analyses tested interactions of APOE4 with sex and amyloid-β positivity, and were compared using continuous measurements of permeability (Ktrans) and an abnormal leakage index (ALI).

RESULTS

BBB permeability was variable, with highest values in cortical gray matter, including inferior frontal, temporal, and some sensory regions across the full sample. APOE4 carriers had elevated permeability throughout superior occipital, parietal, and frontal cortical regions compared to non-carriers. Results were unchanged after controlling for amyloid-β positivity or when using ALI instead of Ktrans. Higher permeability correlated with altered microstructural patterns, with the most robust relationships among APOE4 carriers, amyloid-β positive individuals, and women.

DISCUSSION: Individuals at greater genetic risk for AD demonstrate elevated cortical BBB permeability associated with microstructural abnormalities. These relationships were seen in a widespread spatial pattern that is dissimilar from the stereotypical spread of AD neuropathology.