Blood-brain barrier permeability varies by brain region and APOE4 status and correlates with brain microstructure among high-AD risk groups - PubMed (original) (raw)

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

Seraphina K Solders et al. Neuroimage Clin. 2025.

Abstract

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.

Keywords: APOE; Alzheimer’s disease; Blood–brain barrier; MRI.

Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1

Fig. 1

Spatial heterogeneity of blood–brain barrier permeability. Bilateral average permeability measurements are shown using continuous Ktrans (A-C) or Abnormal Leakage Index (ALI; D-F) for cortical (A, D), subcortical (B, E), and white matter (C, F) regions of interest. Cortical regions are color-coded according to region. The lower and upper hinges of the boxplots correspond to the first and third quartiles, respectively. The lower and upper whiskers represent the smallest and largest values within 1.5 times the interquartile range, respectively. Data points beyond 1.5 times the interquartile range are plotted as outliers and are identified by APOE4 (circles for carriers, triangles for non-carriers).

Fig. 2

Fig. 2

Regional cortical Ktrans by APOE4. A) Grouped boxplots of averaged bilateral Ktrans are shown across cortical regions in APOE4 carriers and non-carriers. Regions with significant group differences (from regressions predicting Ktrans from age and sex) have bold x-axis titles. B-E) Brain maps show standardized beta coefficients (Std. β) within each cortical region from linear regressions predicting cortical Ktrans from: B) APOE4, sex, and age; C) APOE4, sex, age, and amyloid-β; D) the interaction between APOE4 and sex, controlling for age; and E) the interaction between APOE4 and amyloid-β, controlling for sex and age. For each panel in B-E, the mapped beta coefficients represent the bolded terms in the model. The lower and upper hinges of the boxplots correspond to the first and third quartiles, respectively. The lower and upper whiskers represent the smallest and largest values within 1.5 times the interquartile range, respectively. Data points beyond 1.5 times the interquartile range are plotted as outliers.

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