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.

Keywords: APOE; Alzheimer's disease; amyloid; blood–brain barrier; diffusion MRI.

FIGURE 1

Differences in K _trans by APOE4. K _trans for APOE4 carriers (N = 23) and non‐carriers (N = 18) are shown for CN participants. Values represent standardized residuals, adjusted for age, sex, and Aβ using linear regression. CN, cognitively normal.

FIGURE 2

Interactions of K _trans with APOE4 and Aβ on entorhinal microstructure. Associations of entorhinal K _trans with entorhinal microstructure demonstrating significant interactions with (A) Aβ (amyloid‐negative N = 15; amyloid‐positive N =  26) or (B) APOE4 (APOE4 non‐carrier N = 21; APOE4 carrier N = 23) are shown for CN participants. Values represent standardized residuals, adjusted for age, sex, and scanner software, using linear regression. CN, cognitively normal.