APOE ��4-related blood-brain barrier breakdown is associated with microstructural abnormalities

Area of Science:

• Neuroimaging
• Neurodegeneration
• Alzheimer's Disease Research

Background:

• Blood-brain barrier (BBB) dysfunction is implicated in Alzheimer's disease (AD), but its timing and role in neurodegeneration are unclear.
• The APOE ε4 allele is a significant risk factor for AD.

Purpose of the Study:

• To investigate BBB permeability in relation to cognitive status, amyloid-beta (Aβ) levels, and APOE ε4 status.
• To assess the association between BBB permeability and brain microstructure in preclinical AD.

Main Methods:

• Dynamic contrast-enhanced (DCE) MRI and diffusion MRI were used in older adults (61-90 years) across the cognitive spectrum.
• Statistical analyses compared BBB permeability based on cognitive status, Aβ, and APOE4, and examined associations with brain microstructure.

Main Results:

• Elevated BBB permeability was observed in APOE4 carriers, particularly in cortical gray matter, even in amyloid-negative individuals.
• Entorhinal BBB permeability showed interactions with Aβ and APOE4, with the strongest associations in amyloid-positive APOE4 carriers.
• BBB leakage correlated with entorhinal cortex microstructural injury.

Conclusions:

• APOE4 may drive early BBB dysfunction in preclinical AD, potentially contributing to neurodegeneration.
• BBB breakdown associated with APOE4 can occur independently of cognitive decline or amyloid presence.
• These findings highlight BBB as an early target in AD pathogenesis, especially for APOE4 carriers.