APOE ε4 dose associates with increased brain iron and β-amyloid via blood-brain barrier dysfunction

Objective To examine the effect of apolipoprotein E (APOE) epsilon 4 dose on blood-brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and beta-amyloid accumulation in the early stages of the Alzheimer's continuum. Methods In this single-centre observational prospective cohort study, 24 APOE epsilon 4 non-carriers, 22 heterozygotes and 20 homozygotes in the early stages of the Alzheimer's continuum were scanned with diffusion-prepared arterial spin labelling, which estimates the water exchange rate across the BBB (k(w)). Participants also underwent quantitative susceptibility mapping, [C-11] Pittsburgh compound B-positron emission tomography and neuropsychological testing. Using an atlas-based approach, we compared the regional k(w) of the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings. Results The BBB k(w) values in the neocortices differed significantly among the groups (APOE epsilon 4 non-carriers> heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe: r=-0.476, 95% CI=-0.644 to -0.264, p=0.011; medial temporal lobe: r=-0.455, 95% CI=-0.628 to -0.239, p=0.017), P-amyloid loads (frontal lobe: r=-0.504, 95%CI=-0.731 to -0.176, p=0.015; medial temporal lobe: r=-0.452, 95% CI=-0.699 to -0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex and APOE epsilon 4 dose. Interpretation Our results suggest that an increased APOE epsilon 4 dose is associated with decreased effective brain-waste clearance, such as iron and beta-amyloid, through the BBB.