APOE ɛ4dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction

Objective To examine the effect of apolipoprotein E ( APOE ) ɛ4 dose on blood–brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and β-amyloid accumulation in the early stages of the Alzheimer’s continuum. Methods In this single-centre observational prospective cohort study, 24 APOE ɛ4 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, [ 11 C]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 ɛ4 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), β-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 ɛ4 dose. Interpretation Our results suggest that an increased APOE ɛ4 dose is associated with decreased effective brain-waste clearance, such as iron and β-amyloid, through the BBB.