<i>APOE ɛ4</i> dose associates with increased brain iron and β-amyloid via blood-brain barrier dysfunction.

Abstract

To examine the effect of apolipoprotein E (<i>APOE</i>) <i>ɛ4</i> 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. In this single-centre observational prospective cohort study, 24 <i>APOE ɛ4</i> 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, [¹¹C]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. The BBB k_w values in the neocortices differed significantly among the groups (<i>APOE ɛ4</i> non-carriers>heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe: <i>r</i>=-0.476, 95% CI=-0.644 to -0.264, p=0.011; medial temporal lobe: <i>r</i>=-0.455, 95% CI=-0.628 to -0.239, p=0.017), β-amyloid loads (frontal lobe: <i>r</i>=-0.504, 95% CI=-0.731 to -0.176, p=0.015; medial temporal lobe: <i>r</i>=-0.452, 95% CI=-0.699 to -0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex and <i>APOE ɛ4</i> dose. Our results suggest that an increased <i>APOE ɛ4</i> dose is associated with decreased effective brain-waste clearance, such as iron and β-amyloid, through the BBB.