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Neurodegeneration
Original research
APOE ɛ4 dose associates with increased brain iron and β-amyloid via blood–brain barrier dysfunction
  1. Yuto Uchida1,2,
  2. Hirohito Kan3,
  3. Keita Sakurai4,
  4. Yoshihiko Horimoto5,
  5. Emi Hayashi6,
  6. Akihiko Iida6,
  7. Nobuyuki Okamura7,
  8. Kenichi Oishi8,
  9. Noriyuki Matsukawa1
  1. 1 Department of Neurology, Nagoya City University, Nagoya, Japan
  2. 2 Department of Neurology, Toyokawa City Hospital, Toyokawa, Japan
  3. 3 Department of Integrated Health Sciences, Nagoya University, Nagoya, Japan
  4. 4 Department of Radiology, National Center for Geriatrics and Gerontology, Obu, Japan
  5. 5 Department of Neurology, Nagoya City Rehabilitation Center Group, Nagoya, Japan
  6. 6 Department of Radiology, Nagoya City Rehabilitation Center Group, Nagoya, Japan
  7. 7 Division of Pharmacology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
  8. 8 Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, Maryland, USA
  1. Correspondence to Dr Noriyuki Matsukawa, Department of Neurology, Nagoya City University, Nagoya, Japan; norim{at}med.nagoya-cu.ac.jp

Abstract

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 (kw). 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 kw of the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings.

Results The BBB kw 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.

  • alzheimer's disease
  • blood-brain barrier
  • MRI

Data availability statement

Data are available upon reasonable request. Anonymised data will be shared upon reasonable request from any qualified investigator.

https://doi.org/10.1136/jnnp-2021-328519

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    Data availability statement

    Data are available upon reasonable request. Anonymised data will be shared upon reasonable request from any qualified investigator.

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    Footnotes

    • Contributors YU contributed to drafting the manuscript, study concept and design, acquisition, analysis and interpretation of data; HK to revision of the manuscript, study concept and design, analysis and interpretation of data; KS to study concept and design, analysis and interpretation of data; YH to study concept and design, analysis and interpretation of data; EH, AI, NO and KO to analysis and interpretation of data; NM to analysis and interpretation of data and critical correction of the manuscript.

    • Funding This work was supported by Grants-in-aid of the 24th General Assembly of the Japanese Association of Medical Sciences and Reiwa 3 Grants-in-aid for Young Scientists of the Kowa Life Science Foundation.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.