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APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline

Nature volume 581, pages 71–76 (2020)Cite this article

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Abstract

Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized1,2,3,4,5,6. Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction7, including the early clinical stages of Alzheimer’s disease5,8,9,10. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer’s disease11,12,13,14, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes15,16,17,18,19, which maintain BBB integrity20,21,22. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography23. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers.

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Fig. 1: BBB breakdown in the HC and PHG in APOE4 carriers increases with cognitive impairment, independently of CSF Aβ and tau status.
Fig. 2: Blood-brain barrier breakdown in APOE4 carriers is independent of amyloid and tau accumulation in the brain.
Fig. 3: Elevated baseline CSF levels of sPDGFRβ predict cognitive decline in APOE4 carriers.
Fig. 4: Elevated CSF sPDGFRβ, cyclophilin A and matrix metalloproteinase-9 in APOE4 carriers.

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Data availability

All data generated and/or analysed during this study are either included in this article (and its Supplementary Information) or are available from the corresponding author on reasonable request. Source Data for Figs. 1–4 are provided with the article.

Code availability

All software used in this study are publicly available: Rocketship v1.2 (https://github.com/petmri/ROCKETSHIP/blob/master/dce/compare_gui.m), FreeSurfer (v5.3.0) (http://surfer.nmr.mgh.harvard.edu/), FSL-FLIRT (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FLIRT), SPM12 (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/), and Quantitative Imaging Toolkit (https://cabeen.io/about/publication/cabeen2018quantitative/).

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Acknowledgements

The work of B.V.Z. is supported by National Institutes of Health (NIH) grant nos. R01AG023084, R01NS034467, R01AG039452, 5P01AG052350 and 5P50AG005142, in addition to an Alzheimer’s Association strategic 509279 grant, Cure Alzheimer’s Fund, the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease reference no. 16 CVD 05, and Open Philanthropy. D.A.N. is supported by NIH grant nos. R01AG060049, R01AG064228, P01AG052350 and P50AG016573, Alzheimer’s Association grant AARG-17–532905 and Alzheimer’s Association strategic grant 509279. D.P.B and M.G.H. are supported by the L. K. Whittier Foundation, grant nos. P01AG052350, R01AG054434 and R01AG055770. Enrolment of participants into the WashU Knight ADRC is supported by NIH grant nos. P50AG05681, P01AG03991 and P01AG026276 (J.C.M.). E.M.R. is supported by National Institute of Aging (NIA) grant nos. P30AG19610 and R01AG031581, in addition to the state of Arizona. Enrolment of participants into the USC ADRC is supported by NIH grant no. 5P50AG005142 (H.C.C.). Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, provided doses of FBP and financial support for FBP scanning at the WashU site. Avid Radiopharmaceuticals also provided the WashU site with AV1451 precursor and technology transfer for producing the tracer on site. Avid Radiopharmaceuticals was not involved in data analysis or interpretation.

Author information

Author notes

  1. These authors contributed equally: Axel Montagne, Daniel A. Nation, Abhay P. Sagare, Giuseppe Barisano, Melanie D. Sweeney

Authors and Affiliations

  1. Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Axel Montagne, Daniel A. Nation, Abhay P. Sagare, Giuseppe Barisano, Melanie D. Sweeney, Ararat Chakhoyan, Maricarmen Pachicano, Amy R. Nelson, Yining Chen & Berislav V. Zlokovic

  2. Alzheimer’s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Daniel A. Nation, Elizabeth Joe, Lina M. D’Orazio, John M. Ringman, Lon S. Schneider, Helena C. Chui, Judy Pa, Meng Law, Arthur W. Toga & Berislav V. Zlokovic

  3. Department of Psychological Science, University of California, Irvine, Irvine, CA, USA

    Daniel A. Nation

  4. Institute for Memory Disorders and Neurological Impairments, University of California, Irvine, Irvine, CA, USA

    Daniel A. Nation

  5. Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Elizabeth Joe, Lina M. D’Orazio, John M. Ringman, Lon S. Schneider & Helena C. Chui

  6. Huntington Medical Research Institutes, Pasadena, CA, USA

    David P. Buennagel & Michael G. Harrington

  7. Department of Radiology, Washington University School of Medicine, St Louis, MO, USA

    Tammie L. S. Benzinger

  8. The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St Louis, MO, USA

    Tammie L. S. Benzinger & Anne M. Fagan

  9. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    Anne M. Fagan & John C. Morris

  10. The Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, USA

    Anne M. Fagan & John C. Morris

  11. Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, USA

    Lon S. Schneider

  12. Banner Alzheimer Institute, Phoenix, AZ, USA

    Eric M. Reiman

  13. Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA

    Richard J. Caselli

  14. Department of Neuroscience & Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Julia TCW

  15. Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Julia TCW

  16. Laboratory of Neuroimaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Judy Pa & Arthur W. Toga

  17. Molecular Imaging Center, Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Peter S. Conti

  18. Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Meng Law

  19. Department of Neuroscience and Radiology, Monash University, Alfred Health, Melbourne, Victoria, Australia

    Meng Law

Authors
  1. Axel Montagne
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  2. Daniel A. Nation
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  27. Berislav V. Zlokovic
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Contributions

A.M., D.A.N., A.P.S., G.B., M.D.S. and B.V.Z. designed the research study and analysed and interpreted the data. A.M., D.A.N., A.P.S., G.B., M.D.S., A.C., M.P. and Y.C. performed the experiments and analysed the data. A.M. and G.B. performed the MRI analysis. A.M., G.B. and A.C. performed the PET analysis. A.P.S., M.D.S. and M.P. performed the biofluids analysis. D.A.N. performed the neuropsychological analysis. A.P.S., Y.C., B.V.Z. and J.TCW. contributed to human iPSC-pericyte experiments. L.M.D. and A.R.N. prepared and submitted the study to the IRB. M.P., E.J., D.P.B., M.G.H., T.L.S.B., A.M.F., J.M.R., L.S.S., J.C.M., E.M.R., R.J.C., H.C.C., J.TCW., J.P., P.S.C., M.L. and A.W.T. recruited the participants and performed and provided the imaging scans. A.P.S., G.B., M.G.H., T.L.S.B., A.M.F., J.M.R., L.S.S., J.C.M., E.M.R., R.J.C., H.C.C., J.TCW., P.S.C. and A.W.T. provided critical reading of the manuscript. A.M. and D.A.N. contributed to manuscript writing and B.V.Z. wrote the manuscript.

Corresponding author

Correspondence to Berislav V. Zlokovic.

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The authors declare no competing interests.

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Peer review information Nature thanks Ronald Thomas, Yi-Fen Yen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Regional BBB Ktrans constant in eight additional brain regions in APOE4 carriers and non-carriers (APOE3) with CDR status 0 and 0.5.

BBB Ktrans constant in the ITG (a), superior frontal gyrus (SFG, b), caudate nucleus (CN, c), thalamus (Thal, d), striatum (Str, e), subcortical watershed normal-appearing white matter (Subcort. WS NAWM, f), corpus callosum (CC, g), and internal capsule (IC, h) in individuals with CDR 0 bearing APOE3 (black, n = 128) and APOE4 (red, n = 68), and with CDR 0.5 bearing APOE3 (black, n = 14) and APOE4 (red, n = 25). Continuous lines, median; dotted lines, IQR. Significance by ANCOVAs for main effects and post hoc comparisons controlling for age, sex, and education.

Extended Data Fig. 2 BBB breakdown in the HC and PHG in APOE4 carriers increases with cognitive domain impairment.

a, b, Ktrans constant in the HC (a) and PHG (b) in individuals with no cognitive domains impaired bearing APOE3 (black, n = 70) or APOE4 (red, n = 40); one cognitive domain impaired bearing APOE3 (n = 18) or APOE4 (n = 21); and two or more cognitive domains impaired bearing APOE3 (n = 7) or APOE4 (n = 12). Continuous lines, median; dotted lines, IQR. c, d, Ktrans (estimated marginal mean ± s.e.m.from ANCOVA models corrected for age, sex, education, CSF Aβ1–42 and pTau status, and HC and PHG volumes) in the HC (c) and PHG (d) in individuals with no cognitive domains impaired bearing APOE3 (n = 70) or APOE4 (n = 40); one cognitive domain impaired bearing APOE3 (n = 18) or APOE4 (n = 21); and two or more cognitive domains impaired bearing APOE3 (n = 7) or APOE4 (n = 12). Significance by ANCOVA for main effects and post hoc comparisons controlling for age, sex, and education. All ANCOVA omnibus tests remained significant at FDR threshold of 0.05.

Extended Data Fig. 3 Regional BBB Ktrans constant in eight additional brain regions in APOE4 carriers and APOE3 carriers with different degrees of cognitive domain impairment.

Ktrans constant in the ITG (a), SFG (b), CN (c), thalamus (d), striatum (e), subcortical WS NAWM (f), CC (g), and IC (h) in individuals with no cognitive domains impaired bearing APOE3 (black, n = 70) or APOE4 (red, n = 40): one cognitive domain impaired bearing APOE3 (n = 18) or APOE4 (n = 21); and two or more cognitive domains impaired bearing APOE3 (n = 7) or APOE4 (n = 12). Continuous lines, median; dotted lines, IQR. Significance tests from ANCOVAs for main effects and post hoc comparisons controlling for age, sex, and education.

Extended Data Fig. 4 Regional BBB Ktrans constant in all studied brain regions in APOE4 carriers and APOE3 carriers in relation to vascular risk factors.

Ktrans constant in the HC (a), PHG (b), ITG (c), SFG (d), CN (e), thalamus (f), striatum (g), subcortical WS NAWM (h), CC (i), and IC (j) in APOE3 (green, n = 80) and APOE4 (brown, n = 42) carriers with 0–1 vascular risk factors (VRFs), and APOE3 (n = 58) and APOE4 (n = 51) carriers with 2+ VRFs. Continuous lines, medians; dotted lines, IQR. Significance by ANCOVAs for main effects and post hoc comparisons controlling for age, sex, and education.

Extended Data Fig. 5 Amyloid and tau PET analysis in APOE4 carriers and correction of 18F-AV1451 off-target binding in the choroid plexus.

All studies were performed in individuals with CDR score 0. Amyloid and tau PET studies were conducted using 18F- FBB or 18F- FBP, and 18F- AV1451, respectively. For amyloid PET data analysis, FBP and FBB data sets were combined. a, Uptake of amyloid tracers by the OFC in APOE4 (n = 29) relative to APOE3 (n = 45) carriers (voxel-wise two-sample one-tailed t-tests). b, Representative amyloid PET SUVR maps from an APOE3 homozygote (top) and an APOE4 carrier (APOE4) (bottom). Slices 1 and 2, regions of interest (ROIs) for amyloid PET and BBB DCE-MRI scans (see e). Arrow, amyloid tracer uptake by OFC. The APOE3 and APOE4 representative images used FBP. c, Uptake of tau tracer shows undetectable tau accumulation in APOE3 (n = 60) or APOE4 (n = 37) carriers (voxel-wise two-sample one-tailed t-tests). d, Representative tau PET SUVR maps from APOE3 (top) and APOE4 (bottom) carriers. Slices 1 and 1′, ROIs for tau PET and BBB DCE-MRI scans, respectively (see e). e, Coronal 3D scans of regions studied in Fig. 2: HC (red), PHG (green), medial OFC (yellow), and ITG (blue). f, Correction of 18F-AV1451 off-target binding in the choroid plexus. Step 1, HC masks were generated from the 3D T1-weighted magnetization prepared–rapid gradient echo (MP-RAGE). Step 2, CP masks were generated from the T1-weighted VIBE post-GBCA image (flip angle, 15°). Step 3, HC and CP masks were overlaid (arrowheads, red). Step 4, areas of CP overlap with HC masks (arrowheads, yellow) were subtracted to obtain CP-corrected HC tau PET signal after adding 6-mm voxel size on top of CP mask generated from DCE data. g, Representative images of HC tau PET signal before (top) and after (bottom) applying the CP correction (arrows and white dotted lines show overlap between HC and CP).

Extended Data Fig. 6 CSF biomarkers of glia and inflammatory response and endothelial and neuronal cell injury in APOE4 and APOE3carriers.

a, CSF astrocytic S100B levels in individuals with CDR 0 bearing APOE3 (black, n = 77) or APOE4 (red, n = 41), and with CDR 0.5 bearing APOE3 (n = 39) or APOE4 (n = 32). b, CSF IL6 levels in individuals with CDR 0 bearing APOE3 (n = 71) or APOE4 (n = 47), and with CDR 0.5 bearing APOE3 (n = 34) or APOE4 (n = 32). c, CSF IFNγ levels in individuals with CDR 0 bearing APOE3 (n = 54) or APOE4 (n = 29), and with CDR 0.5 bearing APOE3 (n = 25) or APOE4 (n = 17). d, CSF IL1β levels in individuals with CDR 0 bearing APOE3 (n = 43) or APOE4 (n = 18), and with CDR 0.5 bearing APOE3 (n = 17) or APOE4 (n = 13). (e) CSF TNFα levels in individuals with CDR 0 bearing APOE3 (n = 70) or APOE4 (n = 46), and with CDR 0.5 bearing APOE3 (n = 34) or APOE4 (n = 32). f, CSF soluble intercellular adhesion molecule 1 (sICAM1) levels in individuals with CDR 0 bearing APOE3 (n = 77) or APOE4 (n = 40), and with CDR 0.5 bearing APOE3 (n = 39) or APOE4 (n = 33). g, CSF NSE levels in individuals with CDR 0 bearing APOE3 (n = 47) or APOE4 (n = 32), and with CDR 0.5 bearing APOE3 (n = 29) or APOE4 (n = 29). Continuous lines, median; dotted lines, IQR. a and b had one outlier each, which were removed before statistical analysis (see Methods). Significance by ANCOVAs for main effects and post hoc comparisons controlling for age, sex, and education.

Extended Data Fig. 7 Decreased CSF Aβ1–42 and increased pTau levels in APOE4 carriers with cognitive impairment.

a, CSF Aβ1–42 levels in individuals with CDR 0 bearing APOE3 (black, n = 141) or APOE4 (red, n = 83) and with CDR 0.5 bearing APOE3 (n = 39) or APOE4 (n = 41). b, CSF Aβ1–42 levels in APOE3 (n = 89) and APOE4 (n = 55) carriers with no cognitive domains impaired, APOE3 (n = 29) and APOE4 (n = 31) carriers with one cognitive domain impaired, and APOE3 (n = 17) and APOE4 (n = 14) carriers with two or more cognitive domains impaired. c, CSF Aβ1-42 levels (estimated marginal means ± s.e.m. from ANCOVA models corrected for age, sex, education, and CSF sPDGFRβ levels) in individuals with CDR 0 bearing APOE3 (n = 141) or APOE4 (n = 83) and with CDR 0.5 bearing APOE3 (n = 39) or APOE4 (n = 41). d, CSF pTau levels in individuals with CDR 0 bearing APOE3 (n = 141) or APOE4 (n = 82) and with CDR 0.5 bearing APOE3 (n = 39) or APOE4 (n = 43). e, CSF pTau levels in APOE3 (n = 89) and APOE4 (n = 56) carriers with no cognitive domains impaired, APOE3 (n = 29) and APOE4 (n = 30) carriers with one cognitive domain impaired, and APOE3 (n = 17) and APOE4 (n = 15) carriers with two or more cognitive domains impaired. f, CSF pTau levels (estimated marginal means ± s.e.m. from ANCOVA models corrected for age, sex, education, and CSF sPDGFRβ levels) in individuals with CDR 0 bearing APOE3 (n = 141) or APOE4 (red, n = 82) and with CDR 0.5 bearing APOE3 (n = 39) or APOE4 (n = 43). Violin plots: continuous lines, median; dotted lines, IQR. CSF Aβ1–42 and pTau values were log10-transformed before statistical analysis because they had a non-normal distribution. Significance tests from ANCOVAs for main effects and post hoc comparisons controlling for age, sex, and education.

Extended Data Fig. 8 Full scans of western blots.

Full scans of western blots for CypA shown in Fig. 4m (top).

Extended Data Table 1 APOE3 and APOE4 carriers studied for regional BBB permeability changes by DCE-MRI
Full size table
Extended Data Table 2 APOE3 and APOE4 carriers studied for regional amyloid or tau brain accumulation by PET and BBB permeability changes by DCE-MRI
Full size table
Extended Data Table 3 APOE3 and APOE4 carriers studied for CSF sPDGFRβ levels
Full size table

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Montagne, A., Nation, D.A., Sagare, A.P. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 71–76 (2020). https://doi.org/10.1038/s41586-020-2247-3

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