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Blood–brain barrier link to human cognitive impairment and Alzheimer’s disease

Nature Cardiovascular Research volume 1, pages 108–115 (2022)Cite this article

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Abstract

Vascular dysfunction is frequently observed in disorders associated with cognitive impairment, dementia and Alzheimer’s disease (AD). Recent advances in neuroimaging and fluid biomarkers suggest that vascular dysfunction is not an innocent bystander only accompanying neuronal dysfunction. Loss of cerebrovascular integrity, often referred to as breakdown of the blood–brain barrier (BBB), was recently shown to be an early biomarker of human cognitive dysfunction and possibly an underlying mechanism of age-related cognitive decline. Damage to the BBB may initiate or further invoke a range of tissue injuries, causing synaptic and neuronal dysfunction and cognitive impairment that may contribute to AD. Therefore, better understanding of how vascular dysfunction caused by BBB breakdown interacts with amyloid beta and tau AD biomarkers to confer cognitive impairment may lead to new ways of thinking about pathogenesis and possibly treatment and prevention of early cognitive impairment, dementia and AD, for which we still do not have effective therapies.

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Fig. 1: The BBB and associated cell types.
Fig. 2: The ATv(N) matrix.

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Acknowledgements

The work of B.V.Z. is supported by the National Institutes of Health (grant nos. R01AG023084, R01NS090904, R01NS034467, R01AG039452, 1R01NS100459, 5P01AG052350 and 5P50AG005142), in addition to the Alzheimer’s Association (strategic 509279 grant), the Cure Alzheimer’s Fund and the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease (reference no. 16 CVD 05). The work of A.M. is supported by the UK Dementia Research Institute (MRC, Alzheimer’s Society, ARUK) and the UKRI Medical Research Council (Career Development Award MR/V032488/1). The work of J.M.W. is supported by the Fondation Leducq (16 CVD 05), the UK Dementia Research Institute (MRC, ARUK, Alzheimer’s Society), European Union Horizon 2020 (PHC-03-15, project no. 666881, ‘SVDs@Target’), the Row Fogo Centre for Research into Ageing and the Brain (AD.ROW4.35, BRO-D.FID3668413) and the Selfridges Group Foundation (UB190097). Graphical illustrations for Fig. 1 were made in part using BioRender (https://biorender.com). We apologize to those authors whose original work we were not able to cite due to the limited number of references.

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  1. These authors contributed equally: Giuseppe Barisano, Axel Montagne.

Authors and Affiliations

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

    Giuseppe Barisano, Axel Montagne, Kassandra Kisler & Berislav V. Zlokovic

  2. Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA

    Giuseppe Barisano

  3. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK

    Axel Montagne & Joanna M. Wardlaw

  4. UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK

    Axel Montagne & Joanna M. Wardlaw

  5. Departments of Pathology and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

    Julie A. Schneider

  6. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

    Julie A. Schneider

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

    Berislav V. Zlokovic

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Contributions

G.B., A.M., K.K. and B.V.Z. prepared the figures and wrote the manuscript. All authors performed literature searches, edited the text, critically read the manuscript and approved the final version for submission. B.V.Z. provided final edits to the manuscript.

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Correspondence to Berislav V. Zlokovic.

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G.B., A.M., K.K. and B.V.Z. declare no competing interests related to this work. J.A.S. reports personal fees from the National Hockey League and the National Football League, outside the submitted work; J.M.W. reports grants from the UK Dementia Research Institute (MRC, Alzheimer’s Society, ARUK), grants from the Fondation Leducq, grants from EU Horizon 2020, grants from the Row Fogo Charitable Trust and grants from the Selfridges Group Foundation while conducting the study; and grants from the British Heart Foundation, grants from the Stroke Association and grants from the Wellcome Trust, outside the submitted work.

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Barisano, G., Montagne, A., Kisler, K. et al. Blood–brain barrier link to human cognitive impairment and Alzheimer’s disease. Nat Cardiovasc Res 1, 108–115 (2022). https://doi.org/10.1038/s44161-021-00014-4

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