Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction

Daniel A. Nation, Melanie D. Sweeney, Axel Montagne, Abhay P. Sagare, Lina M. D’Orazio, Maricarmen Pachicano, Farshid Sepehrband, Amy R. Nelson, David P. Buennagel, Michael G. Harrington, Tammie L.S. Benzinger, Anne M. Fagan, John M. Ringman, Lon S. Schneider, John C. Morris, Helena C. Chui, Meng Law, Arthur W. Toga, Berislav V. Zlokovic

Research output: Contribution to journalArticleResearchpeer-review

175 Citations (Scopus)


Vascular contributions to cognitive impairment are increasingly recognized1–5 as shown by neuropathological6,7, neuroimaging4,8–11, and cerebrospinal fluid biomarker4,12 studies. Moreover, small vessel disease of the brain has been estimated to contribute to approximately 50% of all dementias worldwide, including those caused by Alzheimer’s disease (AD)3,4,13. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)3,11,14, and more recently tau15. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown14–16. Although neurovascular dysfunction3,11 and BBB breakdown develop early in AD1,4,5,8–10,12,13, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia17, remains unknown. To address this question, we studied brain capillary damage using a novel cerebrospinal fluid biomarker of BBB-associated capillary mural cell pericyte, soluble platelet-derived growth factor receptor-β8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging8–10. Our data show that individuals with early cognitive dysfunction develop brain capillary damage and BBB breakdown in the hippocampus irrespective of Alzheimer’s Aβ and/or tau biomarker changes, suggesting that BBB breakdown is an early biomarker of human cognitive dysfunction independent of Aβ and tau.

Original languageEnglish
Pages (from-to)270-276-+
Number of pages20
JournalNature Medicine
Issue number2
Publication statusPublished - 1 Feb 2019
Externally publishedYes

Cite this

Nation, D. A., Sweeney, M. D., Montagne, A., Sagare, A. P., D’Orazio, L. M., Pachicano, M., Sepehrband, F., Nelson, A. R., Buennagel, D. P., Harrington, M. G., Benzinger, T. L. S., Fagan, A. M., Ringman, J. M., Schneider, L. S., Morris, J. C., Chui, H. C., Law, M., Toga, A. W., & Zlokovic, B. V. (2019). Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nature Medicine, 25(2), 270-276-+.