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 journalArticlepeer-review


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 pages7
JournalNature Medicine
Issue number2
Publication statusPublished - Feb 2019


  • Amyloid beta-Peptides/cerebrospinal fluid
  • Biomarkers/metabolism
  • Blood-Brain Barrier/pathology
  • Cognitive Dysfunction/cerebrospinal fluid
  • Humans
  • Imaging, Three-Dimensional
  • Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid
  • tau Proteins/cerebrospinal fluid


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