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

Vascular contributions to cognitive impairment are increasingly recognized^1-5 as shown by neuropathological^6,7, neuroimaging^4,8-11, and cerebrospinal fluid biomarker^4,12 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) breakdown^14-16. Although neurovascular dysfunction^3,11 and BBB breakdown develop early in AD^{1,4,5,8-10,12,13}, 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-β^8,18, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging^8-10. 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.