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 tau 15 . 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 dementia 17 , 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.