Vascular contributions to cognitive impairment are increasingly recognized^{, , , –} as shown by neuropathological^,, neuroimaging^{,, , –}, and cerebrospinal fluid biomarker^, 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)^,,. Vascular changes in AD have been typically attributed to the vasoactive and/or vasculotoxic effects of amyloid-β (Aβ)^,,, and more recently tau. Animal studies suggest that Aβ and tau lead to blood vessel abnormalities and blood–brain barrier (BBB) breakdown^{, –}. Although neurovascular dysfunction^, and BBB breakdown develop early in AD^{,,,, –,,}, how they relate to changes in the AD classical biomarkers Aβ and tau, which also develop before dementia, 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^,, and regional BBB permeability using dynamic contrast-enhanced magnetic resonance imaging^{, –}. 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.