A blood-brain barrier (BBB) breakdown in the aging human hippocampus was investigated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to quantify regional BBB permeability. The study found age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory, which is affected early in Alzheimer's disease (AD). BBB breakdown in the hippocampus and its subdivisions (CA1 and dentate gyrus) worsened with mild cognitive impairment (MCI), correlating with injury to BBB-associated pericytes. The BBB breakdown was more pronounced in MCI compared to age-matched controls, suggesting it may contribute to early cognitive impairment. CSF analysis confirmed BBB breakdown in MCI individuals, with increased levels of soluble platelet-derived growth factor receptor β (sPDGFRβ), a marker of pericyte injury. The study also showed that BBB integrity in other brain regions remained relatively unaffected during normal aging or aging associated with MCI. These findings suggest that BBB breakdown begins in the hippocampus during normal aging and may contribute to early stages of dementia associated with AD. The results highlight the importance of the BBB in maintaining brain health and its potential role in neurodegenerative diseases.A blood-brain barrier (BBB) breakdown in the aging human hippocampus was investigated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to quantify regional BBB permeability. The study found age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory, which is affected early in Alzheimer's disease (AD). BBB breakdown in the hippocampus and its subdivisions (CA1 and dentate gyrus) worsened with mild cognitive impairment (MCI), correlating with injury to BBB-associated pericytes. The BBB breakdown was more pronounced in MCI compared to age-matched controls, suggesting it may contribute to early cognitive impairment. CSF analysis confirmed BBB breakdown in MCI individuals, with increased levels of soluble platelet-derived growth factor receptor β (sPDGFRβ), a marker of pericyte injury. The study also showed that BBB integrity in other brain regions remained relatively unaffected during normal aging or aging associated with MCI. These findings suggest that BBB breakdown begins in the hippocampus during normal aging and may contribute to early stages of dementia associated with AD. The results highlight the importance of the BBB in maintaining brain health and its potential role in neurodegenerative diseases.