Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders

Key Points The blood–brain barrier (BBB) protects neurons from factors present in the systemic circulation and maintains the highly regulated brain internal milieu, which is required for proper synaptic and neuronal functioning BBB breakdown facilitates entry into the brain of neurotoxic blood-derived products, cells and pathogens and is associated with inflammatory and immune responses, which can initiate multiple neurodegenerative pathways Neuroimaging studies have demonstrated early BBB dysfunction in Alzheimer disease and other neurodegenerative disorders, which is also supported by biofluid biomarker data and is consistently observed in post-mortem tissue BBB dysfunction in neurodegenerative disorders includes increased BBB permeability, microbleeds, impaired glucose transport, impaired P-glycoprotein 1 function, perivascular deposits of blood-derived products, cellular infiltration and degeneration of pericytes and endothelial cells Here, Sweeney and colleagues focus on advanced neuroimaging evidence of blood–brain barrier (BBB) breakdown in several neurodegenerative disorders. The role of the ageing cerebrovascular system in neurodegeneration and dementia and the implications of BBB dysfunction for treatment and drug delivery are also discussed. The blood–brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, p