The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia, and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), and maintains the chemical composition of the neuronal 'milieu'. Recent evidence indicates that BBB dysfunction is associated with the accumulation of vasculotoxic and neurotoxic molecules, reduced CBF, and hypoxia, which may initiate or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, particularly Alzheimer's disease, and highlights therapeutic opportunities related to these neurovascular deficits. The review discusses transport mechanisms across the BBB, processes leading to BBB breakdown, and the consequences of BBB breakdown, hypoperfusion, hypoxia, and endothelial metabolic dysfunction for neuronal function. It also reviews evidence for neurovascular changes during normal aging and neurovascular BBB dysfunction in various neurodegenerative diseases, including the possibility that vascular defects precede neuronal changes. The article further explores specific mechanisms associated with BBB dysfunction in Alzheimer's disease and amyotrophic lateral sclerosis (ALS) and potential therapeutic strategies.The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia, and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), and maintains the chemical composition of the neuronal 'milieu'. Recent evidence indicates that BBB dysfunction is associated with the accumulation of vasculotoxic and neurotoxic molecules, reduced CBF, and hypoxia, which may initiate or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, particularly Alzheimer's disease, and highlights therapeutic opportunities related to these neurovascular deficits. The review discusses transport mechanisms across the BBB, processes leading to BBB breakdown, and the consequences of BBB breakdown, hypoperfusion, hypoxia, and endothelial metabolic dysfunction for neuronal function. It also reviews evidence for neurovascular changes during normal aging and neurovascular BBB dysfunction in various neurodegenerative diseases, including the possibility that vascular defects precede neuronal changes. The article further explores specific mechanisms associated with BBB dysfunction in Alzheimer's disease and amyotrophic lateral sclerosis (ALS) and potential therapeutic strategies.