Neurovascular Uncoupling in Alzheimer’s and Parkinson’s Diseases: Mechanisms and Therapeutic Strategies

Neurovascular coupling (NVC) maintains appropriate cerebral blood flow (CBF) in response to neuronal activity, and its disturbance, known as neurovascular uncoupling (NVU), is increasingly recognised as a major contributor to neurodegenerative disease. Alzheimer's disease (AD) NVU is caused by Aβ buildup, tau pathology, endothelial dysfunction, and persistent neuroinflammation, leading to poor CBF control and blood-brain barrier (BBB) disintegration. Parkinson's disease (PD) is characterised by α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, and dopaminergic neuronal loss, all of which impede cerebrovascular regulation. These disease-specific mechanisms interact via similar vascular pathways, establishing NVU as a critical connection between neuronal degeneration and cerebrovascular dysfunction. This study highlights the critical role of NVU in neurodegeneration by investigating shared and disease-specific processes in AD and PD. Tau pathology disturbs vascular regulation in AD, whereas dopaminergic neuron loss impairs cerebrovascular control in PD. Both Aβ and α-synuclein are linked to endothelial dysfunction and oxidative stress, albeit originating in different pathologies. Comparative analysis reveals distinct vascular abnormalities in each condition, as well as shared processes such as inflammation and BBB disruption. The study also covers developments in biomarker discovery and neuroimaging techniques that allow for exact characterisation of NVU, facilitating early diagnosis and treatments. In addition, lifestyle changes and pharmacological treatments for oxidative stress and endothelial injury are being examined. This study highlights the significance of NVU as a fundamental pathogenic mechanism, underscoring its importance for comprehending disease development and formulating novel therapeutic strategies.