The Systemic Link: Characterising Neurovascular Breakdown in Mixed Vascular and Alzheimer’s Disease Pathology.
Not stated
- Funding
- Self-Funded PhD Students Only
- Application deadline
- 14 July 2027
About the project
About the Project Despite the global burden of Alzheimer’s disease (AD), disease-modifying treatments remain elusive. Traditional research has focused on amyloid-beta (Aβ) and tau protein, yet the limited clinical success of Aβ- or tau-targeting therapies suggests a need for a more holistic approach. Clinically, dementia rarely exists in isolation; patients frequently present with co- morbidities, particularly cardiovascular disease (CVD), yet the mechanistic interaction between these pathologies remains poorly understood. Growing evidence suggests that early in AD brain blood flow is reduced and neurovascular coupling - which regulates the supply of oxygen and glucose to active brain regions - is dysfunctional. This neurovascular breakdown has been suggested to lead to neuronal death and cognitive deficits. While neurovascular coupling (NVC) dysfunction is widely cited as an early driver of AD-related cognitive decline, our recent findings challenge this dogma. We demonstrated that NVC remains largely preserved at key developmental stages in preclinical AD models. This suggests that the neurovascular breakdown observed in humans may be driven not by AD pathology alone, but by its synergy with peripheral vascular dysfunction. This project will employ a novel dual-pathology model combining AD with atherosclerosis (ATH) to elucidate how peripheral vascular health modifies central neurovascular function. Typical techniques to be used in this project include: longitudinal optical imaging—including wide-field spectroscopy and high-resolution 2-photon microscopy to quantify cellular calcium dynamics and cerebral blood flow; behavioural assays of cognitive decline; and post-mortem immunohistochemistry to map the cellular architecture of the failing neurovascular unit. Throughout the project, the student will be trained in the advanced computational (e.g. MATLAB) and statistical skills necessary for data analysis. This project will further our understanding of how, and when, neurovascular dysfunction contributes to AD progression and combine preclinical models of AD with a novel model of ATH to study how cardiovascular disease might affect AD progression.