The mechanobiology of preclinical Alzheimer's disease

In this fellowship, I will transform our understanding of the pathophysiological events behind the development of Alzheimer's disease. The prevailing theory of Alzheimer's disease progression is neuron-centric and provides no explanation for the silent incubation period of Alzheimer's disease. The very latest non-invasive neuroimaging techniques can now robustly quantify new biomechanical and compartment-specific microstructural features in vivo. An extensive, multi-domain characterisation of Alzheimer's disease pathology can potentially discover perturbations initially amenable to treatment before pathology develops into irreversible, progressive neurodegeneration. Knowledge of changes to the cellular microstructure and glial reactivity related to chronic neuroinflammatory processes is limited, particularly before the emergence of the typical hallmarks of Alzheimer's disease (amyloid plaques, neurofibrillary tau, and neurodegeneration).

To address these important knowledge gaps, I will longitudinally examine brain health in midlife with and without inherited Alzheimer's disease predisposition (APOE4 carriership) by combining state-of-the-art magnetic resonance elastography (MRE) and diffusion-weighted magnetic resonance spectroscopy (dMRS), with novel causal inference statistics. My original published work using advanced MRE to understand the biomechanics of ageing and neurodegeneration is recognised internationally. Basing my Fellowship at CUBRIC, a world-leading site for microstructural neuroimaging, puts me in an unrivalled position to answer these questions.