Does sleep and circadian rhythm disruption influence brain health? (360G-Wellcome-214571_Z_18_Z)

BACKGROUND Age-related neurodegenerative diseases are a public health priority. Alongside the urgent need for neuroprotective drugs to slow the natural history of AD and PD, it is crucial to identify risk factors that are amenable to primary prevention strategies. Studies to date have been unable to determine whether sleep and circadian disruption contribute to neurodegeneration (as opposed to being early markers of neurodegeneration). APPROACH This fellowship proposal is inspired by the landmark experimental studies (mainly in animal models) linking sleep and circadian rhythm disruption with neurodegeneration. I seek to extend this research into large- scale human studies capable of determining whether this link is clinically meaningful. I have forged new collaborations with four large prospective cohort studies: UK Biobank, Million Women Study, Rush Memory and Aging Project, and Lothian Birth Cohort 1936. I will study subjective (questionnaires) and objective (accelerometry-derived) sleep and circadian measures and relate them to brain health outcomes, both cross-sectionally (cognitive performance and brain MRI) and longitudinally (incident AD/PD and post-mortem neuropathology). Causal inference will be supported by mendelian randomisation analysis and studying the potential underlying mechanisms. KEY GOALS The goal of this fellowship is to provide credible evidence linking sleep and circadian disruption with neurodegeneration in humans.