Identifying and correcting for chronic circadian misalignment in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia. Unfortunately, there are no effective treatments for this devastating disease. The Alzheimer’s Society estimates that without new treatments, 1.4 million Canadians will be living with dementia by 2031.

Patients with AD often experience disrupted circadian rhythms, manifested as disrupted sleep. Although largely attributed to the underlying disease process, recent findings suggest that sleep directly impacts the pathophysiology of AD. A promising, emerging hypothesis for identifying novel treatments is correcting for changes in the body’s internal time-keeping mechanism, the circadian system.

It is largely assumed that disrupted rhythms are caused by the dampening of central suprachiasmatic nucleus (SCN)-driven rhythms; however, bright light and melatonin treatments, which have putative action on central SCN-driven rhythms, have only had limited success improving cognitive and non-cognitive symptoms. Alternatively, AD pathology may be disrupting synchrony between central and peripheral rhythms, which would cause similar symptoms but require different interventions.

Peripheral rhythms control the timing of cellular and metabolic processes in organs (e.g. liver) and brain regions (e.g. hippocampus). Synchrony ensures that physiological processes throughout the body occur at optimal times. In contrast, desynchrony is extremely detrimental to health and affects the clearance and repair mechanisms necessary to combat the misfolded proteins driving pathogenesis.

The goal of my research is to identify the cause of circadian dysfunction and potential targets for interventions. First, I will characterize the circadian phenotype in a mouse model by measuring behavioural rhythms and sleep. Second, I will measure bioluminescence linked to circadian gene expression, as a real-time reporter of oscillators throughout the body and brain. This has never been done in an AD model and allows us to directly evaluate synchrony between oscillators. Third, I will evaluate whether the “hunger hormone” ghrelin, which directly affects circadian rhythms, neuroplasticity, and memory processes, can improve synchrony between oscillators. Finally, in AD patients I will characterize circadian dysfunction and sleep, and evaluate whether ghrelin can aid in restoring circadian synchrony. My project is the first to explore whether the peripheral circadian system can be modulated as a therapeutic intervention in AD.