The crucial role of the sleep-wake system in Alzheimer’s Disease pathophysiology

 

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This is one of two research projects exploring the sleep-wake cycle of patients with Alzheimer's disease. KU Leuven is the home institution for this project. View the Melbourne-based partner project.

Applications for this project are no longer being accepted

There is accumulating evidence, both neurobiological and clinical, that dysregulation of the sleep-wake cycle could be fundamental in Alzheimer’s Disease (AD). From a neurobiological perspective, clear links have been found between changes in sleep and changes in amyloid, tau and atrophy. Mouse model for tauopathies are characterized by marked sleep wake imbalance/hyperarousal, which is strikingly similar to the severe neuropsychiatric symptoms present in most AD patients. Indeed, sleeping problems and daytime agitation in are major causes for institutionalization of AD patients.

The Locus coeruleus (LC) is a major regulator of wakefulness/arousal, cognition and stress, and the first brain region to be affected by tau pathology in AD. Orexins are neuropeptides crucial in the sleep-wake function. The orexine receptor type 1 is highly expressed in the LC. Recently, orexin receptor antagonists (ORAs) were developed to treat insomnia, and very interestingly produce physiological sleep. Changes in the sleep/wake system, are crucial in the pathophysiology of AD. Dysregulation of the LC is a key cause of hyperarousal in AD, and it can be treated to improve AD symptoms and progression. This system will be the investigated in detail in both mouse models for AD (in Melbourne) and in patients with AD (in Leuven). The next step is to look at the effect of ORAs on the sleep-wake system in a mouse model for tauopathy and in patients with AD.

Project goals

To improve disease treatment, by normalizing the sleep wake cycle of the patients: this would be of great benefit for the patients, but also their carers. In addition, if treatment were to start sufficiently early, before full blown pathology and cognitive decline are established, it may even help to delay disease onset. It is suggested that by improving sleep at night, especially deep or SWS (slow wave sleep), brain clearance of toxic metabolites by the glymphatic system, e.g. phosphorylated amyloid and Tau, may delay disease onset by inhibiting the spread of toxic amyloid and Tau throughout the brain.

  1. Gain more insight in the relationship between sleeping problems, sundowning and daytime agitation.
  2. Discover new markers for agitation/sleeping problems in AD.
  3. Study in detail the effect of a DORA on sleep and behavioural problems in AD.

Supervision team

KU Leuven: Associate Professor Maarten Van Den Bossche

The University of Melbourne: Associate Professor Laura Jacobson

Who we are looking for

We are seeking a PhD candidate with the following skills:

  • Demonstrated experience in the field of neuroscience/psychological sciences.
  • Demonstrated experience with scientific computation.
  • Demonstrated ability to work independently and as part of a team.
  • Demonstrated time and project management skills.
  • Demonstrated ability to write research reports or other publications to a publishable standard (even if not published to date).
  • Excellent written and oral communication skills.
  • Demonstrated organisational skills, time management and ability to work to priorities.
  • Demonstrated problem-solving abilities.

Further details

The PhD candidate will benefit from the combined expertise of the project supervisors, and the embedding into two research environments.

Associate Professor Maarten Van Den Bossche will contribute his expertise in sleep and behavioural problems in dementia, which is fully intertwined with his clinical work on the clinical ward cog K for patients with dementia and severe neuropsychiatric symptoms and as the supervising psychiatrist at the Leuven University Centre for Sleep-Wake disorders at the University Hospital Leuven. Associate Professor Laura Jacobson shares an interest in the hypothesis that changes in the sleep-wake system have a fundamental role in the etiology, progression and symptomatology of neurodegenerative disorders.  For over 25 years there have been ongoing collaborations with the discoverer of orexin, Luis de Lecea and there are also extensive possibilities for collaborations with other Australian universities (like sleep researchers Professor Sharon Naismith and Professor Ron Grunstein at the University of Sydney).

This PhD project will be based at KU Leuven with a minimum 12-month stay at the University of Melbourne.

The candidate will be enrolled in the PhD program at the Department of Neurosciences at KU Leuven, and in the PhD program at the Florey Department of Neuroscience and Mental Health at the University of Melbourne.

Applications for this project are no longer being accepted

First published on 1 February 2022.

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