Research Accepted project proposals Sleep biomarkers associated with genetic risk of Alzheimers disease

Authors: Yevgenia Rozenblum, Martin Dresler
Affiliation(s): Radboudumc/ Donders Center for Cognitive Neuroimaging
Keywords: sleep, biomarkers, APOE, genetic risk, polygenic risk score, Alzheimer's disease


Research question(s):

Main Research question 1: Have participants with a higher genetic AD risk any alterations in the quantity, quality and night-to-night variability of slow-wave sleep (SWS)?
Main Research question 2: Is (now hypothetical) relationships between altered patterns of SWS and a higher genetic AD risk modulated by the participants’
a) stress level,
b) cognitive performance,
c) lifestyle,
d) well-being?
This research question is exploratory, i.e., we have no prior hypotheses.
Main Research question 3: Have participants with a higher genetic AD risk changes in other than SWS sleep patterns and their night-to-night variability, specifically, REM sleep parameters?

This research question is exploratory, i.e., we have no prior hypotheses.
Secondary Research question 1: How does the presence of the e4 allele influence cognitive performance in healthy adults in their thirties?
This research question is exploratory, i.e., we have no prior hypotheses.
Secondary Research question 2: Is night-to-night variability of sleep parameters a more sensitive metric than mean characteristics averaged over several nights?
This research question is exploratory, i.e., we have no prior hypotheses.

 

Link: OSF preregistration

 

Abstract:

One of the functions of slow-wave sleep (SWS) is to clear the brain from neurotoxic metabolites like amyloid-β. Reduced SWS can result in inadequate clearance and ultimately neurodegeneration and Alzheimer’s disease (AD). In healthy older adults, both sleep and Aβ metabolism are possibly independently affected by the presence of APOE ε4 allele(s), the genetic AD risk factor. Here, we aim to explore whether healthy APOE-ε4 carriers before the onset of any pathogenesis show alterations in SWS quantity and quality and an increase in night-to-night variability of these parameters. Given that AD is a polygenic disease, we will also consider participants’ polygenic risk scores, the metric that quantifies the cumulative effect of genetic variation for multiple small effects, and thus provides a more comprehensive than APOE only perspective for assessing genetic AD risk.

We will analyze a unique dataset of ~850 participants aged 30–39 years with longitudinal all-night EEG recorded at home for 21 nights (>100,000 h of recordings in total). We hypothesize to observe some SWS alterations in participants with a higher compared to a lower genetic AD risk. Given that we will study individuals before the onset of any brain changes due to neurodegenerative processes, our future findings are expected to reflect causative changes that come solely from genetic polymorphism (with some confounding effects of the environment, which will be controlled for in our statistical models). This point is critical as AD is a multidimensional disease with many parameters acting at a time.

We expect that our future description of SWS alterations in young individuals with a higher genetic AD risk will create a new target for neurostimulation aimed at facilitating brain clearance. This might in turn prevent or slow down the development of neurodegenerative processes, leading to cognitive decline and dementia later in one’s life.