PROJECT SUMMARY
Emerging evidence suggests that shift workers, particularly those who work nights, are at a higher risk of mild
cognitive impairment or Alzheimer’s disease (AD). This is mainly due to the repeated disruption of the sleep-
wake schedule (circadian disruption) and poor sleep (e.g., less deep sleep and/or shorter sleep time). However,
there are inter-individual differences in the ability to adapt (resilience) or not adapt (intolerance) to night-shift
work, resulting in different sleep problems and cognitive responses in shift workers. Yet, we do not have a
physiological or biological marker sensitive enough to reflect the level of adaptability to shift work and predict the
risk of future cognitive impairment. The overarching goal of our research program is to identify biomarkers that
may determine resilient vs. intolerance subtypes of shift workers and predict the risk of AD in the future. As a
first step, the proposed study will examine the feasibility of establishing a cohort of active and retired shift workers
and evaluate the study procedures for the comprehensive assessment of sleep, shift work-related symptoms,
cognitive function, and biological markers. We will also generate preliminary data on whether objective sleep
quality measures on night and day sleep (Aim 1) and/or epigenetic changes (i.e., DNA methylation) in circadian
genes (Aim 2) can explain variations in shift work-related symptoms and early plasma markers of AD. Findings
will inform future larger studies to evaluate potential mechanisms by which disrupted sleep due to shift work may
develop AD. We will recruit (a) active, younger shift workers (n=25; night shift, aged 40-64 years) and 25-day
workers (without known sleep issues) and (b) retired, older shift workers (n=25; worked night shifts ≥ 10 years
in the past and aged ≥ 65 years) and 25 age-matched controls, in Las Vegas, NV, the largest 24-hour city in the
world. Baseline assessments will include: (a) a survey about work history and conditions, sleep patterns, shift
work-related symptoms (insomnia, excessive sleepiness, and fatigue), medical conditions and medications,
lifestyle and demographic factors, (b) cognitive function, (c) blood draw for AD markers and DNA methylation,
(d) overnight-urine collection for melatonin, (e) two-week actigraphy with sleep-and-activity log, and (f) multiple-
night home sleep studies (≥2 nights and ≥2 days in night-shift workers; ≥2 nights in day workers). Primary
measures for objective sleep quality will include percentage of deep sleep in total sleep time, wake time after
sleep onset, and sleep depth index, calculated using raw electroencephalogram (EEG) signals from the sleep
studies. We will quantify the level of DNA methylation at CpG sites across 22 core circadian genes. To affirm the
role of those potential markers in the diagnosis of shift work tolerance and prediction of severe cognitive
impairment/AD, both younger and older preclinical AD cohorts will be expanded and prospectively followed in
future grants. A prospective investigation of AD biomarkers in younger adults will significantly impact public
health by guiding personalized, biobehavioral interventions that can detect the risk of AD and prevent AD onset
in the early stage of life.
