Background
Worldwide, there is one new case of dementia detected every 4 s [
1] and the costs of treating this epidemic are staggering. As of 2015 the estimated worldwide costs for dementia treatment were US$818 billion, and in 2018 the costs are expected to balloon to over US$1 trillion [
2]. There is not yet a cure for dementia, and thus intervening with lifestyle strategies on known risk factors for cognitive impairment is an important strategy for reducing dementia risk—or at least delaying its onset [
3].
Older adults with mild cognitive impairment (MCI) are at increased risk for dementia [
4]. MCI is a clinical entity characterized by cognitive decline greater than expected for an individual’s age and education level, but which does not interfere notably with everyday function [
5]. Importantly, 30% of older adults diagnosed with MCI develop dementia within 5 years [
6], while in the same 5-year timespan only 2% of older adults without MCI are diagnosed with dementia [
7]. There is currently a lack of effective pharmaceutical options for treating MCI, and thus lifestyle modifications to reshape the cognitive trajectory of older adults with MCI are an important line of scientific inquiry [
8].
Improving older adult sleep quality is a promising strategy for maintaining older adult cognitive health. More than half of adults over 65 years report at least one chronic sleep complaint—the most common being the inability to stay asleep at night [
9]. Poor sleep quality is also an important risk factor for Alzheimer’s disease (the most common form of dementia) [
10], and older adults with MCI are more likely to experience poor sleep quality than healthy older adults [
11]. Moreover, epidemiological evidence suggests poor sleep quality is associated with an increased risk of conversion from MCI to dementia [
12], and thus improving sleep quality among individuals with MCI may help reduce dementia risk.
Sleep quality is closely tied to the function of circadian rhythms (i.e., ~ 24-h biological clock [
13]), which coordinates physiology and behavior with the solar light-dark cycle [
14‐
16]. Briefly, the process by which the biological clock is synchronized with the solar light-dark cycle is known as
entrainment [
17], and is regulated by the activity of the suprachiasmatic nuclei (SCN) which serves as “the master biological clock” of the central nervous system [
18]. This process of entrainment occurs through certain external stimuli, known as
zeitgebers (from the German
time-givers), and helps to prevent inadvertent drifting or divergence from the 24-h day [
19]. Of particular importance, aging is associated with (1) the biological clock initiating sleep-promoting mechanisms earlier in the day [
20,
21]; and (2) decreased amplitude in circadian signals that increase sleep need [
22,
23]. The weakening of circadian regulation that occurs with aging likely plays a prominent role in the fragmentation of sleep-wake rhythms observed in older adults during (1) the wake maintenance zone, which occurs 2–3 h before habitual bedtime and (2) the sleep maintenance zone, which occurs 2–3 h before habitual wake time [
24]. Because aging appears to be linked to the divergence of the biological clock, chronotherapies that use effectively timed zeitgebers to help strengthen the entrainment of the SCN to the solar light-dark cycle may improve older adult sleep quality [
25].
The principal entraining zeitgeber for the human biological clock is light [
25,
26], which exerts its influence on blue-light-sensitive receptors in the retina [
27]. Retinal light exposure directly stimulates greater activity of the SCN, which
phase delays the biological clock such that the desire for sleep decreases and wakefulness increases (or is maintained); reduced retinal light exposure results in less activity of the SCN and increases the desire to sleep by
phase advancing the biological clock [
17]. While the importance of light is thus integral for the proper function of the SCN and the biological clock, older adults have reduced sensitivity to light, which leads to poorer function of the SCN and divergence of the biological clock from the solar light-dark cycle [
28]. Behavioral changes in older adulthood—such as spending less time outdoors—could also further decrease bright light exposure, which may be a key factor in decreased amplitude of circadian rhythms [
24]. Thus, older adults in particular may benefit from effectively timed bright light to strengthen the entrainment of the SCN to the solar light-dark cycle.
Bright light therapy (BLT) is an increasingly popular chronotherapy strategy [
24]. While the efficacy of BLT as an intervention strategy is currently inconclusive [
29,
30], the biological clock is not equally amenable to shifts at each phase in the circadian rhythm [
17]. Indeed, any zeitgeber can cause the biological clock to phase advance, phase delay, or be entirely phase neutral depending on the biological clock time at which a zeitgeber is administered. As such, successful BLT requires an individualized approach where proper timing is essential [
24].
Another potential zeitgeber for use as chronotherapy is physical activity (PA) [
28,
31,
32]. Briefly, PA performed in the morning or early afternoon does not appear to have a consistent effect on phase shifts of the biological clock; however, engaging in PA in the late afternoon causes a phase advance of the biological clock, while late night PA causes phase delay of the biological clock [
31,
32]. The time-based response to how PA can impact the SCN is hypothesized to coincide with the timing of the opening of the “sleep gate”—the shift of the biological clock from generating a waking signal that reduces sleep need, to generating a signal that facilitates sleep [
33].
However, the use of PA in chronotherapy is challenging. The current evidence describing the effects of PA as a zeitgeber comes from controlled laboratory experiments, where the timing and intensity of PA in the form of exercise is tightly controlled. Conducting an intervention where participants would be asked to engage in regularly timed PA at a prescribed intensity would (1) be burdensome to participants and (2) require enormous resources to ensure participant adherence. More importantly, evidence suggests that regular PA—regardless of timing—is associated with better sleep quality [
34,
35]. Less than 5% of older adults meet the current guidelines of 150 min/week of PA [
36], and older adults with MCI are less active than their cognitively healthy peers [
37]. Given that individually-timed BLT appears to be the most powerful chronotherapeutic [
24], promoting older adult PA in conjunction with BLT may be a feasible approach to providing personalized chronotherapy.
In addition to the potential benefit of combining individually timed BLT with PA, improving sleep hygiene can positively impact sleep quality and aid chronotherapy [
38]. Poor sleep hygiene exacerbates or even causes poor sleep, whereas good sleep hygiene results in feeling more rested and alert upon awakening—as well as a greater ability to function throughout the day. Sleep hygiene education, which teaches behavioral strategies to promote healthy sleep (e.g., avoiding watching television before bed), can also be useful as a strategy to promote behaviors which may improve circadian regulation—including light exposure and PA [
39]. Current recommendations for improving older adult sleep quality therefore suggest combining (1) BLT; (2) PA; and (3) sleep hygiene education [
40]. Importantly, preliminary evidence suggests combined BLT and PA in the form of exercise training, and sleep hygiene can improve sleep quality in older adults with insomnia [
41].
While these results are promising, there remains a gap in our understanding of whether personalized chronotherapy is an effective approach to improving sleep quality among older adults with MCI. Thus, we propose a proof-of-concept randomized controlled trial (RCT) to examine the efficacy of a personalized chronotherapy intervention combining (1) individually timed BLT; (2) individually tailored PA promotion; and (3) general sleep hygiene education to improve the sleep quality of older adults with MCI. We will use a multimodal personalized chronotherapy intervention for improving the sleep quality of older adults with MCI, which may ultimately help in maintaining cognitive function and reduce dementia risk in this population.