We investigated global brain amyloid-β levels and cognitive function in a unique population experiencing long-term sleep disruption, wherein every other week was characterized by sleep disruption due to irregular working hours.
Our main finding is that, in this relatively small, but deeply phenotyped sample, this intensity and pattern of sleep disruption was not associated with elevated brain amyloid-β levels, nor with cognitive decline.
In previous studies, a single night of full sleep deprivation, or selective restriction of deep sleep, and chronic partial sleep fragmentation (rodents only) increased brain amyloid-β levels (8-13). These observations have fueled the hypothesis that repeated nights of sleep loss may contribute to the risk of dementia due to AD by gradually increasing amyloid-β levels.
The sample of maritime pilots offered a unique opportunity to explore if long-term, externally induced sleep disruptions increase dementia risk in terms of AD-related impaired cognitive function and amyloid-β burden. Their sleep behavior is characterized by workweeks with disrupted sleep, alternating with rest weeks of unrestricted sleep. This pattern was confirmed using a combination of methods: self-reported disrupted sleep during workweeks was objectified by sleep diaries, actigraphy, and home-EEG measurements. Relatively normal sleep during rest weeks of maritime pilots was furthermore confirmed with PSG (compared to controls) and home-EEG measurements. Moreover, using PSG we were able to exclude intrinsic sleep disorders in this group, which is important because sleep loss may be an early manifestation of Alzheimer’s pathology and could lead to a reverse causality association (42, 43). To explore possible AD-related impaired cognitive performance, we applied a cognitive test battery that was chosen for its sensitivity to cognitive changes in early, preclinical AD (24). On all cognitive domains, maritime pilots showed normal cognitive performance, compared not only to the control group, but also to normative values. This was also the case for overnight episodic memory consolidation, which is dependent on deep sleep (5, 44).
We considered that normal cognitive function would not rule out increased amyloid-β levels, since early stages of amyloid-β accumulation (indicated by PET or CSF) can have a long asymptomatic stage. Therefore, we performed additional global brain amyloid-β imaging in maritime pilots. None of the maritime pilots had evidence of elevated amyloid-β levels, with SUVR values remaining well below the values established for a healthy population (27, 40). In a recent meta-analysis, the estimated prevalence of PET amyloid-positivity in cognitively healthy men aged 55–60 years was 13% (95% CI 10.3% to 16%) (45). This indicates that our observation of a prevalence of 0/19 confidently rules out elevated amyloid-β levels, even considering the relatively small sample size.
What could explain the observed absence of elevated amyloid-β levels or impaired cognitive function, despite evidence of long-term sleep disruptions?
First, assuming that the hypothesis that sleep disruption may cause AD is correct, the alternating pattern of a week with unrestricted sleep following a week of disrupted sleep may be insufficient to cause elevated brain amyloid-β levels. Either sleep disruption during ≈50% of nights for ≈20 years is insufficient to affect amyloid-β clearance/production, or the week of normal sleep following a week of sleep disruption provides compensatory reductions in brain amyloid-β levels. This latter option would then suggest that disrupted sleep is a modifiable risk factor, and that it may not be necessary to achieve full normalization of sleep to reduce AD-risk. Whether this can be extrapolated to the general population is uncertain however. The maritime pilots may, due to their profession, be better able to compensate normal sleep in their rest weeks. While most studies link reduced total sleep time (<6 hours) to increased AD risk (1, 20), other work suggests that the risk is specifically linked to reduced deep sleep (12, 17). The maritime pilots had reduced total sleep time during workweeks, but the home-EEG recordings indicate that they still achieved an average of 37 minutes of deep sleep per sleep period. Therefore, SWS may have been insufficiently impaired to result in abnormal amyloid-β levels. This argument is, however, not supported by recent work demonstrating that a reduction in total sleep time, but not SWS, determined the increase in amyloid-β production (20).
Second, it is possible that sleep disruption alone is insufficient to increase AD-risk, but requires the presence of other risk factors, such as impaired glucose metabolism (46), oxidative stress (47), depression (48), or general poor vascular health (49). Our study population was healthy and had a low vascular risk (Table 1).
Current research on this topic is still in its very early stage, with limited evidence supporting a causal relationship between sleep loss and risk of AD dementia. The association between sleep loss and AD may be driven by reverse causality (sleep loss as an early manifestation of AD), or by a shared common pathway that causes sleep loss and increases AD risk. There is also recent evidence that found no association between sleep (subjective sleep quality) and risk of dementia (50).
Previous evidence suggesting a link between sleep and AD have been limited to a small number of studies in rodents and humans, with variations in methodology and study population selection. Furthermore, the human studies focused on the relationship between poor sleep for a short period of time (1 or 2 nights) and its effects on amyloid-β (or tau), but have not studied actual development of AD dementia.
Longitudinal studies are available but lack rigorous assessment of sleep and biomarker evidence of AD. Our study adds information on the long-term association between poor sleep and AD, combining objective sleep measures with established biomarkers for AD.
Strengths and Limitations
A strength of the study is the comprehensive assessments of all outcome measures: cognitive function was assessed with an extensive test battery sensitive to early, preclinical symptoms of AD; sleep was assessed with various measurements including self-reported but also objectively measured sleep, implementing innovative techniques for sleep assessments (home-EEG); sleep disorders were ruled out using PSG; and PET-amyloid imaging was used as a validated AD biomarker. A further strength is the unique cohort of maritime pilots, with prolonged and consistent exposure to sleep loss related to their work, making this a highly valuable population that allowed us to explore poor sleep as isolated variable in relationship with the risk of AD dementia.
Our study is limited by the small sample size. Home-EEG measurements were available in 13 of the 19 maritime pilots. However, outcomes of these sleep measurements confirmed observations of work-related disrupted sleep based on PSQI, sleep-wake dairy and actigraphy data in the whole sample, and added novel data on total and deep sleep time during workweeks and rest weeks.
The uniqueness of the population may also cause bias. Maritime pilots are healthy, have no cardiovascular risk, and are physically active in their work, factors that may reduce their AD-risk. They may be resilient to the consequences of sleep disruption, because they have successfully performed this work for >10 years. One example of such resilience could be their ability to achieve deep sleep even under conditions of fragmented and restricted total sleep during workweeks, or their capacity to generate sufficient deep sleep during rest weeks.
Another limitation is that controls, although matched for sex, age, education, and general health might not have been matched entirely with regard to personality, resilience, physical activity, or cognitive skills/general intelligence.
One could argue that the absence of tau measurements is a limitation, as recent evidence now also suggests that sleep affects tau in a similar manner as amyloid-β (51). We did not perform
tau measurements because the maritime pilots had no evidence of cognitive impairment. Since tau pathology is strongly correlated with cognitive decline (52-54), it is highly unlikely to find evidence of tau accumulation in subjects with normal cognitive function, even more so when they are amyloid-negative. A final limitation is that amyloid-β status was not obtained from the controls. Instead we compared our outcomes to normative values from the literature, which were acquired with additional MRI measurements for co-registration of the amyloid PET-CT scans. Since we used CT to identify global amyloid-β instead of MRI, this difference in methodology has to be kept in mind when interpreting our results.