Examining sleep deficiency and disturbance and their risk for incident dementia and all-cause mortality in older adults across 5 years in the United States

Introduction

Approximately 5.8 million adults in the U.S. are living with Alzheimer’s disease or related dementia, and 16 million are expected to be living with Alzheimer’s disease by 2050 [1]. Both sleep disturbances and abnormal sleep duration, although both often modifiable, are associated with the development and progression of Alzheimer’s disease [2]. Furthermore, recent work suggests that older adults (above age 65) who report signs of good sleep health (i.e., reports of waking and feeling refreshed) demonstrate better cognitive function [3], which may buffer against the development of Alzheimer’s disease and dementia. According to the National Sleep Foundation, there is more sleep disturbance reported among older adults than any other age group [4]. Data collected as part of a prospective observational study among older adults found over 50% of the participants reported at least one sleep difficulty “most of the time,” [5] whereas these complaints were reported by only 20% of younger adults (below age 65) [6].

Sleep disturbance and insufficiency have been shown to be associated with both the development and progression of Alzheimer’s disease and with all-cause mortality [7, 8]. Among a cohort of 737 older adults without dementia, adults with high sleep fragmentation had a 1.5-fold risk of developing Alzheimer’s Disease compared to those with low sleep fragmentation [9]. Similarly, in a prospective analysis, sleep disturbance was linked with incident cognitive impairment [10], while another prospective analysis found sleep disturbance was linked with both incident dementia as well as mortality [11]. In related studies, prospective analyses of 1,951 older adults found that difficulty maintaining alertness was associated with increased risk for dementia [12]; in a cohort of 1,245 older women, longer sleep latency was associated with higher risk of cognitive impairment over an average follow-up period of 4.9 years [13]. Furthermore, compared to cognitively normal individuals, those with either with self-reported obstructive sleep apnea (OSA) diagnosis [14] or physician-diagnosed OSA [15] developed more Alzheimer’s disease biomarkers, such as amyloid-beta plaques or tau proteins, over time compared to those without OSA. In addition, previous research has found associations between both long (>9 hours) and short (<7 hours) sleep duration and Alzheimer’s disease and dementia. Specifically, in research with data from the Framingham Heart Study, self-reports of longer sleep (>9 hours) were associated with all-cause dementia and clinical Alzheimer disease, but self-reports of short sleep (<6 hours) were not [16]. However, according to a meta-analysis of 27 studies, both short (< 7 hours) and long sleep duration (> 8 hours) were both associated with approximately 86% greater risk for Alzheimer’s disease and dementia [7].

Prior research has also examined the association among sleep characteristics, sleep deficiency, alertness and all-cause mortality [17–19]. In a prospective analysis, researchers found that older short (<6 hours) habitual sleepers were at approximately 50% greater risk for all-cause mortality after adjusting for confounders [18]. In research conducted by Chen and colleagues using the Pittsburgh Sleep Quality Index (PSQI), researchers found an association between high PSQI scores (indicative of poor sleep) and all-cause mortality, but this relationship disappeared after controlling for confounders such as depression [19]. In the same study, but with the sub-components of the PSQI (i.e., sleep medication use, sleep quality, and sleep duration), researchers found that those reporting long sleep (>9 hours) were at greater risk for all-cause mortality, but short sleepers were not [19]. Another prospective cohort study found an opposite result. Specifically, Bertisch and colleagues found an association between objectively measured short sleep duration and all-cause mortality, but not long sleep [17]. The same study examined the relationship between those reporting either short or long sleep duration and insomnia in relation to all-cause mortality, but did not find any significant associations [17]. According to a meta-analysis of prospective studies, both short and long sleep were associated with greater risk of all-cause mortality in adults [20, 21]. Another meta-analysis of 24-hour sleep duration found only long sleep (>9 hours) was associated with greater risk of mortality.

Research on sleep disturbance and deficiency and all-cause mortality therefore has shown conflicting results. Further, few studies have included a comprehensive set of sleep characteristics in a single examination of incident dementia and all-cause mortality. We address these gaps in the literature and examine the relationship between sleep disturbance, sleep duration, alertness and incident dementia and all-cause mortality across a five-year time interval using nationally representative data collected among older adults in the U.S.

Results

Table 1 displays demographic characteristics of the sample at baseline (Year 2013: n = 1,575; Year 2014: 1,237). The average age was 76.9 (s.d. = 7.5 years). The sample was comprised of 60% female respondents (both years) and 72% white respondents (both years), followed by approximately 20% black (2013: 20%; 2014: 19%), 3% Hispanic/Latino (both years), and 6% Asian (both years) respondents. Among respondents, 48% and 44% reported being married in 2013 and 2014, respectively. Nearly 44% and 45% demonstrated clinical depression in 2013 and 2014, respectively. The most common comorbid condition among the sample was cancer (2013: 5%; 2014: 7%), followed by hypertension (2013: 3%; 2014: 2%).

Table 2 displays descriptive statistics summarizing sleep variables. Approximately 60% of participants reported experiencing difficulty with alertness “never” or “rarely” (2013: 59.63%, 2014: 61.35); nearly one half of participants reported “never” or “rarely” taking naps (2013: 44.09%, 2014: 44.03%). More than half of participants reported taking fewer than 15 minutes to fall asleep (2013: 52.93%, 2014: 52.22%), and more than half reported sleeping 7-8 hours per night (2013: 55.05%, 2014: 54.74%). Nearly 70% of participants reported a sleep quality of “good” or “very good” (2013: 68.74%, 2014: 69.62%), and over 90% of participants reported snoring “never” or “rarely” (2013: 91.87%, 2014: 92.84%).

Examining the relationship between each sleep characteristic and incident dementia

Table 3 summarizes results of Cox proportional hazard models examining each sleep characteristic and incident dementia.

Table 3. Cox models examining each sleep disturbance characteristic and incident dementia (N = 2,812).

	Incident dementia				Incident dementia
	Unadjusted models				Fully adjusted modelsa
	HR	p-value	Lower	Upper	HR	p-value	Lower	Upper
Difficulty with Alertness
Never/Rarely	Reference
Some Days	1.32	0.034	1.02	1.71	1.13	0.392	0.83	1.43
Most Days/Every Day	1.20	0.286	0.85	1.71	1.01	0.970	0.69	1.46
Nap Frequency
Never/Rarely	Reference
Some Days	1.22	0.160	0.92	1.61	1.08	0.631	0.76	1.45
Most Days/Every Day	1.21	0.185	0.94	1.58	0.96	0.786	0.71	1.29
Sleep Latency
<15 minutes	Reference
15-30 minutes	1.41	0.017	1.06	1.89	1.22	0.192	0.92	1.67
>30 minutes	1.65	0.002	1.20	2.27	1.45	0.032	1.03	2.03
Sleep Quality
Good/Very Good	Reference
Fair	1.08	0.574	0.82	1.43	1.03	0.828	0.73	1.31
Poor/Very Poor	1.01	0.954	0.65	1.58	1.11	0.644	0.65	1.59
Sleep Duration
7-8 hours	Reference
≤5 hours	1.81	0.011	1.14	2.86	2.04	0.004	1.26	3.33
6-7 hours	0.88	0.250	0.62	1.12	0.86	0.330	0.63	1.17
≥ 9 hours	1.43	0.030	1.04	1.97	0.97	0.857	0.66	1.39
Snoring
Never/Rarely	Reference
Some Nights	1.62	0.024	1.06	2.54	1.52	0.079	0.95	2.44
Most Nights/Every Night	0.70	0.479	0.26	1.88	0.39	0.184	0.09	1.56
Note: bold indicates significance at the p<0.05 level.
aAdjusted models control for demographic characteristics, including age, marital status, race, education, health conditions, and body weight.

In the unadjusted models, participants who slept both fewer than 5 hours (HR = 1.81, 95% CI: 1.14 - 2.86, p<0.05). And more than 9 hours per night (HR = 1.43, 95% CI: 1.04 - 1.97, p<0.05) demonstrated significantly higher risk for incident dementia. Participants who reported taking between 15 and 30 minutes to fall asleep showed a higher risk for incident dementia (HR = 1.41, 95% CI: 1.06 - 1.89, p<0.05), as did those who took longer than thirty minutes to fall asleep (HR = 1.65, 95% CI: 1.20 - 2.27, p<0.01).

In fully adjusted models, participants who reported taking 30 minutes or longer to fall asleep demonstrated higher risk for incident dementia (HR = 1.45, 95% CI: 1.03 - 2.03, p<0.05, see Figure 1A). Participants who reported sleeping 5 hours or fewer per night demonstrated significantly higher risk for incident dementia (HR = 2.04, 95% CI: 1.26 - 3.33, p<0.01, see Figure 1B).

Figure 1. Estimated survival curves displaying the relationships between sleep variables and incident dementia, adjusting for covariates, which were found to be significant in the Cox hazard proportional models. (A) Survival curve from the Cox model examining incident dementia and sleep latency, adjusting for covariates. Sleep latency >30 minutes, as compared to <15 minutes, was associated a greater risk of incident dementia (p<0.05). (B) Survival curve from Cox model examining incident dementia and sleep duration, adjusting for covariates. Sleep duration ≤5 hours, compared to 7-8 hours, was associated a greater risk of incident dementia (p<0.01).

Examining the relationship between each sleep variable and all-cause mortality

Table 4 summarizes results of the Cox proportional hazard models examining each sleep characteristic and all-cause mortality. In the unadjusted models, a greater risk for all-cause mortality was associated with self-reported difficulty with alertness both “most/every day” (HR = 2.23, 95% CI: 1.79 - 2.75, p<0.001) and “some days” (HR = 1.50, 95% CI: 1.25 - 1.82, p<0.001). Risk for all-cause mortality was increased for participants who slept for longer than eight hours per night (HR = 2.14, 95% CI: 1.73 - 2.65, p<0.001) and for participants who reported napping “some days” (HR = 1.32, 95% CI: 1.06 - 1.64, p<0.05) or “most/every day” (HR = 2.23, 95% CI: 1.84 - 2.79, p<0.001). Additionally, increased risk of all-cause mortality was associated with self-reported sleep quality of “poor” or “very poor” (HR = 1.33, 95% CI: 1.00 - 1.77, p<0.05).

Table 4. Cox models examining each sleep disturbance characteristic and all-cause mortality (N = 2,812).

	All-cause mortality				All-cause mortality
	Unadjusted models				Fully adjusted modelsa
	HR	p-value	Lower	Upper	HR	p-value	Lower	Upper
Difficulty with Alertness
Never/Rarely	Reference
Some Days	1.50	0.000	1.25	1.82	1.49	0.004	1.13	1.94
Most Days/Every Day	2.23	0.000	1.79	2.75	1.65	0.004	1.17	2.32
Nap Frequency
Never/Rarely	Reference
Some Days	1.32	0.012	1.06	1.64	1.38	0.032	1.03	1.85
Most Days/Every Day	2.23	0.000	1.84	2.79	1.73	0.000	1.29	2.32
Sleep Latency
<15 minutes	Reference
15-30 minutes	1.37	0.012	1.06	1.64	1.32	0.053	0.99	1.75
>30 minutes	1.20	0.140	0.94	1.54	1.14	0.444	0.81	1.63
Sleep Quality
Good/Very Good	Reference
Fair	1.13	0.225	0.93	1.37	1.24	0.119	0.94	1.63
Poor/Very Poor	1.33	0.043	1.00	1.77	1.75	0.006	1.17	2.61
Sleep Duration
7-8hours	Reference
≤5 hours	1.40	0.087	0.95	2.07	2.38	0.001	1.44	3.92
6-7 hours	1.05	0.623	0.86	1.29	1.22	0.160	0.92	1.61
≥9 hours	2.14	0.000	1.73	2.65	1.31	0.171	0.88	1.94
Snoring
Never/Rarely	Reference
Some Nights	1.41	0.037	1.02	1.96	1.40	0.181	0.85	2.29
Most Nights/Every Night	0.98	0.959	0.56	1.75	0.71	0.506	0.26	1.92
Note: bold indicates significance at the p<0.05 level.
aAdjusted models control for demographic characteristics, including age, marital status, race, education, health conditions, body weight, and incident dementia.

In the fully adjusted Cox proportional hazard models, the risk of all-cause mortality was higher for those participants who reported difficulty maintaining alertness “some days” (HR = 1.49, 95% CI: 1.13 - 1.94, p<0.01) and “most/every day” (HR = 1.65, 95% CI: 1.17 - 2.32, p<0.01, see Figure 2A); for those who reported napping “some days” (HR = 1.38, 95% CI: 1.03 - 1.85, p<0.05) and “most/every day” (HR = 1.73, 95% CI: 1.29 - 2.32, p<0.001, see Figure 2B); those reporting “poor/very poor” sleep quality (HR = 1.75, 95% CI: 1.17 - 2.61, p<0.01, see Figure 2C), and those reporting sleeping 5 or fewer hours per night (HR = 2.38, 95% CI: 1.44 - 3.92, p<0.01 see Figure 2D).

Figure 2. Estimated survival curves displaying the relationships between sleep variables and all-cause mortality, adjusting for covariates, which were found to be significant in the Cox hazard proportional models. (A) Survival curve from Cox model examining all-cause mortality and difficulty maintaining alertness, adjusting for covariates. Difficulty maintaining alertness “Some Days” and “Most Days/Every Day,” as compared to “Never/Rarely,” were associated a greater risk of all-cause mortality (p<0.01 and p<0.01, respectively). (B) Survival curve from the Cox model examining all-cause mortality and napping, adjusting for covariates. Napping “Some Days” and “Most Days/Every Day,” as compared to “Never/Rarely,” were associated a greater risk of all-cause mortality (p<0.05 and p<0.01, respectively). (C) Survival curve from Cox model examining all-cause mortality and sleep quality, adjusting for covariates. Sleep quality reported to be “Poor/Very Poor,” as compared to “Good/Very Good,” was associated a greater risk of all-cause mortality (p<0.01). (D) Survival curve from Cox model examining all-cause mortality and sleep duration, adjusting for covariates. Sleep duration ≤5 hours, as compared to 7-8 hours, was associated a greater risk of all-cause mortality (p<0.01).

Discussion

Overall, our findings show a strong relationship between several sleep disturbance and deficiency variables and incident dementia over time. Compared to sleeping 7-8 hours per night, sleeping fewer than 5 hours per night was associated with two-fold greater risk for incident dementia, and routinely taking 30 minutes or longer to fall asleep was associated with a 45% greater risk for incident dementia. We also found associations between sleep disturbance and deficiency variables and all-cause mortality. Specifically, an increased risk of all-cause mortality was observed for those routinely experiencing difficulty maintaining alertness, those reporting routinely napping, those with poor sleep quality, and those reporting sleeping 5 or fewer hours per night.

Whereas previous research on sleep among older adults and risk for incident dementia or all-cause mortality focus on specific sleep constructs, our study prospectively examined a broad array of sleep characteristics and incident dementia and all-cause mortality. We did not observe consistent associations between all sleep characteristics and the two outcomes (i.e., incident dementia and all-cause mortality). For instance, longer sleep latency was associated with incident dementia but not all-cause mortality, yet short sleep duration was associated with both incident dementia and all-cause mortality. Further, in the combined analyses where all sleep characteristics were entered into the same model predicting either incident dementia or all-cause mortality, we found only sleep duration ≤5 hours to be a significant predictor of incident dementia, whereas difficulty maintaining alertness (i.e., “some days,” “most days” or “every day”) and sleep duration ≤5 hours were the only significant predictors of all-cause mortality. Taken together, these results from individual Cox models and the combined Cox models suggest that short sleep duration, after controlling for relevant covariates, is the most important predictor of incident dementia and all-cause mortality.

Given the literature showing a strong association between sleep apnea (a disorder for which loud snoring is the most common symptom) and cognitive impairment [7, 15], it was surprising not to see an association between frequent snoring and either incident dementia or all-cause mortality. Several possible explanations may be hypothesized for this lack of a significant relationship between snoring and either incident dementia or all-cause mortality. First, the wording of the snoring question (“In the last month, how often did you have trouble staying asleep because you snored loudly, or you woke up gasping or choking”) is problematic as it does not account for hearing impairment, which is common among the sample of older adults. Additionally, the question combines several symptoms, which are not necessarily part of the same continuum (i.e., difficulty staying asleep and loud snoring). Furthermore, common questionnaire wording asks for participants to consider others and their reports of the participant and their snoring. By way of example, one common snoring questionnaire asks participants “do you snore loudly, loud enough to be heard through closed doors or your bed-partner elbows you for snoring at night?” [22] Finally, there were few individuals who reported snoring “most nights” or “every night” in the sample. Specifically, 9% of the sample in 2013 reported snoring “most nights” or “every night” and 2% of the sample in 2014 reported snoring “most nights” or “every night.”

Nevertheless, the results from our primary objective in this study highlight an adverse association between sleeping 5 hours or fewer and both incident dementia and all-cause mortality. Our findings are consistent with other cohorts measuring sleep deficiency at baseline and cognitive impairment at follow up [23] and a meta-analysis that also documented a strong association between short sleep and all-cause mortality [20]. The association observed in our study between short sleep (5 hours or less) and incident dementia screening may be understood via the research drawing upon animal models to demonstrate brain toxin removal during sleep [24]. Specifically, research has shown that clearance of Alzheimer’s disease biomarkers, including amyloid-beta plaques or tau proteins [24], takes place at an accelerated rate in the brain during sleep compared to wakefulness, and the rate of buildup of Alzheimer's disease biomarkers is greater during wakefulness than during sleep. These data are consistent with the hypotheses that extended wakefulness and/or sleep deficiency are associated with greater buildup of toxic metabolites and/or impaired clearance of those metabolites, thereby increasing the risk of Alzheimer's disease [25, 26].

It is interesting, however, that our study documented an association between long sleep (9 hours or more) and both incident dementia and all-cause mortality in unadjusted models, but the relationship between long sleep and both incident dementia and all-cause mortality disappeared after controlling for confounders (e.g., age and chronic conditions). In contradistinction, the relationships between short sleep and both incident dementia and all-cause mortality remained significant after full adjustment. Our findings therefore stand in contrast to several meta-analyses that have found associations between both short and long sleep and all-cause mortality in adults [20, 21]. The most parsimonious explanation for the disappearance of the effect of long sleep on dementia and mortality in adjusted models is that the deleterious impact of long sleep is a reflection of underlying disease.

Conclusions

Our study offers a contribution to the literature on sleep among aging populations in its assessment of incident dementia and all-cause mortality and a range of sleep characteristics among older adults. According to our findings from Cox proportional hazard models examining each sleep characteristic and outcome, we found that longer time to fall asleep and short sleep duration predicted incident dementia, while short sleep duration, difficulty maintaining alertness, napping, and poor sleep quality predict all-cause mortality. Short sleep duration was a strong predictor of both incident dementia and all-cause mortality, suggesting this may be a sleep characteristic that is important—over and above the other predictors—of adverse outcomes among older adults. Also, future research may consider the development of novel behavioral interventions to improve sleep among older adults.

Materials and Methods

Data from the National Health and Aging Trends Study (NHATS), an annual in-home, computer-assisted, longitudinal, nationally representative survey of community-dwelling Medicare beneficiaries 65 years and older drawn from the Medicare enrollment database, were analyzed. The NHATS data collection began in 2011 with a core interview administered annually. Adults ages 65 and older were sampled from the Medicare enrollment file. NHATS also used proxy respondents for those individuals who were unwilling or unable to complete an interview, a practice which has been shown to reduce attrition bias in longitudinal studies with older adults [27]. Additional information regarding the study’s sampling strategy, design and content are available to the public [28]. All respondents provided consent, and the study protocol was approved by the Johns Hopkins University Institutional Review Board (IRB). Our analysis of the publicly available, de-identified data from NHATS was considered exempt from IRB review.

Supplementary Materials

Supplementary Figure 1