APOE ɛ 4 and REM Sleep Behavior Disorder as Risk Factors for Sundown Syndrome in Alzheimer’s Disease

Abstract

Background:

Sundown syndrome (SS) in patients with Alzheimer’s disease (AD) is characterized by aggravation of behavioral problems at sunset. Disturbance of the circadian rhythm, a possible cause of SS, also facilitates amyloidopathy and reduces sleep quality. However, the associations of SS with amyloidopathy and sleep quality remain unclear.

Objective:

To investigate the prevalence of SS in patients with AD, the association between SS and APOE ɛ4 carrier, representing an enhanced amyloid pathology, and the relationship between SS and sleep quality in AD.

Methods:

We included 104 patients with late-onset AD and known APOE genotype. All participants underwent a structured interview via informant-based questionnaires to assess sleep quality and the presence of SS. Binary logistic regression analysis was performed to determine odds ratios (ORs) of APOE ɛ4 carrier and parameters of sleep quality for SS.

Results:

The prevalence of SS in AD was 27.8% (n = 29). Patients with SS were significantly more likely to be APOE ɛ4 carriers and to have rapid eye movement sleep behavior disorder (RBD) and a higher Clinical Dementia Rating (CDR) score compared to those without SS. In the multivariate regression analysis, APOE ɛ4 carrier (OR 3.158, CI 1.022–9.758), RBD (OR 2.166, CI 1.073–4.371), and higher CDR score (OR 2.453, CI 1.084–5.550) were associated with an increased risk of SS.

Conclusion:

The prevalence of SS in patients with AD was 27.8%. The presence of the APOE ɛ4 allele, RBD, and more severe dementia are associated with an increased risk of SS in AD.

Keywords

Alzheimer’s disease circadian rhythm REM sleep behavior disorder sundown syndrome

INTRODUCTION

Sundown syndrome (SS) is a term describing the worsening of neuropsychiatric symptoms in the late afternoon, early evening, or at night in persons with dementia [1]. The behavioral symptoms include anxiety, agitation, yelling, hallucination, aggression, wandering, disorientation, and others [2]. SS aggravates preexisting cognitive impairment, increases the probability of institutionalization [3], and causes economic and caregiver burden [4]. Nonetheless, studies about the consensus of its definition, proper assessment tools, robust evidence of the prevalence, or risk factors are scarce.

A disturbance of circadian rhythm has been suggested as a possible underlying mechanism of SS [1, 5]. Circadian system of our body provides 24-hour rhythmicity to cellular processes, sleep-wake cycle, and physiologic changes including body temperature, hormone secretion, and rest-activity behavior [6]. There is growing evidence that a circadian behavioral change resembling SS is regulated by a network of neurotransmitters in the circadian system [7, 8].

In Alzheimer’s disease (AD), disturbances of circadian rhythm are common, such as higher nocturnal activity and delayed acrophase of activity [9]. Circadian behavioral change was also demonstrated in animal models of amyloidopathy [10, 11]. In a mouse model with overexpression of human amyloid precursor protein, representing aggressive amyloidosis, a disturbed diurnal activity pattern was observed even before the detection of AD pathology [11].

From these findings, we postulated that advanced amyloidopathy aggravates disturbance of the circadian rhythm by disrupting connections of neurotransmitters in the circadian system, leading to SS. The ɛ4 allele of the apolipoprotein E (APOE) gene promotes amyloidopathic changes and is a strong genetic risk factor for late-onset AD [12, 13]. Thus, we hypothesized that SS would occur more frequently in APOE ɛ4 carriers than in non-APOE ɛ4 carriers.

Additionally, poor sleep quality, an important indicator of circadian dysfunction, is common in patients with AD [14]. However, the association between sleep quality and SS in AD, which might have in common the pathophysiology of a disturbed circadian rhythm, has not been researched systematically.

In this study, we aimed to investigate 1) the prevalence of SS in patients with AD, 2) the association between SS and the APOE4 genotype, and 3) the relationship between SS and sleep quality.

MATERIALS AND METHODS

Study population

A cross-sectional, observational study was conducted in the Neurocognitive Behavior Clinic of Seoul National University Bundang Hospital in Korea between October 2018 and January 2019. Participants who met the following inclusion criteria were recruited: 1) a diagnosis of probable AD dementia according to the diagnostic criteria for AD of the National Institute on Aging-Alzheimer’s Association [15], 2) onset of cognitive decline at age 65 years or older, and 3) known APOE genotype. All legal representatives of the participants provided written informed consent. The study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB Number B-1807-481-301).

Data collection

Epidemiological data such as age, gender, education level, and APOE genotype were collected. Data about prescribed medications, that could affect cognition, sleep, and behavior, were obtained and categorized as cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), antipsychotics, antidepressants, and benzodiazepines. Global cognitive status was measured by the Mini-Mental State Examination (MMSE) [16], and the severity of dementia was assessed with the Clinical Dementia Rating (CDR) [17].

Assessment and definition of SS

To evaluate the presence of SS, all participants and their caregivers underwent a structured interview via a questionnaire. The Sundown Syndrome Questionnaire (SSQ) was developed for this study. The SSQ was completed by a caregiver who was very familiar with the behavior pattern of the patient during the previous month. The SSQ consists of four parts (A–D), and the time required to complete the SSQ was approximately 15 minutes.

Part A is composed of 11 items assessing possible behavioral problems (disorientation to time, place, or person, anxiety, depression, wandering, aggression, emotional lability, hoarding behavior, delusion, hallucination), that can occur in individuals with SS according to previous literatures and our clinical experiences [2 , 19]. The presence or absence of each symptom was assessed; presence received a score of 1 point, and absence received a score of 0. The sum of the scores was designed Total A with a range of 0 to 11. The item in part B assessed whether the selected behavioral problems in part A worsened in the afternoon or evening compared to the morning. If the answer was yes, single or multiple choices could be made among four time periods of symptom aggravation (12–3 pm, 3–6 pm, 6–9 pm, and 9 pm–12 am) in part C. In part D, the frequency of the behavioral problem was assessed. If a participant had several behavioral problems with different frequencies, the most frequent symptom was chosen for the assessment. Total B, the value obtained by multiplying Total A and question D, had a range of 0–44, which indicated the severity of the behavioral problem. The SSQ is shown in Table 1.

Table 1

Sundown Syndrome Questionnaire (SSQ)

A. Symptoms	Yes (1)	No (0)
1. Disorientation to time (Does the patient have difficulty identifying daytime/night-time, day, month, or year?)	□ Yes	□ No
2. Disorientation to place (Does the patient have difficulty identifying where he/she is?)	□ Yes	□ No
3. Disorientation to person (Does the patient have difficulty correctly identifying family members or old friends?)	□ Yes	□ No
4. Anxiety (Is the patient nervous, unable to relax, or feel excessively tense?)	□ Yes	□ No
5. Depression (Does the patient seem depressed or sad?)	□ Yes	□ No
6. Wandering (Does the patient walk around aimlessly?)	□ Yes	□ No
7. Aggression (Does the patient act aggressively such as kick, spit, or resist help from others?)	□ Yes	□ No
8. Emotional lability (Does the patient laugh or cry in inappropriate situations?)	□ Yes	□ No
9. Hoarding behavior (Does the patient collect objectives obsessively or have difficulty discarding objectives that lack a useful purpose?)	□ Yes	□ No
10. Delusion (Does the patient have false beliefs, such as thinking others are stealing from him/her or planning to harm him/her?)	□ Yes	□ No
11. Hallucination (Does the patient see or hear things that are not present?)	□ Yes	□ No
Total A (range: 0–11)
B. Are these behavioral problems aggravated in the afternoon or evening compared to in the morning?	□ Yes	□ No
C. If the behavioral problems are aggravated in the afternoon or evening, please check the time periods of the aggravation. (multiple choices are possible, if applicable)	□ 12 pm–3 pm
	□ 3 pm–6 pm
	□ 6 pm–9 pm
	□ 9 pm–12 am
D. How often do the behavioral problems occur?	□ Five or more times a week (4)
	□ Three or four times a week (3)
	□ Once or twice a week (2)
	□ Once or twice a month (1)
Total B (Total A×D) (range: 0–44)

For the purpose of this study, the time period for SS was defined as 3 pm to 12 am, and the patients presenting with aggravated behavioral problems within this time period were referred to as SS patients.

Assessment of sleep quality

Sleep quality was evaluated based on a structured caregiver interview. Due to the lack of a questionnaire appropriate for use in assessing sleep quality of patients with dementia that could be completed by an informant, we developed a questionnaire named the Sleep Quality Questionnaire for patients with Dementia (SQQD). The information was gathered from an informant who was familiar with the sleep pattern of the patient over the last previous month. The time required for the interview was approximately 15 minutes. We performed the sleep quality interview on the same day that the SSQ was administered.

The questionnaire was composed of nine items assessing known sleep problems in patients with dementia: sleep latency [20], sleep fragmentation [21], sleep-related breathing problems [22], rapid eye movement (REM) sleep behavior disorder (RBD) [23, 24], daytime sleepiness [25], and sleep efficiency [26]. The detailed questions and scoring method of the SQQD are shown in Supplementary Table 1.

Statistical analysis

To compare the demographic data, behavioral problems of SS, and sleep quality between the patients with SS and without SS, we used the Pearson chi-squared test for the categorical variables and the Student’s t-test for the continuous variables. Univariate and multivariate binary logistic regression analyses were performed to investigate which factor is associated with the presence of SS. For the multivariate analysis, the clinically or statistically relevant covariates with a p-value <0.05 in the univariate binary regression analysis were included. Multicollinearity between the covariates was tested by calculating the variance inflation factor [27]. Statistical significance was set at <0.05. We used IBM SPSS version 25 (IBM Corp., Armonk, NY, USA) for the analyses.

RESULTS

Characteristics of the participants

A total of 104 patients were included in the study, and demographic data are summarized in Table 2. The mean age of patients was 80.5 years, and 64 (57.7%) were female. The mean MMSE score was 16.6, and 49 (44.1%) patients had at least one APOE ɛ4 allele. All patients were treated with one of the cholinesterase inhibitors. Among the participants, 29 (27.8%) had SS. The APOE ɛ4 allele was significantly more frequent in SS patients than in those without SS. Additionally, SS patients had higher CDR scores than those without SS, indicating more severe dementia. There were no significant differences in age, gender, education level, MMSE score, and medications between SS patients and those without SS.

Table 2

Clinical characteristics of patients with and without sundown syndrome

	All (n = 104)	Non-SS patients (n = 75)	SS patients (n = 29)	p
Age, y	80.5±6.1	81.0±6.2	79.3±5.8	0.220
Female	64 (57.7)	44 (58.6)	20 (68.9)	0.457
Education, y	10.0±5.8	10.5±5.8	8.6±5.7	0.137
APOEɛ4 carrier	49 (44.1)	30 (40.0)	19 (65.5)	0.034
MMSE	16.6±4.0	17.0±4.0	15.7±4.1	0.168
CDR	1.2±0.5	1.1±0.4	1.5±0.6	0.005
Medication
Cholinesterase inhibitors	104 (100)	75 (100)	29 (100)	1.000
Antidepressant	74 (66.7)	54 (72.0)	20 (68.9)	0.948
Antipsychotic	16 (14.4)	10 (13.3)	6 (20.6)	0.529
Benzodiazepine	12 (10.8)	8 (10.6)	4 (13.7)	0.916

SS, sundown syndrome; MMSE, Mini-Mental State Examination; CDR, Clinical Dementia Rating. Data are presented as n (%) unless otherwise specified.

SS occurred most frequently between 6–9 pm, followed by 9 pm–12 am and 3–6 pm. Beyond our definition of SS, there were 5 (13%) patients, who showed aggravation of behavioral problems between 12–3 pm (Fig. 1).

Fig.1

Distribution of time periods of worsening behavioral problems.

Behavioral problems in patients with and without sundown syndrome

SS patients had more frequent anxiety, depression, wandering, aggression, emotional lability, delusion, and hallucination than those without SS (Table 3). The total behavioral problems score was also higher in SS patients than in those without SS. Disorientation to time, place, and person and hoarding behavior did not significantly differ between the groups.

Table 3

Comparison of behavioral problems in patients with and without sundown syndrome

	Non-SS patients (n = 75)	SS patients (n = 29)	p
Disorientation to time	67 (89.3)	26 (89.6)	1.000
Disorientation to place	40 (53.3)	20 (68.9)	0.220
Disorientation to person	22 (29.3)	15 (51.7)	0.056
Anxiety	14 (18.6)	16 (55.1)	0.001
Depression	32 (42.6)	22 (75.8)	0.005
Wandering	4 (5.3)	11 (37.9)	<0.001
Aggression	9 (12.0)	11 (37.9)	0.006
Emotional lability	0 (0.0)	6 (20.6)	<0.001
Hoarding behavior	17 (22.6)	7 (24.1)	1.000
Delusion	15 (20.0)	12 (41.3)	0.048
Hallucination	13 (17.3)	15 (51.7)	0.001
Total scores (range 0–11)	3 (2–4)	5 (4–7)	<0.001

SS, sundown syndrome. Data are presented as n (%).

Sleep quality in patients with and without sundown syndrome

Regarding sleep quality, SS patients had significantly more RBD than those without SS. There was no difference between groups in the other parameters of sleep quality including sleep latency, sleep fragmentation, sleep-related breathing problems, daytime sleepiness, and sleep efficiency (Table 4). There was also no significant correlation between total sleep score and the SS severity score (Total B) (data not shown).

Table 4

Sleep quality in patients with and without sundown syndrome

	Non-SS patients (n = 75)	SS patients (n = 29)	p
Sleep latency	0.40±0.67	0.62±0.72	0.148
Sleep fragmentation	1.12±0.69	1.24±0.87	0.460
Sleep related breathing problem	1.83±2.11	2.31±2.26	0.308
REM sleep behavioral disorder	0.68±0.79	1.10±0.86	0.019
Daytime sleepiness	2.03±1.53	1.76±1.59	0.431
Sleep efficiency	1.09±1.21	1.03±1.08	0.820
Total (range 0–23)	7.15±3.76	8.07±4.11	0.276

SS, sundown syndrome; REM, rapid eye movement.

Risk factors for sundown syndrome

In univariate analysis, the factors APOE ɛ4 carrier, RBD, and higher CDR score showed significantly increased odds ratios (ORs) (95% confidence interval [CI]) for the presence of SS with values of 2.850 (1.165–6.970), 1.859 (1.096–3.152), and 2.868 (1.324–6.213) respectively. In the multivariate analysis, the factors APOE ɛ4 carrier, RBD, and higher CDR score remained significant (OR 3.158, CI 1.022–9.758; OR 2.166, CI 1.073–4.371; and OR 2.453, CI 1.084–5.550 respectively) (Table 5). Variance inflation factors were less than 1.358 for all variables, indicating a low degree of collinearity. MMSE score and education were excluded from the multivariable analysis, because we considered the CDR score to be comparable to the MMSE score as an indicator of dementia severity, and education as an adjustment factor of the MMSE score.

Table 5

Univariate and multivariate analysis of the factors related to the presence of sundown syndrome

	Univariate OR (95% Cl)	Multivariate OR (95% Cl)
Age	0.957 (0.890–1.029)	0.949 (0.865–1.040)
Female	1.566 (0.630–3.894)	2.274 (0.718–7.203)
Education	0.946 (0.880–1.018)	Not included
APOEɛ4 carrier	2.850 (1.165–6.970)^*	3.158 (1.022–9.758)^*
MMSE	0.927 (0.831–1.033)	Not included
CDR	2.868 (1.324–6.213)^*	2.453 (1.084–5.550)^*
Sleep quality
Sleep latency	1.539 (0.852–2.777)	1.653 (0.746–3.660)
Sleep fragmentation	1.243 (0.701–2.202)	0.847 (0.420–1.708)
Daytime sleepiness	0.892 (0.674–1.182)	1.010 (0.709–1.437)
Sleep-related breathing problem	1.107 (0.911–1.345)	1.069 (0.829–1.378)
REM sleep behavior disorder	1.859 (1.096–3.152)^*	2.166 (1.073–4.371)^*
Sleep efficiency	0.957 (0.661–1.386)	0.926 (0.547–1.566)
Medication
Antipsychotic	1.696 (0.554–5.188)	1.787 (0.466–6.856)
Antidepressant	0.864 (0.340–2.200)	0.635 (0.187–2.161)
Benzodiazepine	1.340 (0.371–4.844)	0.866 (0.169–4.445)

MMSE, Mini-Mental State Examination; CDR, Clinical Dementia Rating; REM, rapid eye movement. ^*p < 0.05.

DISCUSSION

In this study, we found that the prevalence of SS in patients with AD was 27.8%, and the presence of APOE ɛ4 genotype, RBD, and more severe dementia (higher CDR score) increased the risk of SS in patients with AD.

In previous studies, the prevalence of SS in AD ranged widely from 24% to 66% depending on the assessment methods or settings such as hospital, nursing facility, or home [4 , 29]. The prevalence in our study (27.8%) was within this range, and was based on a systematic interview with questions about specific behavioral patterns and time periods of symptoms, suggesting a result with systematical methodology.

The pathophysiology of SS is not fully elucidated, and various hypothesis including neurobiological, pharmacological, physiological, medical, and environmental factors have been proposed. From the perspective of neurobiological factor, the disruption of circadian rhythm has been focused as one of the most accepted mechanism for SS [3 , 19]. The circadian rhythm is controlled by the suprachiasmatic nucleus (SCN) of the hypothalamus, a central clock in our body [30]. The way, the central clock impacts daily behavioral patterns directly or indirectly is not well understood. However, disrupted signaling between behavioral regulation and the circadian system has been postulated [8, 10]. Several studies showed that a circadian change in emotion and motor activity is mediated by a daily oscillation of dopaminergic neurotransmitter-related gene expression [8, 31]. A recent study demonstrated that a functional polysynaptic circuit of SCN via GABAergic subparaventricular zone neurons regulates circadian aggression [7]. These findings might indicate the potential association between SS and SCN.

The alteration of circadian rhythm due to degeneration of the SCN in AD has been reported, showing neuronal loss and volume reduction in SCN [32, 33]. A study on the cellular level revealed that AD pathology has a direct impact on the circadian system. Amyloid-β (Aβ) induces degradation of BMAL1, an important transcriptional factor, by which activation the transcription of clock-controlled genes in SCN is driven [34]. Degeneration of BMAL1 results in a disturbed circadian rhythmicity of gene expression, mitochondrial respiratory capacity, sleep-wake cycle, and locomotor activity [35 –37]. In animal models with amyloidopathy, a disorganized daily activity pattern has been demonstrated [10, 38]. Furthermore, in a model with extensive amyloidopathy, the arrhythmic activity pattern preceded the detection of amyloid plaques [11].

Our finding that APOE ɛ4 carrier was significantly more frequent in SS patients than in those without SS could be explained in the context of its associated amyloidopathic effects. The presence of the APOE ɛ4 allele increases Aβ production and decreases Aβ clearance, aggravating amyloidopathy [12]. The increased Aβ may promote degeneration of the SCN and alteration of circadian gene expression [39], which interferes with the circuit of behavioral regulation and leads to SS [7]. In our study, AD was diagnosed clinically, and a future study with a confirmation of amyloidopathy by autopsy, amyloid imaging, or cerebrospinal fluid analysis might provide more supporting evidence.

Another finding of our study was that RBD symptoms were associated with the increased occurrence of SS. RBD is a parasomnia characterized by the loss of normal REM sleep muscle atonia [40]. Although the association between RBD and synucleinopathies like Parkinson’s disease, dementia with Lewy body, and multiple system atrophy is well established [41], only a few studies have reported the relationship between RBD and AD. The prevalence of RBD in AD varies from 4% to 39% [42, 43]. In our study, 50.5% of all participants had symptoms of RBD, which is higher than has been reported in previous studies. However, the lack of confirmation of RBD by polysomnography should be considered in the interpretation of the results. Additionally, there were 8 patients taking clonazepam among total population and 4 patients among 56 patients with RBD symptoms. There were no differences of the emergence of SS between patients with and without clonazepam (data not shown). A future longitudinal study investigating the effects of RBD treatment such as clonazepam on the symptoms of SS would be helpful to examine the relationship between the two conditions.

The underlying pathophysiology of RBD in AD could be explained by an imbalance of acetylcholine transmission [42, 44], neuronal loss in the locus coeruleus [45], and a mixed pathology with Lewy body in AD [46]. Up to 60% of AD cases also have Lewy body pathology [47], and patients with clinically-diagnosed AD presenting with RBD may show overlapping Lewy body pathology on autopsy [46]. Regarding circadian rhythmicity, a phase shifting in melatonin secretion and the alteration of circadian gene expression has been observed in patients with AD presenting RBD [48, 49]. Although the relationship between SS and RBD has not yet been studied, both phenomena might be based on dopaminergic dysfunction in the ventral tegmental area affecting daily mood or motor fluctuation [8, 50]. Further studies of this relationship and associated mechanism are required.

Regarding the relationship between higher dementia severity and SS, our result is in concordance with those of previous studies [1, 29]. However, the CDR scores in our study population were most commonly 1 or 2, indicating mild to moderate dementia [17]. Further study is needed to determine whether our findings could be generalized to individuals with severe or highly severe stages.

In this study, we assessed SS systematically, including a clear description of symptoms, time periods, and frequency. This has not been performed before, and SSQ may be useful in subsequent studies regarding SS.

However, this study has several limitations that should be considered. First, the sample size was small. Second, polysomnography was not performed to assess sleep and to confirm the results of the sleep quality questionnaire. A previous study demonstrated that screening for RBD with a single question, “Have you ever been told, or suspected yourself, that you seem to ‘act out your dream’ while asleep (for example, punching, flailing your arms in the air, making running movement, etc.)?”, had a sensitivity of 93.8% and a specificity of 87.2% [24]; this question was used in out SQQD for assessing RBD. Nevertheless, future studies including verification of RBD with polysomnography are warranted. Third, the SSQ and SQQD have not yet validated; they should be validated for further use. Fourth, SS can be influenced by multiple factors such as comorbidities, environmental factors, lifestyle, non-neurological therapies, or caregiver’s characteristics, which were difficult to measure in our study. In a future study, multiple influential factors should be also considered.

In conclusion, this study showed a prevalence of SS in AD of 27.8%. Our findings indicate that APOE ɛ4 carrier, RBD, and more severe dementia are associated with an increased risk of SS in patients with AD.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-0032r2).

Footnotes

The supplementary material is available in the electronic version of this article: .

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