Original article

Sleep disturbance in mild to moderate Alzheimer’s disease

Maria Moran*, C.A. Lynch, C. Walsh, R. Coen, D. Coakley, B.A. Lawlor

Mercer’s Institute for Research on Ageing, St James’s Hospital, Dublin 8, Ireland

Received 6 August 2003; received in revised form 24 September 2004; accepted 11 December 2004

Abstract

Background and purpose: To determine the prevalence of sleep disturbance in a memory clinic population of Alzheimer’s disease (AD)

patients and identify its clinical correlates.

Patients and methods: Data from 215 attendees at a memory clinic, who were diagnosed with Alzheimer’s disease, were examined. This

included data from cognitive, functional and neuropsychological assessments. Sleep disturbance was determined using the question about

diurnal rhythm disturbance on the BEHAVE-AD questionnaire. Two groups, with and without sleep disturbance, were compared. Group

differences were analysed using univariate analysis and stepwise logistic regression analysis.

Results: The prevalence of sleep disturbance in this sample was 24.5%. The BEHAVE-AD ‘aggressiveness’ (PZ0.009) and ‘global

rating’ (PZ0.029) (a measure of global impact of behavioural disturbance) were found to be significant predictors of sleep disturbance

in AD.

Conclusions: Sleep disturbance in AD is associated with other behavioural symptoms, notably aggressiveness. Sleep disturbance in AD has

significant impact on the patient and/or caregiver. Consideration of co-morbid behavioural symptoms may aid the clinician in choosing a

suitable treatment for sleep disturbance in AD.

q 2005 Published by Elsevier B.V.

Keywords: Sleep disturbance; Alzheimer’s disease; Dementia; Caregiver burden; Aggression; BEHAVE-AD

1. Introduction

Sleep disturbance in Alzheimer’s disease (AD) is

common. Cross-sectional studies of clinic- and commu-

nity-based studies have reported that up to 40% of patients

with AD have sleep disturbance [1].

The cause of sleep disturbance in AD is thought to be

multi-factorial. Pathophysiological changes resulting from

the disease itself interfere with the maintenance of normal

sleep. Damage to neuronal pathways, such as the cholin-

ergic pathways, that initiate and maintain sleep is thought to

contribute to sleep changes in AD [2]. The circadian

pacemaker, in the suprachiasmatic nucleus, is also import-

ant in maintaining a normal sleep-wake cycle. Researchers

have demonstrated dysregulation of the circadian timing

system in AD, and this may play a role in the development

of sleep disturbance [3].

1389-9457/$ - see front matter q 2005 Published by Elsevier B.V.

doi:10.1016/j.sleep.2004.12.005

* Corresponding author. Tel.: C353 87 7461854.

E-mail address: 56k@eircom.net (M. Moran).

Sleep disturbance is also known to occur as part of

associated medical and psychiatric illnesses, such as chronic

obstructive airways disease, arthritis, nocturia, and

depression, which are frequently diagnosed in patients

with AD [4].

For patients with dementia, sleep disturbance will reduce

quality of life, and some reports suggest that it is associated

with cognitive and functional decline [5,6]. For caregivers,

sleep disturbance is a source of physical and psychological

burden and is often cited as a reason for a family’s decision

to institutionalise a patient [7,8].

It is therefore important that sleep disturbance in AD is

recognised and treated appropriately. Recognition of

associated symptoms may help in determining the cause

of sleep disturbance in AD. It may also assist the clinician in

choosing an appropriate treatment and reduce the likelihood

of polypharmacy.

The aim of this study is to determine the prevalence of

sleep disturbance in a memory clinic population of patients

with AD and identify its clinical correlates.

Sleep Medicine 6 (2005) 347–352

www.elsevier.com/locate/sleep

M. Moran et al. / Sleep Medicine 6 (2005) 347–352348

2. Method

The sample was recruited through Mercer’s Institute for

Research on Ageing (MIRA), a national referral centre for

people with memory difficulties. All first-appointment

attendees who fulfilled the National Institute for Neurologi-

cal and Communicative Disorders/Alzheimer’s Disease and

Related Disorders Association (NINCDS/ADRDA) con-

sensus criteria for probable AD were included [9]. This

consensus diagnosis was assigned at a Consultant Geria-

trician and Consultant Psychogeriatrician led consensus

meeting, based on information gathered during the standard

MIRA assessment. The standard MIRA assessment

involved a detailed clinical history from the patient and a

reliable informant, physical and neurological examination,

routine dementia screen laboratory tests, neuropsychologi-

cal tests and a CT brain scan. Informants were asked to bring

a list of the patients’ current medication with them, which

was noted. Data were stored on a database and retro-

spectively searched to produce the above sample. The

clinical assessment and clinical rating scales were com-

pleted by a medical doctor, and the neuropsychological

testing was performed by a trained neuropsychologist.

2.1. Sleep disturbance

Sleep disturbance was determined using the behavioural

pathology in AD rating scale, the BEHAVE-AD [10]. Section

E, question 19, is in three parts and relates to sleep disturbance.

The first part asks about ‘repetitive wakenings during the

night’, the second part asks about ‘50–75% of former sleep

cycle at night’, and the third part asks about ‘complete

disturbance of diurnal rhythm (less than 50% of former sleep

cycle at night)’. These symptoms were counted if they were

present in the month prior to evaluation, and a score of one,

two or three was given depending on which question best

described the sleep pattern. Only six individuals in the sample

scored greater than one. For the purpose of the present study,

anyone who scored one or more was assigned to the sleep-

disturbed group.

2.2. Behavioural and psychological symptoms

The BEHAVE-AD was used to determine the presence of

behavioural and psychological symptoms in the previous

one month. Part 1 is divided into seven categories, including

the diurnal rhythm disturbance described above. The other

categories are (A) paranoid and delusional ideation, (B)

hallucinations, (C) activity disturbance, (D) aggressiveness,

(F) affective disturbance, (G) anxieties and phobias. Part 2

assesses the global impact of behavioural symptoms on the

caregiver and the patient. The questions in each category are

scored from 0 to 3, 0 signifying that the symptom is absent

and 1–3 representing increasing degrees of severity. A

reliable informant was used to provide information to

complete the BEHAVE-AD. The validity of information

obtained from proxy reports using the BEHAVE-AD has

been demonstrated [11]. Significant scorer consistency and

scorer agreement co-efficients of reliability have also been

demonstrated for the BEHAVE-AD. [12].

2.3. Cognitive and functional assessments

Functional impairment was measured using the Blessed

Dementia Scale [13] and the Instrumental Activities of

Daily Living [14]. Cognitive function was assessed using

the Mini Mental State Examination (MMSE) [15] and the

cognitive and self-contained part of the Cambridge

Examination for Mental Disorders of the Elderly

(CAMCOG) [16]. Severity of dementia was assessed

using the Clinical Dementia Rating Scale (CDR) [17].

2.4. Data analysis

Subjects were divided into two groups depending on the

presence or absence of sleep disturbance. It was not possible

to look at differences in terms of severity of sleep

disturbance as determined by BEHAVE-AD, as there were

only six patients with a score greater than one. Group

differences were analysed using two sample t-tests for

continuous variables and Chi-squared analysis for categori-

cal variables. For the purpose of the univariate analysis we

determined whether the behavioural symptoms were present

(R1) or absent for the past month. No explicit correction

was made for multiple testing with the univariate tests.

However, in order to combat the increased risk of type I

error, only results with a p value less than 0.01 were

considered significant. This is effectively the same as using

other explicit methods of correcting P-values for the case of

multiple testing.

In order to investigate the combined effect of the

recorded variables on sleep disturbance a step-wise binary

logistic regression model was fitted and all of the above

variables entered. Terms that were not significant were

removed one at a time until the model converged. The

stepwise procedure was also fitted forward adding terms one

at a time and retaining if significant. The resulting model

was the same. Data were analysed using Datadesk 5.0 and

Minitab 12.

3. Results

Fifty-eight percent of the sample lived with their

informant, and 94.2% were first-degree relatives of their

informant. There was no difference in the sleep-disturbed

compared to the non-sleep-disturbed group in terms of

relationship to informant.

Of the 224 people evaluated 55 (24.5%) had sleep

disturbance. The mean age of the sample was 74.91 years

(SDZ7.74). There was no significant difference between

the sleep-disturbed and the non-sleep-disturbed group with

Table 1

Univariate analysis of the difference between the sleep-disturbed and the non-sleep-disturbed group

Characteristic No sleep disturbance nZ169 Sleep disturbance nZ55 Univariate analysis

Mean age (SD) 74.34 (7.47) 76.67 (8.30)

Female (%) 122 (72.18) 35 (63.63) PZ0.224

Mean MMSE 7 (SD) 18 (5.42) 18 (4.77) PZ0.9112

Mean CAMCOG (SD) 63.2 (12.57) 63 (12.001) PZ0.866

Mean CDR (SD) 1.062 (0.48) 1.154 (0.48) PZ0.217

IADL (SD) 0.63 (0.93) 0.56 (0.84) PZ0.1522

BDRS (SD) 3.711 (2.32) 4.30 (2.50) PZ0.1624

Delusions (%) 64 (37.8) 30 (54.54) PZ0.0295

Hallucinations (%) 13 (7.69) 7 (12.7) PZ0.225

Activity disturbance (%) 111 (65.68) 44 (80) PZ0.0457

Aggression (%) 68 (40.23) 36 (65.45) PZ0.0011*

Affective disturbance (%) 64 (37.7) 27 (49.1) PZ0.1411

Anxieties (%) 86 (50.88) 37 (67.27) PZ0.0339

Global rating (%) 99 (58.57) 44 (80) PZ0.0041*

M. Moran et al. / Sleep Medicine 6 (2005) 347–352 349

regard to age (95% C.I.Z74.43–78.91 and 73.20–75.47,

respectively). Of the sample, 70.1% were female, and there

was no significant difference in terms of gender balance

between the two groups (PZ0.244). The mean MMSE

score of the total sample was 18.33 (SDZ4.35), and the

mean CAMCOG was 62.77 (SDZ13.12). There was no

significant difference between those with sleep disturbance

and those without, in terms of these cognitive tests (MMSE

tZ0.1119, PZ0.91, CAMCOG tZ0.1686, PZ0.87). Using

the Blessed Dementia Scale, and the Instrumental Activities

of Daily Living, no significant differences were found

between the two groups in terms of functional impairment

(tZK1.409, PZ0.1624, tZK1.443, PZ0.1522,

respectively).

With regard to other behavioural and psychological

symptoms on the BEHAVE-AD, the univariate analysis

showed significant differences between the two groups

at the P!0.01 level on measures of aggressiveness,

(c2Z10.61, PZ0.0011), and global rating, (c2Z8. 247,

PZ0.0041). Global rating is a measure of how

troubling the behavioural symptoms identified by the

BEHAVE-AD are to the caregiver or to the patient. (See

Table 1).

From the logistic regression analysis, the primary finding

was that aggressiveness (PZ0.009) and global rating (PZ0.029) were significant predictors of sleep disturbance. The

anxiety measure (PZ0.051) had borderline significance.

The other co-variates were examined but were eliminated

from the model. (See Table 2).

Table 2

Logistic regression analysis of the sleep-disturbed versus the non-sleep-disturbed

Predictor Coefficient St deviation

Constant K2.2778 0.3199

Aggression 0.3377 0.1288

Anxieties 0.2756 0.1412

Global rating 0.488 0.2236

Goodness of fit test: Hosmer–Lemeshow (on 6 d.f.), 2.868 (PZ0.825).

Medications were categorised into nine different cat-

egories, anti-depressants, benzodiazepines, hypnotics, other

psychiatric medications, analgesics, cardiac medications,

respiratory medications, gastrointestinal medications and

medications for urinary conditions. There was no significant

difference in the number of patients taking medications

from these categories in the sleep-disturbed group compared

to the non-sleep-disturbed group. However, there was a

trend toward benzodiazepines and hypnotics being more

commonly prescribed to those with sleep complaints, as

expected. Furthermore, while not statistically significant,

most medications were prescribed more commonly in the

sleep-disturbed group. (See Table 3).

4. Discussion

Before discussing these results it is important to address

methodological issues.

While the BEHAVE-AD is a well established and widely

used tool for assessing behavioural and psychological

symptoms of AD it is not an ideal tool for assessing sleep

disturbance. It provides limited information on

sleep maintenance, and no detail of sleep times or other

sleep parameters. It is important to remember this when

considering the findings. Unfortunately to date there is no

sleep questionnaire validated for use in dementia.

While the sample used in this study was a clinic-based

convenience sample, it is a relatively large sample of mild to

group

Z score P value

K7.12 !0.0001

2.62 0.009

1.95 0.051

2.18 0.029

Table 3

Chi-square analysis of the use of medications between the two groups

Medication Non-sleep disturbed

NZ169 (%)

Sleep disturbed

NZ55 (%)

Chi square P value

Anti-depressants 29 (17%) 13 (24%) 1.143 0.28

Benzodiazepines 14 (8%) 9 (16%) 2.4 0.09

Hypnotics 8 (5%) 6 (11%) 2.701 0.1

Other psychiatric medications 31 (18%) 9 (16%) 0.1109 0.7

Analgesics 20 (12%) 9 (16%) 0.775 0.38

Cardiac medications 83 (49%) 27 (49%) 7.68 0.99

Respiratory medications 5 (3%) 3 (5%) 0.75 0.38

Gastrointestinal 9 (5%) 5 (9%) 1.004 0.3

Genitourinary 3 (2%) 1 (2%) 4.38 0.98

M. Moran et al. / Sleep Medicine 6 (2005) 347–352350

moderate AD patients. The results are clinically relevant to

clinic-based populations. Fifty-eight percent of the infor-

mants lived with the patient and 94.16% were first-degree

relatives. The informants were considered reliable.

The prevalence of sleep disturbance in this group was

24.5%, which is within the range reported by other groups.

However, some studies have reported higher figures and

others lower figures. In a group of AD patients, with

moderate cognitive impairment, 40% of patients were

reported to have disruption of their sleep, with 24% having

multiple awakenings during the night [1]. In another sample,

35% experienced at least one of seven sleep-related

problems in the previous week, with sleeping more than

usual being reported by the caregivers as the most common

sleep-related problem [18]. Conversely, it has also been

reported that in 86.5% of a sample of outpatients with AD,

sleep difficulties rarely or never occurred, according to

informants [19]. Using patient-answered sleep question-

naires, in a sample with an average MMSE score of 18.5

(SDZ6), it was reported that compared to age-matched

controls, the patients with AD, were more satisfied with

their sleep, but more of them reported using sleep

medication often [20]. The variation in these figures appears

to relate to the type of assessment and the sample studied. In

the above examples, the average MMSE (where quoted),

ranged from 15 to 18.5, and all were outpatient samples but

were recruited in different ways. In many cases medical

comorbidity was not controlled for. The questions asked,

which related to sleep, are quite variable, with some being

answered by caregiver only, some by patient only and some

by both. It is clear that these methodological differences will

give different results about the nature and prevalence of

sleep disturbance in AD. This propensity highlights the need

for a standardised and validated approach to the assessment

of sleep disturbance in AD.

Our findings that there was no difference in use of

medication between the group with sleep disturbance and

that without is important. Epidemiological evidence would

suggest that the majority of sleep complaints in the elderly

are due to medical and psychiatric disorders [21]. It is

possible that the sleep complaints in patients with AD are

related to underlying illness other than to the AD. While

most medication groups were prescribed more commonly in

the sleep disturbed group the differences were not

statistically different. This supports the suggestion that

there was no difference between the two groups in terms of

co-morbidity, further suggesting that the repetitive awaken-

ings during the night detected in this sample are related to

AD and not solely due to co-morbid illnesses. McCurry also

reported no association between sleep disturbance in

patients with AD and obesity, hypertension, incontinence

or use of psychotropic medication [18].

While the cause of sleep disturbance in AD remains

unclear, a number of theories have been proposed as

outlined in the introduction. The association with other

behavioural symptoms may shed some light on the

aetiology. We found that sleep disturbance was indepen-

dently associated with other behavioural symptoms,

namely, aggressiveness. Aggressiveness on the BEHAVE-

AD includes the symptoms verbal outbursts, physical

threats and agitation. This association has been suggested

before in a sample of 120 AD patients with an average

MMSE score of 9.4. However, they only showed a

significant correlation between sleep disturbance and

aggression on the BEHAVE-AD [22]. Sleep disturbance

has also been significantly associated with daytime

behavioural disturbance [19,20]. Perhaps both symptoms

are consequences of the same underlying problem, e.g.

disturbance of rest/activity and sleep-wake rhythms due to

circadian rhythm disturbance [3]. Daytime agitation in

institutionalised AD patients has been associated with sleep-

disordered breathing [23]. Morning bright-light therapy

delayed the peak of agitation in institutionalised patients

with severe AD [24]. Further work is necessary to determine

if bright-light therapy would help with sleep disturbance and

agitation in community-dwelling patients with milder AD.

Anxiety and depression are common in persons with AD

[25], and sleep disturbance is often a symptom of these

diagnoses. In a study examining the specificity of depressive

symptoms in patients with AD, depressed patients with AD

had significantly higher scores than the non-depressed

patients with AD on the majority of Hamilton depression

scale items [26], including early insomnia, middle insomnia

and late insomnia. They also reported that non-depressed

M. Moran et al. / Sleep Medicine 6 (2005) 347–352 351

patients with AD, and healthy comparison subjects showed

no significant between-group difference for any Hamilton

depression scale item [27]. This finding suggests that sleep

disturbance in AD is related to depressed mood. However,

the evidence for this in studies specifically examining sleep

disturbance in AD is limited. In our study, there was a trend

towards an association with anxiety in the multivariate

analysis. Affective disturbance (depression and tearfulness)

was not significantly associated with repetitive awakenings

during the night in the univariate or multivariate analysis.

In our study, the failure to show an independent

association between depression and anxiety and sleep

disturbance in AD may be due to the assessment tool used

for both, i.e. the informant-rated BEHAVE-AD. In particu-

lar, the sleep questions ask about repetitive awakenings

during the night and do not ask about early or late insomnia,

which as described above are associated with depression.

Furthermore, the BEHAVE-AD determines the presence of

depressive and anxiety symptoms, but not a diagnosis

of depressive or anxiety disorders. In Carpenter’s study of

sleep disturbance in 215 moderately impaired AD patients,

no significant association was found between Diagnostic

Statistical Manual of Mental Disorders/Research Diagnostic

Criteria (DSM/RDC) [28] or Consortium to Establish a

Registry for Alzheimer’s Disease (CERAD) [29] criteria for

depression and sleep disturbance, but there was a significant

association between the informant’s opinion of depression

and sleep disturbance [1]. The prevalence of depression in

this sample using the DSM/RDC and CERAD criteria was

low at 5%. McCurry et al. used cluster analysis to examine

the characteristics of patients who awakened their care-

givers at night and found that one group had increased levels

of fearfulness, fidgeting and sadness [18]. In the same study,

she reported that depression was associated with higher

sleep disturbance severity ratings. She has also reported that

anxiety symptoms explained more of the variance in AD

patient sleep scores than depression, although depression

and anxiety were highly related [30]. Sleep EEG studies for

patients with AD excluded individuals with significant

depression and found consistent differences in their sleep-

wake pattern compared to normal controls [31]. In addition,

the sleep EEG is qualitatively different in patients with mild

to moderate AD (average MMSEZ19.5, SD 5.2) compared

to those with old-age major depression [32].

Neuropsychiatric symptoms are a well recognised group

of symptoms that commonly occur in AD. It has been

suggested that these symptoms should be further sub-

grouped. Examples of such groups include groups with

predominantly psychotic symptoms, predominantly affec-

tive symptoms, predominantly vegetative symptoms, etc.

[33,34]. These clusters of symptoms may reflect an

underlying pathological process [35]. It is possible that

different types of sleep problems and nighttime behaviours

may be associated with different symptom sub-groups. In

this study, the multivariate analysis demonstrates an

independent association between sleep disturbance

(repetitive awakenings during the night) and aggression.

This suggests that repetitive awakenings during the night

may be part of a broader syndrome of agitation/aggression.

McCurry also grouped AD patients who awaken their

caregivers according to associated behavioural symptoms,

and three groups were identified: those who exhibited

fearfulness, fidgeting and occasional sadness; those who

were generally inactive during the day and had few other

behavioural disorders; and those who were more severely

demented and had multiple behavioural difficulties, such as

frequent hallucinations. Identification of associated beha-

vioural symptoms is important, as it may have implications

for the treatment of the sleep disturbance. Further research is

clearly required to establish the nature of sleep disturbance

in AD, and the associated symptoms of these sleep

problems.

The finding of a significant association between the

presence of sleep disturbance and the global rating on the

BEHAVE-AD is not surprising. The global rating is a

measure of how troubling the behavioural symptoms are to

the patient or caregiver. Sleep disturbance and nighttime

behaviour disturbance have been associated with caregiver

stress and are often cited as the reason for deciding to admit

a patient to long-term care. [8,9]

We found no statistically significant association between

the presence of sleep disturbance and severity of cognitive

and functional impairment. However, there is suggestion of

non-significant correlations between sleep disturbance and

functional impairment as determined by Instrumental

Activities of Daily Living (IADL) and Behavior Dimen-

sions Rating Scale (BDRS) (see Table 1). Previously, using

EEG sleep physiology, sleep observational studies, and

sleep and behavioural questionnaires, sleep disturbance has

been shown to be associated with severity of cognitive and

functional impairment. [6,37,18]. Vitiello and Prinz et al.

cross-sectionally studied the sleep EEG of AD patients at all

stages of the illness: a mild group, a mild moderate group, a

moderate to severe group and an institutionalised group.

Their results suggest that sleep disturbances in AD increase

in magnitude with increasing severity of dementia [36,38].

It is most likely that the method of assessment of sleep

disturbance (i.e. a question about repetitive awakenings

during the night) and the profile of the sample (mean

MMSEZ18) are two reasons why we did not find an

association.

This study demonstrates that sleep disturbance is

common in patients diagnosed with mild to moderate AD

living in the community. Sleep disturbance in AD patients is

independently associated with ‘aggression’ (including

agitation) and with patient and caregiver distress, and

highlights the need to establish effective assessment tools

and treatments for sleep disturbance in AD. Effective

treatment of sleep disturbance in AD is likely to improve the

quality of life for both patient and caregiver and so may

result in delaying institutionalisation.

M. Moran et al. / Sleep Medicine 6 (2005) 347–352352

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