Study ID

Study design

Country

Participants

Exposure/Methods for assessment

Outcomes/Methods for assessment

length of follow up (years)

Analysis methods

Covariates

Results

Authors conclusions

Agudelo [30]

Prospective cohort study

Spain

n.1035 from the Hispanic Community

Health Study/Study of Latinos

Excluded subjects with self-reported narcolepsy and severe sleep apnoea (Respiratory Event Index –REI > 50)

mean age: 55 years

male: 46%.

sleep disturbance

1. Actigraphy derived sleep pattern

2. Epworth sleepiness scale (ESS)

Cognitive decline: change from baseline

1) Six-Item Screener (SIS; mental status);

2) Brief- Verbal Learning Test (B-SEVLT; verbal episodic learning

and memory);

3) phonemic verbal fluency test (Word Fluency WF; verbal fluency)

4) Digit Symbol Subtest (DSS); processing speed

5) Trail Making Test (TMT)

7

Multivariate linear regression

Sex, age, socioeconomic status, self-reported alcohol consumption, BMI, daytime sleepiness (ESS), physical activity, depressive symptoms (CESD 10), anxiety symptoms (STAI-10), use of antidepressants, heart failure (self-reported doctor diagnosis), prevalent cerebrovascular accident (self-report of physician diagnosis of stroke or TIA). field centre, REI, number of weekdays with valid actigraphy data

Average sleep-onset latency was the only considered sleep exposure significantly associated with cognitive change (z-score units)

Higher average sleep-onset latency was inversely associated to the B-SEVLT-Sum (β = –0.003 [0.0009]; P < 0.001), B-SEVLT-Recall (β = –0.004 [0.0016]; P < 0.05), and SIS (β = –0.002 [0.0010]; P < 0.05).

Longer sleep-onset latency was associated with declines in global cognitive function, verbal learning, and verbal memory. We did not observe prospective associations between actigraphy-derived sleep duration and sleep continuity (eg, sleep fragmentation) with cognitive change.

Blackwell [31]

Prospective cohort study

US

n.2.822 cognitively intact community-dwelling older men

Mean age: 76

Male: 100%

Excluded participants who could no forgo use of mechanical devices for sleep apnoea during polysomnography and participants with “probable dementia”

3MS score < 80 or on a medication for dementia

Sleep disturbance

1. Actigraphy derived sleep pattern

2. Epworth sleepiness scale (ESS)

3. Pittsburgh Sleep Quality Index [PSQI]

Cognitive decline, change from baseline

1) Modified Mini-Mental State examination (3MS): Decline in

five points

2) Trail Making Test-Part B (trails B): The worst decile of change scores

3.5

Multivariate logistic regression

Age, race, clinic site, BMI, education, number of depressive symptoms, number of comorbidities, presence of an IADL impairment, benzodiazepine use, antidepressant use, self-reported health status, physical activity, alcohol use, and smoking status.

TMT-Trails B worst decile of change
Sleep efficiency (SE) < 70 vs. ≥ 70: adj OR 1.53 (95%CI 1.07, 2.18)

Wake after sleep onset (WASO) < 90 vs. ≥ 90: adj OR1.47 (95%CI 1.09, 1.98)

No. of long wake episodes < 8 vs. ≥ 8:  adj OR: 1.38 (95%CI 1.02, 1.86)

PSQI ≤ 5 vs. > 5: adj OR: 1.16 (95%CI 0.86, 1.55)

ESS: ≤ 10 vs. 10: adj OR 1.27 (95%CI 0.87, 1.87)

3MS score decline of five points

SE < 70 vs. ≥ 70: adj OR 1.17 (95%CI 0.88, 1.54)

WASO < 90 vs. ≥ 90: adj OR 1.15 (95%CI 0.92, 1.45)

No. of long wake episodes < 8 vs. ≥ 8: adj OR: 1.36 (95%CI 1.09, 1.71)

PSQI ≤ 5 vs. > 5: adj OR: 0.89 (95%CI 0.71, 1.11)

ESS: ≤ 10 vs. 10: adj OR 0.97 (95%CI 0.71, 1.34)

Among older community-dwelling men, reduced sleep efficiency, greater night-time wakefulness, greater number of LWEP, and poor self-reported sleep quality were associated with subsequent cognitive decline. These associations were stronger for the cognitive domain of executive function than global cognition

Bokenberger [32]

Retrospective cohort study

Sweden

n.11247 from the Swedish Twin Registry without a clinical diagnosis of dementia

mean age: 72.5 years

Male: NR

Sleep disturbance

Karolinska Sleep

Questionnaire

Dementia

ICD- 10

form the National Patient Register,

Cause of Death

Register, Prescription Drug Register

Up to 17 years

median: 14.3

Cox proportional-hazards regression models

Baseline Cognitive Functioning, baseline age, sex, highest educational attainment, night work status, smoking status, habitual alcohol consumption, physical exercise, BMI, type II diabetes, sleep

medication use, cancer history, depression, cardiovascular disease history, chronic obstructive pulmonary disease

Time in bed

≤ 6 h: adj HR 1.40 (95%CI 1.06-1.85)

> 9 h adj HR 1.11 (95%CI 1.00-1.24) compared with middle reference group

Rise time

8 AM or later adj HR 1.12 (95%CI 1.01-1.24)

Sleep quality index

adj HR 0.93 (95%CI 0.85-1.01)

Restorative sleep index

 adj HR 0.94 (95%CI 0.80-1.09)

Short and extended TIB (≤ 6 hours and > 9 hours) and late rising

(8:00 AM or later) among older adults predicted increased dementia incidence in the following 17 years, even when accounting for initial cognitive functioning.

Boland [33]

Prospective cohort study

US

n. 1760 from Sleep Heart Health Study

mean age: 62.3 years

male: 50.1%

excluded participants with race other than white, prevalent stroke at the time of cognitive testing, self-reported physician diagnosed apnoea or

unknown apnoea status

Sleep disordered

breathing

1) Polysomnography (respiratory disturbance

index (RDI)

2) Hypoxemia index

Sleep disturbance

Epworth Sleepiness Scale (ESS)

Cognitive impairment:

1. Delayed Word Recall Test (DWR),

2. WAIS-R Digit

Symbol Subtest (DSS),

3. Word Fluency test (WF).

1-2 years

Analysis of covariance; correlation coefficient

Age, education, occupation, field centre, diabetes, hypertension, body-mass index, use of CNS medications, alcohol drinking status

Men

Spearman correlation coefficient between RDI and:

DWR: -0.05

DSS: -0.04

 WF: -0.05

Hypoxemia index and

 DWR: -0.09

DS: -0.07

WF: -0.04

ESS and

DWR: 0.01

DSS: -0.02

 WF: -0.06

Women

Spearman correlation coefficient between RDI and:

DWR: -0.05

DSS: -0.10

WF: -0.02

Hypoxemia index and

DWR: -0.07

DS: -0.15

WF: -0.03

ESS and

DWR: 0.008

DSS: -0.009

WF: -0.01

ESS and cognitive function: no association (data not shown)

After adjustment for potential confounders, no association was observed between cognitive function scores and hypoxemia index or ESS and RDI.

Chen [34]

Retrospective cohort study

Taiwan

n. 34158 5693 patients with a diagnosis of insomnia

twice within one year and been prescribed at least 30 defined daily doses of hypnotics per year. 28,465 randomly selected patients matched by age and gender. From the Longitudinal Health Insurance Database (LHID).

Excluded patients with a diagnosis of neurotic depression, depressive disorder, anxiety states, anxiety

disorder, bipolar disorder, schizophrenia,

Parkinson’s disease

Median age: 65 years

Male: 44.3%

Insomnia

ICD-9-CM

Dementia

ICD-9-CM. Arteriosclerotic dementia (ICD-

9-CM code 290.4) was excluded

3

Cox proportional-hazards regression models

Hypertension, diabetes mellitus, hyperlipidaemia, and stroke

All sample:

adj HR 2.34 (95%CI 1.92-2.85)

aged 50-65 years

adj HR: 5.22 (95%CI 2.62-10.41)

aged > 65 years adj HR: 2.33 (95%CI 1.90-2.88)

Patients with insomnia and long-term use of hypnotics have more than a 2-fold increased risk of dementia, especially those aged 50 to 65 years

Diem [35]

Prospective cohort study

US

n.1245 women from the Study of Osteoporotic Fractures who completed the wrist actigraphy and cognitive assessment at baseline and two years later

mean age 82.6 years, Male: 0

Sleep disturbance

1) Actigraphy (Sleep-Watch-O) for 72 hours to measure total sleep per night, sleep efficiency, time awake after sleep onset

Mild cognitive impairment or dementia

Mini-Mental State Examination (MMSE)

2

Logistic regression

Age, race, clinic, education, BMI, depressive symptoms, comorbidities, IADL impairments, smoking, alcohol, exercise, living alone, self-reported health status, use of antidepressants, benzodiazepines, and prescription sleep medication use

Sleep Efficiency (SE) < 74% vs. SE > 86%: adj OR 1.53, 95% CI 1.07, 2.19;

Lower average sleep efficiency, longer average sleep latency, and greater variability in sleep efficiency and total sleep time are associated with increased odds of developing cognitive impairment.

Elwood [36]

Prospective cohort study

UK

n. 1225 from the Caerphilly Cohort Study

age range 55 - 69 years.

male: 100%

Insomnia; Sleep apnoea

Wisconsin Sleep Questionnaire

Vascular dementia, or Cognitive Impairment;

Non-vascular dementia or non-vascular cognitive impairment

1. Cambridge Cognitive (CAMCOG) Examination

2. Clinical Dementia

Rating,

3. Informant Questionnaire on Cognitive Decline

in older people

10

Logistic regression

Age, social class,

smoking, weekly alcohol

consumption, height and weight, cognitive function and taking of sleeping tablets at baseline

Vascular dementia or CI

exposure:

Sleep apnea:

adj OR 2.34 (95%CI 1.24 to 4.41)

Insomnia: adJ OR: 2.32 (95%CI 1.05 to 5.11)

Daytime sleepiness: adj OR: 3.15 (95%CI 1.76 to 5.63)

Non-Vascular dementia or CI

exposure:

Sleep apnea:

adj OR 1.02 (95%CI 0.61 to 0.69)

Insomnia: adJ OR: 1.02 (95%CI 0.54 to 1.94)

Daytime sleepiness: adj OR: 1.35 (95%CI 0.88 to 2.07)

Sleep disturbances

appear to be predictive of dementia and CIND of vascular origin,

while there is no suggestion that non-vascular cognitive impairment is predicted by sleep

Hoile [43]

Case control study

UK

n. 30418. 15,209 cases

with dementia (Alzheimer’s, vascular, mixed or non-specific subtypes), matched with the same number of controls on year of birth and gender; from the primary care dataset of the UK’s Clinical Practice Research Datalink (CPRD).

age: 74% of participants were in the age group of 75-89 years

male: 33.6%

Insomnia

1. Red code indicating insomnia in the database, or presence of the hypnotic medication in the prescribing history

Dementia

1. Red code indicating dementia in the database, or presence of the antidementia

medication in the prescribing history

10

Multivariate logistic regression

Chronic pulmonary disease (asthma, chronic

obstructive pulmonary disease and interstitial lung disease), stroke, heart failure, sleep apnoea and mental illness

adj OR 1.34

(95% CI 1.20-1.50)

A small, positive association was found between dementia and symptoms of insomnia recorded in primary care 5-10 years earlier.

Hung [37]

Retrospective cohort study

Taiwan

n. 310449. 0.51,734 patients with primary insomnia

and 258,715 age- and sex-matched nonprimary insomnia participants; from the

Longitudinal Health Insurance Database (LHID 2000)

mean age: 47.39 years.

 male: 40.35%,

Insomnia

ICD-9-CM

Dementia

ICD 9-CM

3

Cox proportional hazards regression model

Age group, geographic location, residential area,

premorbid comorbidities (diabetes, hyperlipidemia,

hypertension, coronary heart disease, chronic liver disease, and chronic kidney disease)

adj HR: 2.14 (95%CI 2.01-2.29)

Taiwanese patients with primary insomnia had a higher risk of developing

dementia than those without primary insomnia.

Lin [38]

Retrospective cohort study

Taiwan

n.3020.

604 patients with SRMD and 2416 control patients randomly selected and age/gender matched with the study group, from the Longitudinal Health Insurance Database (LHID)

Mean age: 56.7 years

male: 56.3%

Sleep-related movement disorders (SRMD)

ICD-9-CM

Dementia, Alzheimer disease

ICD 9-CM

5

Cox proportional hazard regression analysis

Age, gender, comorbidities

(Hypertension, diabetes, ischemic heart diseases, hyperlipidemia, smoking, alcoholism, obesity, atrial fibrillation, Parkinson disease, cerebrovascular accident, major depression,

and chronic kidney disease)

adj HR: 3.952 (95%CI 1.124-2.767)

SRMD is linked to an increased risk for

dementia

Potvin [39]

Prospective cohort study.

Canada

n.1,664 from the Survey on Elders’ Health. Excluded participants with dementia,

cerebrovascular disease, brain trauma /tumor /infections, multiple sclerosis, Parkinson disease, epilepsy, psychosis.

Mean age: 73.5

male: 30.3%

Sleep disturbance

Pittsburgh Sleep Quality Index (PSQI).

Cognitive impairment: Mini-Mental State Examination (MMSE)

1

adjusted OR by a logistic

regression

MMSE score at baseline, age, education, sex, psychotropic drug use, depressive episodes, anxiety, cardiovascular conditions,

and chronic diseases

Women: adj OR: 1.02 (95%CI 0.96-1.10)

Men: adj OR 1.17 (95%CI 1.05-1.30)

Poor subjective sleep quality measured

by the PSQI was linked to incident cognitive impairment.

Tsai [40]

Retrospective cohort study

Taiwan

n.19890. 3,978 with Obstructive Sleep Apnoea (OSA) and 15,912 without OSA, from The National Health Insurance Research

Database (NHIRD).

Mean age. 76 years

Male: 65.9%

Obstructive Sleep Apnoea (OSA)

ICD-9-CM

Alzheimer disease

ICD 9-CM

5,5

Cox proportional hazard model

Gender, age, urbanization level, income, arrhythmia, coronary artery disease, diabetes, hypertension, stroke, heart failure, hyperlipidemia, head injury, depression, anxiety, mortality

adj HR 2.12; 95% CI, 1.27-3.56)

OSA is independently associated with an increased risk of AD.

Yaffe [41]

Prospective cohort study.

USA

298 women 65 years or older from the Study of Osteoporotic Fractures

mean age: 82 years

male: 0

Sleep-disordered breathing

polysomnography (apnoea-hypopnea index)

Mild Cognitive impairment or dementia

1)Mini-Mental State Examination (MMSE)

2) Trail Making Test (Trails B),

3) California Verbal

Learning Test

4)  Informant Questionnaire on Cognitive Decline in the Elderly Mild cognitive impairment

diagnosed using the modified criteria by Petersen 1999, 2001. Dementia diagnosed according to DSM-IV

4.7

Multivariate logistic regression

Age, race, BMI, education level, smoking status, diabetes, hypertension,

medication use (antidepressants, benzodiazepines, nonbenzodiazepine anxiolytics), baseline cognitive scores

adj OR, 2.36 (95% CI,

1.34-4.13)

Among older women, those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment.

Yaffe [42]

Retrospective cohort study

USA

n179738 veterans male from the Department of Veterans Affairs (VA) National Patient Care Database.

Mean age: 67.5

male: 100%

Sleep disturbance

Sleep apnoea, insomnia

ICD-9-CM

Dementia

ICD 9-CM

8

Cox regression models

Diabetes, hypertension, myocardial infarction, cerebrovascular disease, obesity, depression, income and education

Any sleep disturbance: adj HR: 1.27, 95% CI: 1.20, 1.34

sleep apnoea: adj HR 1.23, 95% CI:1.14, 1.33, insomnia: adj HR: 1.29, 95% CI:1.20, 1.39

Sleep disturbance was associated with increased risk of dementia among a large cohort of older, male veterans. The association was fairly consistent between the overarching category of sleep disturbance and the two major subcategories of sleep disturbance (sleep apnoea and insomnia)