Elsevier

The Lancet Neurology

Volume 18, Issue 3, March 2019, Pages 296-306
The Lancet Neurology

Review
Implications of sleep disturbance and inflammation for Alzheimer's disease dementia

https://doi.org/10.1016/S1474-4422(18)30450-2 Get rights and content

Summary

Nearly half of all adults older than 60 years of age report sleep disturbance, as characterised either by reports of insomnia complaints with daytime consequences, dissatisfaction with sleep quality or quantity, or the diagnosis of insomnia disorder. Accumulating evidence shows that sleep disturbance contributes to cognitive decline and might also increase the risk of Alzheimer's disease dementia by increasing β-amyloid burden. That sleep disturbance would be a candidate risk factor for Alzheimer's disease might seem surprising, given that disturbed sleep is usually considered a consequence of Alzheimer's disease. However, a bidirectional relationship between sleep and Alzheimer's disease is supported by advances in our understanding of sleep disturbance-induced increases in systemic inflammation, which can be viewed as an early event in the course of Alzheimer's disease. Inflammation increases β-amyloid burden and is thought to drive Alzheimer's disease pathogenesis. Improved understanding of the mechanisms linking sleep disturbance and Alzheimer's disease risk could facilitate the identification of targets for prevention, given that both sleep disturbance and inflammatory activation might be modifiable risk factors for Alzheimer's disease.

Introduction

More than 47 million people globally were estimated to have dementia in 2015, and the number of dementia cases is projected to triple to nearly 150 million by 2050, due in part to the increasing number of people living more than 65 years.1 An individual's risk of developing dementia, especially Alzheimer's disease dementia, is related to several genetic factors, but emerging evidence has shown that lifestyle factors, such as sleep disturbance, might also increase an individual's risk.1

Sleep benefits the consolidation of memory.2 However, nearly half of all adults older than 60 years of age have difficulty initiating and maintaining normal sleep patterns.3 Accumulating evidence shows that such sleep disturbance contributes to cognitive decline,4, 5, 6 and might also heighten the risk of Alzheimer's disease by increasing β-amyloid burden.7 Although a widely held clinical view is that disturbed sleep is a consequence of Alzheimer's disease,8 a bidirectional relationship appears to exist between sleep and Alzheimer's disease, in which sleep disturbance is associated with Alzheimer's disease biomarkers, including β-amyloid deposition in the brains of adults older than 60 years of age.9 The notion that sleep disturbance is a risk factor for Alzheimer's disease is supported by advances in our understanding that sleep disturbance induces increases in systemic inflammation,10, 11 which is increasingly viewed as an early event in the course of Alzheimer's disease.12, 13 Immune system-mediated actions contribute to β-amyloid burden to drive Alzheimer's disease pathogenesis.12 Better understanding of the mechanisms underlying the effect of sleep disturbance on Alzheimer's disease risk has the potential to optimise efforts for the identification of targets for Alzheimer's disease prevention.14

In this Review, we evaluate the association between sleep disturbance and Alzheimer's disease risk, and we discuss the role of inflammation in explaining how sleep disturbance might contribute to Alzheimer's disease. These findings are contextually framed by evidence that activation of the innate immune system alters CNS inflammatory mechanisms and increases amyloid burden, possibly driving onset and progression of Alzheimer's disease.12 Finally, because sleep disturbances are treatable, they might be targets for the prevention of Alzheimer's disease,14 especially given findings that such treatment, including low-cost, community-based interventions, might mitigate age-related increases in inflammation.10, 15

Section snippets

Clinical characteristics and assessment

Insomnia can be classified into four categories: insomnia symptoms, insomnia complaints with daytime consequences, dissatisfaction with sleep quality or quantity, and insomnia disorder; the latter three categories are characterized as sleep disturbance.16 Insomnia symptoms, such as taking longer to fall asleep and night-time wakefulness, are common occurrences and are not necessarily viewed as bothersome, because the low severity of these symptoms is such that older adults report satisfaction

Inflammation

One biologically plausible mechanism that links sleep disturbance and dementia risk is activation of the inflammatory response, which is thought to be an early event associated with the onset and clinical course of Alzheimer's disease.12, 13, 32

In humans, experimental manipulation of sleep duration provides some of the most robust evidence that sleep disturbance leads to increases in inflammation. A number of different experimental methods, including total night sleep deprivation, chronic sleep

Conclusions and future directions

In their landmark Commission, Livingston and colleagues1 indicated that about 35% of dementia is attributable to a combination of nine modifiable risk factors: education, midlife hypertension, midlife obesity, hearing loss, late-life depression, diabetes, physical inactivity, smoking, and social isolation. However, sleep disturbance was not included in their models evaluating the percentage of preventable cases of Alzheimer's disease dementia. In those individuals with sleep disturbance, the

Search strategy and selection criteria

We performed a systematic search of the PubMed, ISI Web of Science, and PsycINFO databases to identify studies that reported associations between sleep disturbances, insomnia, inflammation, and dementia. Searches were conducted using the following search terms: (sleep OR sleep disorder OR sleep problems OR sleep disturbances OR sleep quality OR insomnia AND dementia OR Alzheimer's disease); (above named sleep terms AND inflammation OR inflammatory); (above named inflammation terms AND dementia

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