Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease?

doi:10.1016/j.tins.2016.05.002

Trends in Neurosciences

Volume 39, Issue 8, August 2016, Pages 552-566

https://doi.org/10.1016/j.tins.2016.05.002 Get rights and content

Trends

A bidirectional, causal interaction exists between NREM sleep and Aβ pathophysiology that may contribute to Alzheimer's disease (AD) risk and progression.

The disruption of NREM sleep may represent a novel pathway through which cortical Aβ impairs hippocampus-dependent memory consolidation.

The disruption of NREM sleep physiology offers potential diagnostic utility in the form of a non-invasive biomarker of Aβ pathology, AD risk, and/or AD pathophysiological progression.

Evidence implicates sleep disturbance as a consequence and cause of AD progression; one that is modifiable, offering preventative and therapeutic treatment potential.

Sleep disruption appears to be a core component of Alzheimer's disease (AD) and its pathophysiology. Signature abnormalities of sleep emerge before clinical onset of AD. Moreover, insufficient sleep facilitates accumulation of amyloid-β (Aβ), potentially triggering earlier cognitive decline and conversion to AD. Building on such findings, this review has four goals: evaluating (i) associations and plausible mechanisms linking non-rapid-eye-movement (NREM) sleep disruption, Aβ, and AD; (ii) a role for NREM sleep disruption as a novel factor linking cortical Aβ to impaired hippocampus-dependent memory consolidation; (iii) the potential diagnostic utility of NREM sleep disruption as a new biomarker of AD; and (iv) the possibility of sleep as a new treatment target in aging, affording preventative and therapeutic benefits.

Section snippets

Alzheimer's Disease and the Emerging Interaction with Sleep

AD is one of the largest public health and economic challenges of the 21st century. One in 10 adults over the age of 65 suffer from AD, representing a worldwide epidemic. As a result, there is a pressing need to develop sensitive biomarkers facilitating early detection, and effective treatment interventions [1]. Only by achieving both can the goals of prevention and therapeutic intervention be accomplished [1]. One emerging candidate that may fulfill all of these objectives is sleep. In this

Sleep in Aging

A physiological hallmark of advancing age is the decline of sleep, wherein NREM slow wave sleep (SWS) declines are particularly significant [2]. These impairments begin in midlife, and in many older adults age 75 years or older, less than 10% of SWS time remains [2]. Similar reductions in the quality of SWS are observed, measurable in the electroencephalographic (EEG) signature of slow wave activity (SWA; ∼0.5–4.5 Hz) 3, 4. These age-related decreases in NREM SWS quantity and quality are

The Role of Sleep Disruption in AD and Aβ-dependent Cognitive Decline

Individuals with higher cortical Aβ burden have proportionally worse hippocampus-dependent memory 21, 48, 49, 50, 51, 52. While Aβ aggregates significantly within specific medial and lateral prefrontal, posterior cingulate, and precuneus cortical regions 48, 50, all of which generate NREM slow oscillations [47] (Figure 1G), Aβ does not accumulate substantively within the hippocampus until relatively late in AD. How, then, does a largely cortical-based pathology produce a subcortical,

Sleep Disruption as an Early Diagnostic Biomarker of AD Risk

There is urgent need to identify biomarkers that predict which individuals are at greatest risk for developing AD, motivated by at least two goals: (i) offering the chance for preventative measures, pre-disease onset, and (ii) allowing nascent treatment intervention, early in the disease process 1, 50. Several lines of evidence now suggest that selective impairments of NREM sleep quality may serve both of these goals, representing a novel, non-invasive, relatively inexpensive, and specific

Treatment Implications–Sleep Intervention as Preventative and Therapeutic

Unlike many other consequences of AD pathology, such as structural brain atrophy or reductions in cerebral blood flow, sleep is a modifiable factor, and thus a treatable target 54, 56, 66. This is especially important considering that Aβ-related sleep disruption may impair hippocampus-dependent memory, thus contributing to cognitive decline [21] (Figure 3A). Therapeutic interventions that restore NREM slow wave sleep quantity and/or quality offer at least two new treatment possibilities. First,

Concluding Remarks

As evidence for causal, bidirectional links between sleep disturbance and AD pathophysiology continues to grow, new key questions are emerging (see Outstanding Questions). We close by outlining a select few that, to us, appear pressing and potentially transformative.

First, most studies examining the relationship between sleep and AD pathology have used cross-sectional designs. No study to date has gathered longitudinal sleep EEG recordings alongside measures of AD pathophysiology and

Acknowledgments

This work was supported by awards R01–AG031164(MPW), R01–AG054019(MPW), R01–AG034570(WJ) and F32–AG039170(BAM), from the National Institutes of Health.

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Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results.
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Trends in Neurosciences

ReviewSleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease?

Trends

Section snippets

Alzheimer's Disease and the Emerging Interaction with Sleep

Sleep in Aging

The Role of Sleep Disruption in AD and Aβ-dependent Cognitive Decline

Sleep Disruption as an Early Diagnostic Biomarker of AD Risk

Treatment Implications–Sleep Intervention as Preventative and Therapeutic

Concluding Remarks

Acknowledgments

Neurobiol. Aging

Neurobiol. Aging

Life Sci.

Neurobiol. Dis.

Curr. Biol.

Lancet Neurol.

Neuron

Cortex

Neurobiol. Aging

Brain Stimul.

Brain Stimul.

Schizophr. Res.

Brain Stimul.

Brain Stimul.

Brain Stimul.

Curr. Biol.

Trends Neurosci.

Neuroimage Clin.

Neuropsychologia

J. Affect. Disord.

Testing the right target and right drug at the right stage

Sci. Transl. Med.

Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan

Sleep

Sleep slow wave changes during the middle years of life

Eur. J. Neurosci.

Prefrontal atrophy, disrupted NREM slow waves and impaired hippocampal-dependent memory in aging

Nat. Neurosci.

Recent advances in understanding sleep and sleep disturbances in older adults: growing older does not mean sleeping poorly

Curr. Dir. Psychol. Sci.

Dementia in institutionalized elderly: relation to sleep apnea

J. Am. Geriatr. Soc.

Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical cross-sectional study on 431 patients

Dement. Geriatr. Cogn. Disord.

Impaired prefrontal sleep spindle regulation of hippocampal-dependent learning in older adults

Cereb. Cortex

Disturbed sleep patterns in elders with mild cognitive impairment: the role of memory decline and ApoE epsilon4 genotype

Curr. Alzheimer Res,

Concurrent impairments in sleep and memory in amnestic mild cognitive impairment

J. Int. Neuropsychol. Soc.

Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease

JAMA Neurol.

Sleep fragmentation and the risk of incident Alzheimer's disease and cognitive decline in older persons

Sleep

Modification of the relationship of the apolipoprotein E epsilon4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep

JAMA Neurol.

Greater risk of Alzheimer's disease in older adults with insomnia

J. Am. Geriatr. Soc.

Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women

JAMA

Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults

JAMA

Sleep-disordered breathing advances cognitive decline in the elderly

Neurology

Cognitive effects of treating obstructive sleep apnea in Alzheimer's disease: a randomized controlled study

J. Am. Geriatr. Soc.

The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study

Sleep

Beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation

Nat. Neurosci.

Self-reported sleep and beta-amyloid deposition in community-dwelling older adults

JAMA Neurol.

In vivo characterization of the early states of the amyloid-beta network

Brain

Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle

Science

Disruption of the sleep-wake cycle and diurnal fluctuation of beta-amyloid in mice with Alzheimer's disease pathology

Sci. Transl. Med.

Sleep drives metabolite clearance from the adult brain

Review
Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease?