See Mander et al. (doi:10.1093/awx174) for a scientific commentary on this article.Sleep deprivation increases amyloid-beta, suggesting that chronically disrupted sleep may promote amyloid plaques and other downstream Alzheimer's disease pathologies including tauopathy or inflammation. To date, studies have not examined which aspect of sleep modulates amyloid-beta or other Alzheimer's disease biomarkers. Seventeen healthy adults (age 35-65 years) without sleep disorders underwent 5-14 days of actigraphy, followed by slow wave activity disruption during polysomnogram, and cerebrospinal fluid collection the following morning for measurement of amyloid-beta, tau, total protein, YKL-40, and hypocretin. Data were compared to an identical protocol, with a sham condition during polysomnogram. Specific disruption of slow wave activity correlated with an increase in amyloid-beta40 (r = 0.610, P = 0.009). This effect was specific for slow wave activity, and not for sleep duration or efficiency. This effect was also specific to amyloid-beta, and not total protein, tau, YKL-40, or hypocretin. Additionally, worse home sleep quality, as measured by sleep efficiency by actigraphy in the six nights preceding lumbar punctures, was associated with higher tau (r = 0.543, P = 0.045). Slow wave activity disruption increases amyloid-beta levels acutely, and poorer sleep quality over several days increases tau. These effects are specific to neuronally-derived proteins, which suggests they are likely driven by changes in neuronal activity during disrupted sleep.

Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels.

Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for cognitive impairment and dementia is advanced age followed by other determinants such as genetic, socioeconomic, and environmental factors, including nutrition and physical activity. In the next decades, a rise in dementia cases is expected due largely to the aging of the world population. There are no hitherto effective pharmaceutical therapies to treat age-associated cognitive impairment and dementia, which underscores the crucial role of prevention. A relationship among diet, physical activity, and other lifestyle factors with cognitive function has been intensively studied with mounting evidence supporting the role of these determinants in the development of cognitive decline and dementia, which is a chief cause of disability globally. Several dietary patterns, foods, and nutrients have been investigated in this regard, with some encouraging and other disappointing results. This review presents the current evidence for the effects of dietary patterns, dietary components, some supplements, physical activity, sleep patterns, and social engagement on the prevention or delay of the onset of age-related cognitive decline and dementia.

Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia

Sleep deprivation and its association with diseases- a review

The growing interest in the preclinical stage of Alzheimer's disease (AD) led investigators to identify modifiable risk and predictive factors useful to design early intervention strategies. The preclinical stage of AD is characterized by β-amyloid (Aβ) aggregation into amyloid plaques and tau phosphorylation and aggregation into neurofibrillary tangles. There is a consensus on the importance of sleep within this context: the bidirectional relationship between sleep and AD pathology is supported by growing evidence that proved that the occurrence of sleep changes starting from the preclinical stage of AD, many years before the onset of cognitive decline. Hence, we review the most recent studies on sleep disturbances related to Aβ and the effects of sleep deprivation on Aβ accumulation in animal and human models. We also discuss evidence on the role of sleep in clearing the brain of toxic metabolic by-products, with original findings of the clearance activity of the glymphatic system stimulated by sleep. Furthermore, starting from new recent advances about the relationship between slow-wave sleep (SWS) and Aβ burden, we review the results of recent electroencephalographic (EEG) studies in order to clarify the possible role of SWS component disruption as a novel mechanistic pathway through which Aβ pathology may contribute to cognitive decline and, conversely, the eventual useful role of SWS in facilitating Aβ clearance. Finally, we discuss some promising innovative, effective, low-risk, non-invasive interventions, although empirical evidence on the efficacy of sleep interventions in improving the course of AD is at the very beginning.

/pdf/sleep-and-b-amyloid-deposition-in-alzheimer-disease-insights-2o6gcf8007.pdf

Sleep and β-Amyloid Deposition in Alzheimer Disease: Insights on Mechanisms and Possible Innovative Treatments.

Alzheimer's disease (AD) is the most common neurodegenerative disease mainly caused by abnormal tau phosphorylation, amyloid β (Aβ) deposition and neuroinflammation. As an important environmental factor, hypoxia has been reported to aggravate AD via exacerbating Aβ and tau pathologies. However, the link between hypoxia and neuroinflammation, especially the changes of pro-inflammatory M1 or anti-inflammation M2 microglia phenotypes in AD, is still far from being clearly investigated. Here, we evaluated the activation of microglia in the brains of APPswe/PS1dE9 transgenic (Tg) mice and their wild type (Wt) littermates, after a single episode of acute hypoxia (24 hours) exposure. We found that acute hypoxia facilitated the activation of M1 microglia in both Tg and Wt mice as evidenced by the elevated M1 markers including cluster of differentiation 86 (CD86), tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2) and CCL3. In addition, the markers of M2 microglia phenotype (Arg-1, CD206, IL-4 and IL-10) were decreased after acute hypoxia exposure, suggesting an attenuated M2 phenotype of microglia. Moreover, the activation of microglial and the release of cytokines and chemokines were associated with Nuclear factor-κB (NF-κB) induction through toll-like receptor 4 (TLR4). In summary, our findings revealed that acute hypoxia facilitated the activation of M1 microglia and attenuated the activation of M2 microglia in a transgenic AD mouse model, indicating the pathological role of hypoxia in the neuroinflammation of AD.

/pdf/acute-hypoxia-induced-an-imbalanced-m1-m2-activation-of-3adj22qa0v.pdf

Acute Hypoxia Induced an Imbalanced M1/M2 Activation of Microglia through NF-κB Signaling in Alzheimer’s Disease Mice and Wild-Type Littermates

Recently, there is an increasing concern over the association between sleep disorders and Alzheimer's disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPP(swe)/PS1(ΔE9) transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β(1-42) production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD.

Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice.

In Western medicine, dementia refers to a spectrum of diseases affecting cognition, mental health, and physical abilities. Ancient medical literatures of traditional Chinese medicine (TCM) also recorded dementia-like symptoms, but described the disease from a totally distinct theoretical point of view. The earliest records of memory loss in ancient China can be traced back 2000 years earlier. In TCM, dementia can be attributed mainly to the Brain dystrophy, Spleen-Kidney weakness, Blood stasis, and Phlegm stagnation. Of interest, ancient Chinese physicians have proposed that dementia manifests as not only cognitive but also noncognitive symptoms including psychiatric disorders and sleep disturbance, which have been investigated widely nowadays in Western medicine. Various TCM prescriptions, herbal medicines, and acupunctures have also been proposed for dementia prevention and therapy. Some of these strategies are still used in current clinical practice. Reviewing and highlighting the unique TCM recognition of treating dementia may shed light on future dementia research.

Traditional Chinese medicine for dementia.

Objective The present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD). Background and Rationale Sleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease. Historical Evolution Sleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD. Updated Hypothesis Based on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage. Early Experimental Data Our data suggested that AβPPswe/PS1ΔE9 transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology. Future Experiments and Validation Studies Future experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow-up studies in high-risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated. Major Challenges for the Hypothesis Studies on human participants with early stage of AD, especially the follow-up studies on the presymptomatic elderly in a large population, are difficult and time-consuming. Linkage to Other Major Theories Our hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression.

Alteration in sleep architecture and electroencephalogram as an early sign of Alzheimer's disease preceding the disease pathology and cognitive decline

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Chronic Sleep Deprivation Exacerbates Learning-Memory Disability and Alzheimer's Disease-Like Pathologies in AβPP(swe)/PS1(ΔE9) Mice.

Traditional Chinese medicine for dementia.

Alteration in sleep architecture and electroencephalogram as an early sign of Alzheimer's disease preceding the disease pathology and cognitive decline