Sleep has been postulated to play an important role in the removal of potentially neurotoxic molecules, such as amyloid-β, from the brain via the glymphatic system. Disturbed sleep, on the other hand, may contribute to the accumulation of neurotoxins in brain tissue, eventually leading to neuronal death. A bidirectional relationship has been proposed between impaired sleep and neurodegenerative processes, which start years before the onset of clinical symptoms associated with conditions like Alzheimer's and Parkinson's diseases. Given the heavy burden these conditions place on society, it is imperative to develop interventions that promote efficient brain clearance, thereby potentially aiding in the prevention or slowing of neurodegeneration. In this review, we explore whether the metabolic clearance function of sleep can be enhanced through sensory (e.g., auditory, vestibular) or transcranial (e.g., magnetic, ultrasound, infrared light) stimulation, as well as pharmacological (e.g., antiepileptics) and behavioral (e.g., sleeping position, physical exercise, cognitive intervention) modulation of sleep physiology. A particular focus is placed on strategies to enhance slow-wave activity during nonrapid eye movement sleep as a driver of glymphatic brain clearance. Overall, this review provides a comprehensive overview on the potential preventative and therapeutic applications of sleep interventions in combating neurodegeneration, cognitive decline, and dementia.

Although sleep duration and sleep-related breathing disorders were associated with dementia previously, few studies examined the association between circadian rhythm association and cognitive status.

We aimed to investigate the association of rest and activity rhythm with cognitive performance in older people with cognitive complaints and less education.

Activity rhythm was evaluated with wrist actigraphy in 109 community-dwelling older people with cognitive complaints without diagnosed dementia. Each participant completed a neuropsychological battery and was classified as having cognitive impairment (MCI), dementia, or normal cognition. We used adjusted multinomial logistic regression and linear regression models to compare sleep and circadian non-parametric measures with cognitive groups and cognitive z-scores, respectively.

The mean age of the 109 participants was 79.3 ± 6.3 years old, 74% were women, 68% were white, and the mean education was 5.6 ± 5.2 years. Daytime activity intensity was associated with better language (β = 0.178; 95% CI = 0.022, 0.334; p = 0.03) and visuospatial performance (β = 0.158; 95%CI = 0.008, 0.308; p = 0.04). Also, less fragmented rhythm was associated with better visuospatial (β = 0.172; 95%CI = 0.025, 0.320; p = 0.02) and global cognitive scores (β = 0.134; 95%CI = 0.005, 0.263; p = 0.04). More interdaily stability was associated with a lower risk of MCI and dementia (RR = 0.54; 95%CI = 0.29-0.99; p = 0.04, and RR = 0.44; 95%CI = 0.21-0.94; p = 0.03, respectively). Moreover, more daytime activity (RR = 0.40; 95%CI = 0.18-0.89; p = 0.02) and less rhythm fragmentation (RR = 0.31; 95%CI = 0.14-0.73; p = 0.007) were associated with lower risk for dementia.

Daytime activity intensity and fragmented rhythm during the day and night may play an important role as markers for cognitive impairment in less educated populations. Future studies with larger samples should confirm these findings.

Alzheimer's disease (AD) is a major devastating neurodegenerative disorder afflicting majorly the geriatric population. Emerging studies augur the connection of gut dysbiosis and circadian disruption with the early onset of AD. Gut dysbiosis is characterized by dysregulated gut microbiota signature and compromised intestinal integrity, which provokes the translocation of bacterial metabolites into the systemic circulation. Noteworthy, gut-derived metabolites like calprotectin, trimethylamine-N-oxide, kynurenine, isoamylamine, and short-chain fatty acids play a key role in AD pathogenesis. Circadian dysregulation also corresponds with the exacerbated AD pathogenesis by accumulating Aβ and tau proteins. Moreover, circadian dysregulation is one of the causative factors for gut dysbiosis. This review discusses the complex interplay between the microbiota-gut-brain axis, circadian rhythmicity, and the emergence of AD. We reviewed preclinical and clinical studies on AD describing potential biomarkers of gut dysbiosis and circadian dysregulation. The identification of new biomarkers associated with the microbiota-gut-brain axis and circadian rhythmicity may help in early diagnosis and development of targeted therapies for mitigating neurodegenerative AD.

Histamine H3 receptor (H3R) antagonists regulate histamine release that modulates neuronal activity and cognitive function. Although H3R is elevated in Alzheimer's disease (AD) patients, whether H3R antagonists can rescue AD-associated neural impairments and cognitive deficits remains unknown. Pitolisant is a clinically approved H3R antagonist/inverse agonist that treats narcolepsy. Here, we find that pitolisant reverses AD-like pathophysiology and cognitive impairments in an AD mouse model. Behavioral assays and in vivo wide-field Ca2+ imaging revealed that recognition memory, learning flexibility, and slow-wave impairment were all improved following the 15-day pitolisant treatment. Improved recognition memory was tightly correlated with slow-wave coherence, suggesting slow waves serve as a biomarker for treatment response and for AD drug screening. Furthermore, pitolisant reduced amyloid-β deposition and dystrophic neurites surrounding plaques, and enhanced neuronal lysosomal activity, inhibiting which blocked cognitive and slow-wave restoration. Our findings identify pitolisant as a potential therapeutic agent for AD treatments.

We reviewed the connections among Alzheimer's disease (AD), sleep deprivation, and circadian rhythm disorders. Evidence is mounting that disrupted sleep and abnormal circadian rhythms are not merely symptoms of AD, but are also involved in accelerating the disease. Amyloid-beta (Aβ) accumulates, a feature of AD, and worsens with sleep deprivation because glymphatic withdrawal is required to clear toxic proteins from the brain. In addition, disturbances in circadian rhythm can contribute to the induction of neuroinflammation and oxidative stress, thereby accelerating neurodegenerative processes. While these interactions are bidirectional, Alzheimer's pathology further disrupts sleep and circadian function in a vicious cycle that worsens cognitive decline, which is emphasized in the review. The evidence that targeting sleep and circadian mechanisms may serve as therapeutic strategies for AD was strengthened by this study through the analysis of the molecular and physiological pathways. Further work on this nexus could help unravel the neurobiological mechanisms common to the onset of Alzheimer's and disrupted sleep and circadian regulation, which could result in earlier intervention to slow or prevent the onset of the disease.

Sleep disturbances and cognitive decline are intricately connected, and both are prevalent in aging populations and individuals with neurodegenerative disorders such as Alzheimer's disease (AD) and other dementias. Sleep is vital for cognitive functions including memory consolidation, executive function, and attention. Disruption in these processes is associated with cognitive decline, although causal evidence is mixed. This review delves into the bidirectional relationship between alterations in sleep and cognitive impairment, exploring key mechanisms such as amyloid-β accumulation, tau pathology, synaptic homeostasis, neurotransmitter dysregulation, oxidative stress, and vascular contributions. Evidence from both experimental research and population-based studies underscores the necessity of early interventions targeting sleep to mitigate risks of neurodegenerative diseases. A deeper understanding of the interplay between sleep and cognitive health may pave the way for innovative strategies to prevent or reduce cognitive decline through improved sleep management.

Investigating brain-enriched proteins with machine learning methods may enable a brain-specific understanding of brain aging and provide insights into the molecular mechanisms and pathological pathways of dementia. The study aims to analyze associations of brain-specific plasma proteomic aging signature with risks of incident dementia. In 45,429 dementia-free UK Biobank participants at baseline, we generated a brain-specific biological age using 63 brain-enriched plasma proteins with machine learning methods. The brain age gap was estimated, and Cox proportional hazards models were used to study the association with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia. Per-unit increment in the brain age gap z-score was associated with significantly higher risks of all-cause dementia (hazard ratio [95% confidence interval], 1.67 [1.56-1.79], P < 0.001), AD (1.85 [1.66-2.08], P < 0.001), and vascular dementia (1.86 [1.55-2.24], P < 0.001), respectively. Notably, 2.1% of the study population exhibited extreme old brain aging defined as brain age gap z-score > 2, correlating with over threefold increased risks of all-cause dementia and vascular dementia (3.42 [2.25-5.20], P < 0.001, and 3.41 [1.05-11.13], P = 0.042, respectively), and fourfold increased risk of AD (4.45 [2.32-8.54], P < 0.001). The associations were stronger among participants with healthier lifestyle factors (all P-interaction < 0.05). These findings were corroborated by magnetic resonance imaging assessments showing that a higher brain age gap aligns global pathophysiology of dementia, including global and regional atrophy in gray matter, and white matter lesions (P < 0.001). The brain-specific proteomic age gap is a powerful biomarker of brain aging, indicative of dementia risk and neurodegeneration.

Boosting slow-wave activity (SWA) by modulating slow waves through closed-loop auditory stimulation (CLAS) might provide a powerful non-pharmacological tool to investigate the link between sleep and neurodegeneration. Here, we established mouse CLAS (mCLAS)-mediated SWA enhancement and explored its effects on sleep deficits in neurodegeneration, by targeting the up-phase of slow waves in mouse models of Alzheimer's disease (AD, Tg2576) and Parkinson's disease (PD, M83). We found that tracking a 2 Hz component of slow waves leads to highest precision of non-rapid eye movement (NREM) sleep detection in mice, and that its combination with a 30° up-phase target produces a significant 15-30% SWA increase from baseline in wild-type (WTAD) and transgenic (TGAD) mice versus a mock stimulation group. Conversely, combining 2 Hz with a 40° phase target yields a significant increase ranging 30-35% in WTPD and TGPD mice. Interestingly, these phase-target-triggered SWA increases are not genotype dependent but strain specific. Sleep alterations that may contribute to disease progression and burden were described in AD and PD lines. Notably, pathological sleep traits were rescued by mCLAS, which elicited a 14% decrease of pathologically heightened NREM sleep fragmentation in TGAD mice, accompanied by a steep decrease in microarousal events during both light and dark periods. Overall, our results indicate that model-tailored phase targeting is key to modulate SWA through mCLAS, prompting the acute alleviation of key neurodegeneration-associated sleep phenotypes and potentiating sleep regulation and consolidation. Further experiments assessing the long-term effect of mCLAS in neurodegeneration may majorly impact the establishment of sleep-based therapies.

The mechanism underlying the possible causal association between long-term sleep disruption and Alzheimer's disease remains unclear Musiek et al. 2015. A hypothesised pathway through increased brain amyloid load was not confirmed in previous work in our cohort of maritime pilots with long-term work-related sleep disruption Thomas et al. Alzheimer's Res Ther 2020;12:101. Here, using functional MRI, T2-FLAIR, and arterial spin labeling MRI scans, we explored alternative neuroimaging biomarkers related to both sleep disruption and AD: resting-state network co-activation and between-network connectivity of the default mode network (DMN), salience network (SAL) and frontoparietal network (FPN), vascular damage and cerebral blood flow (CBF). We acquired data of 16 maritime pilots (56 ± 2.3 years old) with work-related long-term sleep disruption (23 ± 4.8 working years) and 16 healthy controls (59 ± 3.3 years old), with normal sleep patterns (Pittsburgh Sleep Quality Index ≤ 5). Maritime pilots did not show altered co-activation in either the DMN, FPN, or SAL and no differences in between-network connectivity. We did not detect increased markers of vascular damage in maritime pilots, and additionally, maritime pilots did not show altered CBF-patterns compared to healthy controls. In summary, maritime pilots with long-term sleep disruption did not show neuroimaging markers indicative of preclinical AD compared to healthy controls. These findings do not resemble those of short-term sleep deprivation studies. This could be due to resiliency to sleep disruption or selection bias, as participants have already been exposed to and were able to deal with sleep disruption for multiple years, or to compensatory mechanisms Mentink et al. PLoS ONE. 2021;15(12):e0237622. This suggests the relationship between sleep disruption and AD is not as strong as previously implied in studies on short-term sleep deprivation, which would be beneficial for all shift workers suffering from work-related sleep disruptions.

Alzheimer's disease (AD) is a typical neurodegenerative disease that presents challenges due to the lack of biomarkers to identify AD. A growing body of evidence highlights the critical role of circadian rhythms in AD.

The differentially expressed clock genes (DECGs) were identified between AD and ND groups (non-demented controls). Functional enrichment analysis was executed on the DECGs. Candidate diagnostic biomarkers for AD were screened by machine learning. ROC and nomograms were constructed to evaluate candidate biomarkers. In addition, therapeutics targeting predictive biomarkers were screened through the DGIdb website. Finally, the mRNA-miRNA network was constructed.

Nine genes were identified through the DECG analysis between the AD and ND groups. Enrichment analysis of nine genes indicated that the pathways were enriched in long-term potentiation and circadian entrainment. Four clock genes (GSTM3, ERC2, PRKCG, and HLA-DMA) of AD were screened using Lasso regression, random forest, SVM, and GMM. The diagnostic performance of four genes was evaluated by the ROC curve. Furthermore, the nomogram indicated that ERC2, PRKCG, and HLA-DMA are good biomarkers in diagnosing AD. Single-gene GSEA indicated that the main enrichment pathways were oxidative phosphorylation, pathways of neurodegeneration-multiple diseases, etc. The results of immune cell infiltration analysis indicated that there were significant differences in 15 immune cell subsets between AD and ND groups. Moreover, 23 drugs targeting HLA-DMA and 8 drugs targeting PRKCG were identified through the DGIdb website.

We identified three predictive biomarkers for AD associated with clock genes, thus providing promising therapeutic targets for AD.

Amyloid-β protein (Aβ) accumulation is a defining characteristic of Alzheimer's disease (AD), resulting in neurodegeneration and a decline in cognitive function. Given orexin's well-documented role in enhancing memory and cognition, this study investigates its potential to regulate Aβ-induced neurotoxicity, offering new perspectives into AD management.

This paper simulated Aβ accumulation in the hippocampus of AD patients by administering Aβ1-42 oligomers into the bilateral hippocampal dentate gyrus of ICR mice. Inflammatory cytokines (IL-6, TNF-α) and orexin-A levels were measured by ELISA. Additionally, the excitability of orexinergic neurons was assessed by IHC targeting c-Fos expression. These methodologies evaluated the Aβ-induced neuroinflammation, orexinergic system functionality, and dexamethasone's (Dex) effects on these processes.

Injection of Aβ1-42 oligomer resulted in elevated levels of IL-6, TNF-α, and orexin-A in the hippocampus, as well as increased excitability of orexinergic neurons in the lateral hypothalamus (LH). Dex treatment reduced neuroinflammation, causing a reduction in orexin-A levels and the excitability of orexinergic neurons.

Aβ-induced neuroinflammation is accompanied by enhanced levels of orexin-A and orexinergic neuron excitability. These findings suggest that the enhanced functionality of the orexinergic system may become a compensatory neuroprotective mechanism to counteract neuroinflammation and enhance cognitive function.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, beta-amyloid plaques, and tau tangles. Growing evidence suggests a strong link between sleep disturbances and AD progression, with disrupted sleep exacerbating AD progression through increased beta-amyloid and tau accumulation. This relationship indicates that improving sleep quality could slow disease progression and mitigate its effects on the brain. We investigated whether vestibular stimulation (rocking) could mitigate AD pathology in 3xTg mice (n = 58, males). Starting in early adulthood (p60), mice underwent 12-h daily rocking during the light period for four months. Rocking increased non-rapid eye movement (NREM) sleep initially, although habituation reduced this effect over time. Despite habituation, rocking slowed motor decline and reduced beta-amyloid levels in the cerebral cortex and hippocampus. However, tau levels remained unaffected. In conclusion, our findings highlight the potential of non-pharmacological methods to enhance NREM sleep and modify disease trajectory in AD models.

Sleep loss is often regarded as an early manifestation of neurodegenerative diseases given its common occurrence and link to cognitive dysfunction. However, the precise mechanisms by which sleep disturbances contribute to neurodegeneration are not fully understood, nor is it clear why some individuals are more susceptible to these effects than others. This review addresses critical unanswered questions in the field, including whether sleep disturbances precede or result from neurodegenerative diseases, the functional significance of sleep changes during the preclinical disease phase, and the potential role of sleep homeostasis as an adaptive mechanism enhancing resilience against cognitive decline and neurodegeneration.

PurposeTo examine the bidirectional relationships between sleep quality and cognitive function in older Chinese, and further examine the sex differences in the relationships using the random intercept cross-lagged panel model.DesignA secondary observational analysis of a physical activity clustered randomized controlled trial (The Stay Active While Aging).SettingEight villages in Sichuan, China.SubjectsA total of 511 adults aged 60 or older. The response rate was 97.3%.MeasuresThe Pittsburgh Sleep Quality Index was used to examine sleep quality. Cognitive function was assessed by the Telephone Interview for Cognitive Status.ResultsThe mean age was 71.0 (SD, 5.710) years and 227 (44.4%) were men. Sleep quality in the previous wave was associated with cognitive function in the subsequent wave (β = -0.135, [95%CI -0.244 to -0.026], wave 2 to 3; β = -0.108, [95%CI -0.204 to -0.013], wave 4 to 5). Cognitive function in the previous wave was associated with sleep quality in the subsequent wave (β = -0.404, [95%CI -0.566 to -0.242], wave 3 to 4; β = -0.224, [95%CI -0.392 to -0.055], wave 4 to 5). Such relationships were significant only in women.ConclusionsThere were bidirectional relationships between sleep quality and cognitive function in older adults, especially in women. Future cognition interventions may find it helpful to improve sleep quality, and vice versa, particularly in women.

We examine the relationship between sleep, glymphatics and Alzheimer's disease (AD), and recent work questioning glymphatic clearance during sleep. We highlight a need for understanding glymphatic and/or other mechanism of clearance during sleep, and review glymphatic flow measurement methods. Further, we explore dual orexin receptor antagonists (DORAs) potential to mitigate AD sleep disturbances and enhance clearance. Further research could elucidate a linkage between DORAs, improved sleep and reducing AD pathophysiology.

This study aims to explore the relationship between sleep duration and multimorbidity among elderly Chinese and to determine the optimal sleep duration for preventing multimorbidity.

This study is based on data from the 2020 China Health and Elderly Care Longitudinal Survey (CHARLS), which collected detailed information from 5,761elderly individuals, including demographic characteristics, sleep duration, health status, and lifestyle information. Logistic regression models were used to investigate the relationship between sleep duration and multimorbidity, and restricted cubic spline analysis was employed to analyze the dose-response relationship between sleep duration and multimorbidity.

After adjusting for potential confounders, a U-shaped association was found between nighttime sleep duration and the likelihood of multimorbidity among the elderly. Specifically, elderly individuals with a nighttime sleep duration of 7 h had the lowest incidence of multimorbidity. Compared to those with 6-8 h of nighttime sleep, elderly individuals with less than 6 h (OR = 1.24, 95% CI: 1.05-1.48) or more than 8 h (OR = 1.79, 95% CI: 1.37-2.34) of nighttime sleep had a 24% and 79% increased likelihood of multimorbidity, respectively. The restricted cubic spline analysis further confirmed this U-shaped relationship, showing that the likelihood of multimorbidity gradually decreased as sleep duration increased from 6 to 7 h, but gradually increased as sleep duration exceeded 7 h. Additionally, a positive correlation was found between napping habits and the likelihood of multimorbidity, with elderly individuals without napping habits having a lower likelihood of multimorbidity compared to those with napping habits. Subgroup analysis indicated no significant differences in the impact of 6-8 h of nighttime sleep on multimorbidity among male and female elderly individuals and different age groups.

Appropriate nighttime sleep duration may be an important factor in preventing multimorbidity among the elderly, while increased napping duration may increase the likelihood of multimorbidity. These findings provide scientific evidence for sleep health management among the elderly, suggesting the promotion of appropriate sleep duration to reduce the likelihood of multimorbidity in this population.

Sleep plays a role in the elimination of neurotoxic metabolites that are accumulated in the waking brain as a result of neuronal activity. Long-term insomnia and sleep deprivation are associated with oxidative stress, neuroinflammation, amyloid beta (Aβ) deposition, and Lewy body formation, which are known to increase the risk of mild cognitive impairment (MCI) and dementia. Orexin A (OXA) and orexin B (OXB), two neuropeptides produced in the lateral hypothalamus, are known to influence the sleep-wake cycle and the stress responses through their interactions with OX receptor 1 (OX1R) and OX receptor 2 (OX2R), respectively. OX/OXR cascade demonstrates intricate neuroprotective and anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-kB) and PLC/Ca2+ pathway activation. OX1R binds OXA more strongly than OXB by one-order ratio, whereas OX2R binds both OXA and OXB with equal strengths. Overexpression of OXs in individuals experiences sleep deprivation, circadian rhythm disturbances, insomnia-associated MCI, Parkinson's disease (PD), and Alzheimer's disease (AD). Many dual OXR antagonists (DORAs) have been effective in their clinical studies, with suvorexant and daridorexant receiving FDA clearance for insomnia therapy in 2014 and 2022 respectively. The results of clinical studies suggested that there is a new pharmaceutical option for treating insomnia and the sleep deprivation-AD/PD relationship by targeting the OXR system. DORAs treatment reduces Aβ deposition in the brain and improves synaptic plasticity and circadian expression. This review indicates the link between sleep disorders and MCI, DORAs are an appropriate medication category for treating insomnia, and sleep deprivation links AD and PD.

Although sleep disturbances are widely recognized as risk factors for cognitive decline and Alzheimer's disease (AD), their influence on AD biomarkers remains unclear. This study aimed to clarify whether sleep quality or sleep duration affect amyloid beta (Aβ) and tau levels in plasma, cerebrospinal fluid (CSF), and positron emission tomography (PET) in non-demented populations.

PubMed, Web of Science, and Embase were systematically searched up to February 2025.

In total, 30 studies were included comprising 14,997 subjects. Individuals with poor sleep quality exhibited greater PET Aβ burden and higher Aβ42 levels in plasma than those with good sleep quality. Shorter sleep duration was associated with higher Aβ burden on PET. However, no association between either sleep quality or sleep duration and tau levels was found.

Sleep may be a modifiable marker of early AD management by modulating Aβ levels.

lPoor sleep quality and shorter sleep duration were significantly associated with higher amyloid beta (Aβ) burden detected by positron emission tomography (PET) in non-demented populations. Poor sleep quality was also associated with elevated Aβ42 levels in plasma. lNo significant associations were found between sleep quality or sleep duration and tau levels in plasma, cerebrospinal fluid, or PET. lInterventions targeting sleep could serve as a viable and low-cost prevention strategy for early management of Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Sleep-wake disorders are an extremely predominant and often disabling aspect of AD. Ox is vital in maintaining the sleep-wake cycle and promoting wakefulness. Dysfunction of Ox signaling has been associated with sleep disorders such as narcolepsy. In AD patients, the increase in cerebrospinal fluid Ox levels is related to parallel sleep deterioration. The relationship between AD and sleep disturbances has gained increasing attention due to their potential bidirectional influence. Disruptions in sleep patterns are commonly observed in AD patients, leading researchers to investigate the possible involvement of Ox in sleep disturbances characteristic of the disease. This review article explores the role of the Ox system in AD, and the intricate relationship between AD and sleep, highlighting the potential mechanisms, impact on disease pathology, and therapeutic interventions to improve sleep quality in affected individuals.

Microglia, the brain's resident macrophages, are key mediators of neuroinflammation, responding to immune pathogens and toxins. They play a crucial role in clearing cellular debris, regulating synaptic plasticity, and phagocytosing amyloid-β (Aβ) plaques in Alzheimer's disease (AD). Recent studies indicate that microglia not only exhibit intrinsic circadian rhythms but are also regulated by circadian clock genes, influencing specific functions such as phagocytosis and the modulation of neuroinflammation. Disruption of the circadian rhythm is closely associated with AD pathology. In this review, we will provide an overview of how circadian rhythms regulate microglia-mediated neuroinflammation in the progression of AD, focusing on the pathway from the central nervous system (CNS) and the peripheral immune system. We also discuss potential therapeutic targets, including hormone modulation, lifestyle interventions, and anti-inflammatory therapies, aimed at maintaining brain health in AD. This will shed light on the involvement of circadian rhythm in AD and explore new avenues for AD treatment.

Essential hypertension (EH) with secondary insomnia is associated with increased risks of neuroinflammation, neuronal damage, and Alzheimer's disease (AD). However, its relationship with specific cerebrospinal fluid (CSF) biomarkers of neuronal damage and neuroinflammation remains unclear. This case-control study compared CSF biomarker levels across three groups: healthy controls (HC, n = 64), hypertension-controlled (HTN-C, n = 54), and hypertension-uncontrolled (HTN-U, n = 107) groups, all EH participants experiencing secondary insomnia. CSF samples from knee replacement patients were analyzed for key biomarkers, and sleep quality was assessed via the Pittsburgh Sleep Quality Index (PSQI). Our findings showed that the HTN-U group had significantly higher CSF levels of proinflammatory cytokines IL-6, TNF-α, and IL-17 than the HC and HTN-C groups (all p < 0.01). These cytokines correlated positively with secondary insomnia measures, with IL-6 (r = 0.285, p = 0.003), IL-17 (r = 0.324, p = 0.001), and TNF-α (r = 0.274, p = 0.005) linked to PSQI scores. In the HTN-U group, elevated IL-6, TNF-α, and IL-17 levels were also positively associated with neurofilament light (NF-L) and negatively with β-amyloid 42 (Aβ42), both key AD markers (all p < 0.05). Additionally, secondary insomnia was negatively correlated with Aβ42 (r = -0.225, p = 0.021) and positively with NF-L (r = 0.261, p = 0.007). Higher CSF palmitic acid (PA) levels observed in the HTN-U group were linked to poorer sleep quality (r = 0.208, p = 0.033). In conclusion, EH with secondary insomnia is associated with CSF biomarkers of neuronal damage, neuroinflammation, and neurodegeneration, suggesting a potential increase in AD risk among this population.

Brain clearance involves the drainage of waste molecules from the brain, a process that is suggested to be amplified during sleep. Recently proposed MRI-based methods attempt to approximate human brain clearance with surrogate measures. The current study aimed to explore whether two brain clearance surrogates are altered in narcolepsy. We processed diffusion-weighted and functional resting-state images to extract two surrogates: Diffusion Tensor Imaging Along the Perivascular Space (DTI-ALPS index), and dBOLD-CSF coupling. Both measures were analysed in 12 drug-free, awake people with narcolepsy type 1 and 11 age- and sex-matched controls, as well as in relation to clinical features. We also assessed the correlation between the DTI-ALPS index and dBOLD-CSF coupling. The DTI-ALPS index and dBOLD-CSF coupling amplitude did not show significant differences between narcolepsy and controls, nor significant relations with the severity of excessive daytime sleepiness. We found a significant correlation between dBOLD-CSF coupling and sleep efficiency, as well as a significant correlation between the DTI-ALPS index and dBOLD-CSF coupling. The hypothesis of altered brain clearance in narcolepsy type 1 is not supported by evidence from the current study. The two surrogates correlated with each other, suggesting that both offer different perspectives from the same underlying physiology. Yet, the suitability of the surrogates as brain clearance markers remains debatable. Whereas DTI is not exclusively sensitive to perivascular fluid, dBOLD-CSF coupling is reflecting large-scale CSF motion. Future work should explore other surrogate markers, preferably during sleep, to better understand the possible role of altered brain clearance in narcolepsy type 1 symptomatology.

Cerebrospinal fluid (CSF) orexin-A has been suggested to be a biomarker of Alzheimer disease (AD). In both cognitively unimpaired healthy older adults and individuals with symptomatic AD, CSF orexin-A is positively associated with CSF Aβ42, p-tau181, and total tau (t-tau) concentrations. However, a recent systematic review and meta-analysis did not support differences in orexin-A between AD and controls. In this study, we tested the association between CSF orexin-A concentrations, AD biomarkers, and cognitive performance in older adults with and without symptomatic AD.

Two hundred and seventy community-dwelling older adults underwent standardized cognitive assessments, sleep monitoring with a single-channel electroencephalography test, one night of home sleep apnea testing, biofluid and imaging AD biomarker measurement within 1 year of sleep monitoring, and APOE genotyping. Plasma and CSF AD biomarkers were measured by immunoassay or mass spectrometry. CSF orexin-A was measured by radioimmunoassay.

CSF orexin-A levels did not differ by amyloid positivity, cognitive status, or AD stage. However, CSF AD biomarkers (Aβ40, Aβ42, and t-tau) were positively associated with CSF orexin-A levels even after correction for multiple comparisons. CSF orexin-A was not associated with any measure of cognitive performance.

This study showed that CSF orexin-A is associated with multiple CSF AD biomarkers, but not with AD pathology or cognitive performance. We hypothesize that this is due to similar mechanisms of production/release of these proteins with sleep-wake activity. Future studies measuring other forms of orexin peptides, such as orexin-B, may provide evidence for orexin as a marker for AD.

By exposing genes associated with disease, genomic studies provide hundreds of starting points that should lead to druggable processes. However, our ability to systematically translate these genomic findings into biological pathways remains limited. Here, we combine rapid loss-of-function mutagenesis of Alzheimer's risk genes and behavioural pharmacology in zebrafish to predict disrupted processes and candidate therapeutics. FramebyFrame, our expanded package for the analysis of larval behaviours, revealed that decreased night-time sleep was common to F0 knockouts of all four late-onset Alzheimer's risk genes tested. We developed an online tool, ZOLTAR, which compares any behavioural fingerprint to a library of fingerprints from larvae treated with 3677 compounds. ZOLTAR successfully predicted that sorl1 mutants have disrupted serotonin signalling and identified betamethasone as a drug which normalises the excessive day-time sleep of presenilin-2 knockout larvae with minimal side effects. Predictive behavioural pharmacology offers a general framework to rapidly link disease-associated genes to druggable pathways.

Sleep is a crucial lifestyle factor with impacts on mental and cognitive health. The associations between objectively measured sleep and risk of incident dementia are not yet fully understood. To evaluate the associations of device-measured sleep duration and regularity with incident dementia and explore whether sleep regularity moderates the association of sleep duration with dementia.

Population-based prospective cohort study of 82,391 adults aged 43 to 79 years from the UK Biobank accelerometry subsample, collected between 2013 and 2015, followed up to 2022. Device-based sleep duration (h/day) and sleep regularity index (SRI), a metric ranging from 0-100 that quantifies a person's sleep regularity (with a greater value indicating higher consistency), were calculated from wrist-worn accelerometry data recorded over the course of one week. Incident all-cause dementia cases were obtained from national hospital admission, primary care and mortality data followed up to 30 November 2022. We used Cox proportional hazard models to estimate the hazard ratios (HRs) for incident dementia after adjustment for common demographic and clinical covariates.

Over a mean follow-up of 7.9 years, 694 incident dementia cases occurred. We observed a U-shaped association between sleep duration and incident dementia, with only short sleep (< 7 h) being significantly associated with a higher risk of dementia. The median sleep duration for short sleepers (< 7 h) of 6.5 h, compared to the reference point of 7.9 h was associated with HR of 1.19 (95%CI 1.01,1.40) for incident dementia. Sleep regularity was negatively associated with dementia risk in a near-linear fashion (linear p = 0.01, non-linear p = 0.57). When we dichotomized sleep regularity, those in the higher sleep regularity group (SRI ≥ 70) had an HR of 0.74 (95%CI 0.63, 0.87) compared to those with lower sleep regularity (SRI < 70). The beneficial associations between sleep regularity and incident dementia were present only among participants with short (< 7 h) and long (≥ 8 h) sleep duration.

Assuming that the associations we observed are causal, maintaining a regular sleep pattern may help offset the deleterious association of inadequate sleep duration with dementia. Interventions aimed at improving sleep regularity may be a viable option for people not able to achieve the recommended hours of sleep.

Sleep is a stereotyped and well-preserved series of neurophysiological states that are essential for overall health and brain functioning. Emerging research suggests that sleep disturbances are not only associated with but also causally contribute to neurodegenerative disease onset and progression. This mini-review examines some of the current knowledge and evidence for relationships between sleep abnormalities and Alzheimer's disease within context of possible uses and limitations of sleep biomarkers for evaluation of Alzheimer's disease. Understanding these relationships could lead to readily accessible and easily quantifiable biomarkers of Alzheimer's dementia.

Sleep disturbances are common in Alzheimer's disease (AD) and AD-related dementia (ADRD). We performed a sleep study on Tg-SwDI mice, a cerebral amyloid angiopathy (CAA) model, and age-matched wild-type (WT) control mice. The results showed that at 12 months of age, the hemizygous Tg-SwDI mice spent significantly more time in non-rapid eye movement (NREM) sleep (44.6 ± 2.4% in Tg-SwDI versus 35.9 ± 2.5% in WT) and had a much shorter average length of wake bout during the dark (active) phase (148.5 ± 8.7 s in the Tg-SwDI versus 203.6 ± 13.0 s in WT). Histological analysis revealed stark decreases of orexin immunoreactive (orexin-IR) neuron number and soma size in these Tg-SwDI mice (cell number: 2187 ± 97.1 in Tg-SwDI versus 3318 ± 137.9 in WT. soma size: 109.1 ± 8.1 μm2 in Tg-SwDI versus 160.4 ± 6.6 μm2 in WT), while the number and size of melanin-concentrating hormone (MCH) immunoreactive (MCH-IR) neurons remained unchanged (cell number: 4256 ± 273.3 in Tg-SwDI versus 4494 ± 326.8 in WT. soma size: 220.1 ± 13.6 μm2 in Tg-SwDI versus 202.0 ± 7.8 μm2 in WT). The apoptotic cell death marker cleaved caspase-3 immunoreactive (Caspase-3-IR) percentage in orexin-IR neurons was significantly higher in Tg-SwDI mice than in WT controls. This selective loss of orexin-IR neurons could be associated with the abnormal sleep phenotype in these Tg-SwDI mice. Further studies are needed to determine the cause of the selective death of orexin-IR cells and relevant effects on cognition impairments in this mouse model of microvascular amyloidosis.

Sleep disturbances lead to negative health outcomes and caregiver burden, particularly in community settings. This study aimed to investigate a predictive model for sleep efficiency and its associated features in older adults living with dementia in their own homes.

This was an exploratory, observational study. A total of 69 older adults diagnosed with dementia were included in this study. Data were collected via actigraphy for sleep and physical activity for 14 days, a sweat patch for cytokines for 2-3 days, and a survey of diseases, medications, psychological and behavioral symptoms, functional status, and demographics at baseline. Using 730 days of actigraphy, sweat patches, and baseline data, the best prediction model for sleep efficiency was selected and further investigated to explore its associated top 10 features using machine learning analysis.

The CatBoost model was selected as the best predictive model for sleep efficiency. In order of importance, the most important features were sleep regularity, number of medications, dementia medication, daytime activity count, instrumental activities of daily living, neuropsychiatric inventory, hypnotics, occupation, tumor necrosis factor-alpha, and waking hour lux.

This study established the best sleep efficiency predictive model among community-dwelling older adults with dementia and its associated features using machine learning and various sources, such as the Internet of Things. This study highlights the importance of individualized sleep interventions for community-dwelling older adults with dementia based on associated features.

Lee JY, Yang E, Cho AY, Choi Y, Lee S, Lee KH. Sleep efficiency in community-dwelling persons living with dementia: exploratory analysis using machine learning. J Clin Sleep Med. 2025;21(2):393-400.

Memory impairment is a frequent and debilitating symptom in neurodegenerative disorders. The objective of this study was to provide proof-of-principle that deep brain stimulation during sleep can modify memory consolidation in people with Parkinson's disease depending on the stimulation frequency that is applied.

Twenty-four patients with Parkinson's disease who were treated with deep brain stimulation of the subthalamic nucleus were included in this single-blind pilot study. Six patients had to be excluded because of insomnia on the night of testing. Patients were randomized (1:1 ratio) to receiving either low frequency deep brain stimulation (4 Hz) or clinically used high frequency deep brain stimulation (130 Hz) during early non-rapid eye movement (NREM) sleep. The main outcome measure was overnight memory retention as measured by a validated declarative memory task.

Patients receiving low frequency deep brain stimulation during early NREM sleep (n = 9, 4 females, mean age 61.1 ± 4.3 years) showed improved overnight memory retention (z = 2.549, P = 0.011). Patients receiving clinically used high frequency deep brain stimulation (n = 9, 2 females, mean age 62.2 ± 7.1) did not show any improvement (z = 1.023, P = 0.306) leading to a significant difference between groups (z = 2.214, P = 0.027). Stronger improvement in memory function was correlated with increased cortical low frequency activity after low frequency deep brain stimulation as measured by electroencephalography (ρ = 0.711, P = 0.037).

These results provide proof-of-principle that memory can be modulated by frequency-specific deep brain stimulation during sleep. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Alzheimer's disease (AD), the leading cause of dementia, is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. This condition casts a significant shadow on global health due to its complex and multifactorial nature. In addition to genetic predispositions, the development of AD is influenced by a myriad of risk factors, including aging, systemic inflammation, chronic health conditions, lifestyle, and environmental exposures. Recent advancements in understanding the complex pathophysiology of AD are paving the way for enhanced diagnostic techniques, improved risk assessment, and potentially effective prevention strategies. These discoveries are crucial in the quest to unravel the complexities of AD, offering a beacon of hope for improved management and treatment options for the millions affected by this debilitating disease.

Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, its protective mechanism on the central nervous system (CNS) is not clear.

The present study initially evaluated the possible mechanism of PNS to improve cognitive dysfunction due to chronic sleep deprivation (CSD).

In the present study, we used a modified multi-platform aquatic environment sleep deprivation method to induce a cognitively impaired rat model, and explored the mechanism of action of PNS by integrating serum metabolomics and network pharmacology, which was further verified by molecular docking and experiments.

The results showed that PNS significantly shortened the escape latency, increased the target quadrant time and the number of traversing platforms, and attenuated the inflammatory damage in the hippocampal Cornu Ammonis 1 (CA1) region in CSD rats. The non-targeted metabolomics results indicated that 35 biomarkers significantly altered following PNS therapy intervention, with metabolic pathways enriched for the effects of One carbon pool by folate, Riboflavin metabolism, Glycerophospholipid metabolism, Sphingolipid metabolism, Glycerolipid metabolism, Arachidonic acid metabolism, and Tryptophan metabolism. In addition, network pharmacology identified 234 potential targets for PNS intervention in CSD with cognitive impairment. Metabolite-response-enzyme-gene network was constructed by MetaScape and matched with the network pharmacology results to identify a total of five shared targets (LPL, GPAM, HSD11B1, HSD11B2, and SULT2A1) and two metabolic pathways (Sphingolipid metabolism and Steroid hormone biosynthesis). The results of molecular docking revealed that the five active ingredients had good binding ability with the five core targets. qPCR analysis confirmed the ability of PNS to modulate the above five targets.

The combination of metabolomics and network analysis provides a scientific basis for promoting the clinical application of PNS in cognitive impairment.

Cerebrospinal fluid (CSF) dynamics, driven by sensory stimulation-induced neuronal activity, is crucial for maintaining homeostasis and clearing metabolic waste. However, it remains unclear whether such CSF flow is impaired in age-related neurodegenerative diseases of the visual system. This study addresses this gap by examining CSF flow during visual stimulation in glaucoma patients and healthy older adults using functional magnetic resonance imaging. The findings reveal that in glaucoma, CSF inflow becomes decoupled from visually evoked blood-oxygenation-level-dependent (BOLD) response. Furthermore, stimulus-locked CSF patterns, characterized by decreases following stimulus onset and increases after offset, diminish as glaucoma severity worsens. Mediation analysis suggests that this flattened CSF pattern is driven by a flatter BOLD slope, resulting in a shallower CSF trough and a reduced rebound. These findings unveil a novel pathophysiological mechanism underlying disrupted stimulation-driven CSF dynamics in glaucoma and highlight potential in vivo biomarkers for monitoring CSF in the glaucomatous brain.

Improving sleep in murine Alzheimer's disease (AD) is associated with reduced brain amyloidosis. However, the window of opportunity for successful sleep-targeted interventions, regarding the reduction in pathological hallmarks and related cognitive performance, remains poorly characterized.

Here, we enhanced slow-wave activity (SWA) during sleep via sodium oxybate (SO) oral administration for 2 weeks at early (6 months old) or moderately late (11 months old) disease stages in Tg2576 mice and evaluated resulting neuropathology and behavioral performance.

We observed that the cognitive performance of 6-month-old Tg2576 mice significantly improved upon SO treatment, whereas no change was observed in 11-month-old mice. Histochemical assessment of amyloid plaques demonstrated that SO-treated 11-month-old Tg2576 mice had significantly less plaque burden than placebo-treated ones, whereas ELISA of insoluble protein fractions from brains of 6-month-old Tg2576 mice indicated lower Aβ-42/Aβ-40 ratio in SO-treated group vs. placebo-treated controls.

Altogether, our results suggest that SWA-dependent reduction in brain amyloidosis leads to alleviated behavioral impairment in Tg2576 mice only if administered early in the disease course, potentially highlighting the key importance of early sleep-based interventions in clinical cohorts.

Cerebral amyloid angiopathy (CAA) is a neurological disorder in the elderly, involving the deposition of vascular amyloid-β (Aβ). Sleep deprivation (SD) causes memory deficits during CAA. Lysine specific demethylase 6B (KDM6B) is a histone H3 lysine 27-specific demethylase associated with neuronal injury and inflammation. However, the role of KDM6B in CAA has yet to be studied. In the current study, the multi-platform over-water method was used to induce chronic SD in APP/PS1 mice. Pathological analysis revealed that SD exacerbated vascular lesions in this model, as manifested by extensive formation of Aβ-positive deposits. In addition, SD led to a significant increase in the expression of KDM6B in the cerebral cortex of APP/PS1 mice. Next, the effect of KDM6B on CAA progression was explored through loss of function. Further experiments illustrated that KDM6B knockdown diminished SD-induced memory impairment, neuronal injury and vascular lesions in vivo. Additionally, isolated primary cortical neurons were treated with 10 µM Aβ1-42 for 48 h to induce the cell model. As expected, knockdown of KDM6B inhibited the Aβ1-42-induced cytotoxicity in primary neurons. Mechanistically, our results demonstrated that KDM6B knockdown downregulated poly (ADP-ribose) polymerase16 (PARP16) expression by increasing trimethylated lysine 27 on histone 3 (H3K27me3) levels, indicating that KDM6B epigenetically regulated PARP16 expression. Function recovery experiment results further proved that PARP16 overexpression negated the effect of KDM6B knockdown on Aβ1-42-induced cytotoxicity. Overall, our findings uncover an unanticipated role of KDM6B in CAA, and KDM6B may serve as a potential therapeutic target for CAA. Abbreviations: CAA, cerebral amyloid angiopathy; Aβ, amyloid-β; SD, sleep deprivation; KDM6B, lysine specific demethylase 6B; AD, Alzheimer's disease; H3K27me3, trimethylated lysine 27 on histone 3; PARP16, poly (ADP-ribose) polymerase16; AAV2, adeno-associated virus 2; CHIP, chromatin immunoprecipitation; ANOVA, one-way analysis of variance.

In the context of the escalating global health challenge posed by Alzheimer's disease (AD), this comprehensive review considers the potential of melatonin in both preventive and therapeutic capacities. As a naturally occurring hormone and robust antioxidant, accumulating evidence suggests melatonin is a compelling candidate to consider in the context of AD-related pathologies. The review considers several mechanisms, including potential effects on amyloid-beta and pathologic tau burden, antioxidant defense, immune modulation, and regulation of circadian rhythms. Despite its promise, several gaps need to be addressed prior to clinical translation. These include conducting additional randomized clinical trials in patients with or at risk for AD dementia, determining optimal dosage and timing, and further determining potential side effects, particularly of long-term use. This review consolidates existing knowledge, identifies gaps, and suggests directions for future research to better understand the potential of melatonin for neuroprotection and disease mitigation within the landscape of AD.

Obstructive sleep apnea syndrome (OSAS) significantly affects the sleep-wake circadian rhythm through intermittent hypoxia and chronic sleep fragmentation. OSAS patients often experience excessive daytime sleepiness, frequent awakenings, and sleep fragmentation, leading to a disrupted circadian rhythm and altered sleep-wake cycle. These disruptions may exacerbate OSAS symptoms and contribute to neurodegenerative processes, particularly through the modulation of clock gene expression such as CLOCK, BMAL1, and PER. Emerging evidence connects OSAS to cognitive impairment and suggests that these changes may contribute to the development of neurodegenerative disorders such as Alzheimer disease, suggesting that OSAS could be a reversible risk factor for these conditions. Biomarkers, including melatonin and orexin, play crucial roles in understanding these mechanisms. In OSAS patients, melatonin, a marker of circadian rhythmicity, often shows altered secretion patterns that are not fully corrected by continuous positive airway pressure therapy. Orexin, which regulates the sleep-wake cycle, exhibits increased cerebrospinal fluid levels in OSAS patients, possibly due to compensatory mechanisms against sleep impairment and daytime sleepiness. These biomarkers highlight the intricate relationship between circadian rhythm disruptions and neurodegenerative risks in OSAS, emphasizing the need for further research and potential therapeutic strategies to mitigate these effects and improve patient outcomes.

Advanced sleep phase (ASP) is seldom brought to medical attention because many individuals easily adapt to their early chronotype, especially if it emerges before the age of 30 and is present in a first-degree relative. In this case, the disorder is considered familial (FASP) and is mostly discovered coincidentally in the presence of other sleep disorders, mainly obstructive sleep apnea syndrome (OSAS). The prevalence of FASP is currently estimated to be between 0.21% and 0.5%. Autosomal dominant mutations in circadian clock genes like PER2, CK1, PER3, CRY2, TIMELESS, and DEC2 have been linked to FASP, some with pleiotropic effects influencing other health aspects like migraine and depression. Early morning awakening is, instead, more common among older individuals, occurring in almost 4% of cases, without considering associated comorbidities. Advanced sleep-wake phase disorder (ASWPD) is characterized by a consistent and distressing anticipation of sleep-wake timing, affecting almost 1% of middle-aged individuals. On average, women have a shorter circadian period than men, making them more susceptible to ASWPD, albeit no significant gender discrepancies have been observed. Age-related alterations in circadian rhythms are exacerbated and compounded by neurodegenerative disorders, impacting the suprachiasmatic nucleus (SCN), sensitivity to light, and light responsiveness in those affected. Conflicting data has surfaced regarding the protective or detrimental effects of ASWPD in studies on aging, mild cognitive impairment (MCI), and diverse dementia conditions.

The interaction between Alzheimer's disease (AD) and sleep deprivation has recently gained attention in the scientific literature, and recent advances suggest that AD epidemiology management should coincide with the management of sleeping disorders. This review focuses on the aspects of the mechanisms underlying the link between AD and insufficient sleep with progressing age. We also provide information which could serve as evidence for future treatments of AD from the early stages in connection with sleep disorder medication.

Circadian rhythms are intrinsic, 24 h cycles that regulate key physiological, mental, and behavioral processes, including sleep-wake cycles, hormone secretion, and metabolism. These rhythms are controlled by the brain's suprachiasmatic nucleus, which synchronizes with environmental signals, such as light and temperature, and consequently maintains alignment with the day-night cycle. Molecular feedback loops, driven by core circadian "clock genes", such as Clock, Bmal1, Per, and Cry, are essential for rhythmic gene expression; disruptions in these feedback loops are associated with various health issues. Dysregulated lipid metabolism in the brain has been implicated in the pathogenesis of neurological disorders by contributing to oxidative stress, neuroinflammation, and synaptic dysfunction, as observed in conditions such as Alzheimer's and Parkinson's diseases. Disruptions in circadian gene expression have been shown to perturb lipid regulatory mechanisms in the brain, thereby triggering neuroinflammatory responses and oxidative damage. This review synthesizes current insights into the interconnections between circadian rhythms and lipid metabolism, with a focus on their roles in neurological health and disease. It further examines how the desynchronization of circadian genes affects lipid metabolism and explores the potential mechanisms through which disrupted circadian signaling might contribute to the pathophysiology of neurodegenerative disorders.

There is growing evidence that sleep disturbances are associated with cognitive impairment risk, but their association with the incidence of motoric cognitive risk syndrome (MCR)-a predementia syndrome characterized by slow gait speed and cognitive complaints-is unknown. We aimed to examine the association of sleep disturbances, overall and specific subtypes, with (1) incident and (2) prevalent MCR in older adults.

Community-residing adults aged 65 years and older without dementia were recruited from population lists and included in Central Control of Mobility and Aging, a prospective cohort study, in Albert Einstein College of Medicine, Bronx, NY. We included participants with available data for MCR and Pittsburgh Sleep Quality Index (PSQI). MCR was defined as cognitive complaints reported on standardized questionnaires and slow gait speed as recorded on an electronic treadmill and was adjudicated at baseline and annual follow-up visits. Participants were divided into "good" sleepers (≤5) and "poor" sleepers (>5) based on an established PSQI cut score. Among participants without MCR at baseline, Cox proportional hazard models adjusted for (1) age, sex, and education and (2) further for comorbidity index, Geriatric Depression Scale score, and global cognitive score were used to examine the association of baseline sleep disturbances with MCR incidence. Association between poor sleep quality and prevalent MCR at baseline in the overall population was explored using multivariate logistic regression analysis.

445 participants were included (56.9% women, mean age: 75.9 years [75.3; 76.5]). In MCR-free participants at baseline (n = 403), 36 developed incident MCR over a mean follow-up of 2.9 years. Poor sleepers had a higher risk of incident MCR (HR = 2.7 [1.2; 5.2]) compared with good sleepers, but this association was not significant after adjustment for depressive symptoms (adjusted hazard ratio [aHR] = 1.6 [0.7-3.4]). Among the 7 PSQI components, only sleep-related daytime dysfunction (excessive sleepiness and lower enthusiasm) showed a significant risk of MCR in fully adjusted models (aHR = 3.3 [1.5-7.4]). Prevalent MCR was not associated with poor sleep quality (OR [95% CI] = 1.1 [0.5-2.3]).

Overall poor sleep quality was associated with incident MCR, but not with prevalent MCR. Specifically, older adults with sleep-related daytime dysfunction are at increased risk of developing MCR. Further studies are needed to validate mechanisms of this relationship.