BACKGROUND: Tight relationships between sleep quality, cognition, and amyloid-β (Aβ) accumulation, a hallmark of Alzheimer’s disease (AD) neuropathology, have been shown. Sleep arousals become more prevalent with aging and are considered to reflect poorer sleep quality. However, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established. METHODS: We recorded undisturbed night-time sleep with EEG in 101 healthy individuals aged 50–70 years, devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M–) and sleep stage transition (T+/T–). We assessed cortical Aβ burden over earliest affected regions via PET imaging and assessed cognition via neuropsychological testing. RESULTS: Arousal types differed in their oscillatory composition in θ (4–8 Hz) and β (16–30 Hz) EEG bands. Furthermore, T+M– arousals, interrupting sleep continuity, were positively linked to Aβ burden ( P = 0.0053, R² _β * = 0.08). By contrast, more prevalent T–M+ arousals, upholding sleep continuity, were associated with lower Aβ burden ( P = 0.0003, R² _β * = 0.13), and better cognition, particularly over the attentional domain ( P < 0.05, R² _β * ≥ 0.04). CONCLUSION: Contrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep and constitute markers of favorable brain and cognitive health trajectories. TRIAL REGISTRATION: EudraCT 2016-001436-35. FUNDING: FRS-FNRS Belgium (FRSM 3.4516.11), Actions de Recherche Concertées Fédération Wallonie-Bruxelles (SLEEPDEM 17/27-09), ULiège, and European Regional Development Fund (Radiomed Project).

BACKGROUND: The locus coeruleus (LC) is the primary source of norepinephrine in the brain and regulates arousal and sleep. Animal research shows that it plays important roles in the transition between sleep and wakefulness, and between slow wave sleep and rapid eye movement sleep (REMS). It is unclear, however, whether the activity of the LC predicts sleep variability in humans. METHODS: We used 7-Tesla functional MRI, sleep electroencephalography (EEG), and a sleep questionnaire to test whether the LC activity during wakefulness was associated with sleep quality in 33 healthy younger (~22 years old; 28 women, 5 men) and 19 older (~61 years old; 14 women, 5 men) individuals. RESULTS: We found that, in older but not in younger participants, higher LC activity, as probed during an auditory attentional task, was associated with worse subjective sleep quality and with lower power over the EEG theta band during REMS. The results remained robust even when accounting for the age-related changes in the integrity of the LC. CONCLUSION: These findings suggest that LC activity correlates with the perception of the sleep quality and an essential oscillatory mode of REMS, and we found that the LC may be an important target in the treatment of sleep- and age-related diseases. FUNDING: This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, T.0242.19 & J. 0222.20), Action de Recherche Concertée – Fédération Wallonie-Bruxelles (ARC SLEEPDEM 17/27-09), Fondation Recherche Alzheimer (SAO-FRA 2019/0025), ULiège, and European Regional Development Fund (Radiomed & Biomed-Hub).

Arousals during sleep are transient accelerations of the EEG signal, considered to reflect sleep perturbations associated with poorer sleep quality. They are typically detected by visual inspection, which is time consuming, subjective, and prevents good comparability across scorers, studies and research centres. We developed a fully automatic algorithm which aims at detecting artefact and arousal events in whole-night EEG recordings, based on time-frequency analysis with adapted thresholds derived from individual data. We ran an automated detection of arousals over 35 sleep EEG recordings in healthy young and older individuals and compared it against human visual detection from two research centres with the aim to evaluate the algorithm performance. Comparison across human scorers revealed a high variability in the number of detected arousals, which was always lower than the number detected automatically. Despite indexing more events, automatic detection showed high agreement with human detection as reflected by its correlation with human raters and very good Cohen’s kappa values. Finally, the sex of participants and sleep stage did not influence performance, while age may impact automatic detection, depending on the human rater considered as gold standard. We propose our freely available algorithm as a reliable and time-sparing alternative to visual detection of arousals.

Modern lifestyle curtails sleep and increases nighttime work and leisure activities. This has a deleterious impact on vigilance and attention, exacerbating chances of committing attentional lapses, with potential dramatic outcomes. A full characterization of the brain mechanisms associated with lapses is still lacking. Here, we investigated the brain signature of attentional lapses and assessed whether cortical excitability and brain response propagation were modified during lapses and whether these modifications changed with aging. We compared electroencephalogram (EEG) responses to transcranial magnetic stimulation (TMS) during lapse and no-lapse periods while performing a continuous attentional/vigilance task at night, after usual bedtime. Data were collected in healthy younger (N=12; 18-30 y) and older individuals (N=12; 50-70 y) of both sexes. Amplitude and slope of the first component of the TMS-Evoked Potential (TEP) and Response Scattering (ReSc) were used to assess cortical excitability and brain response propagation, respectively. In line with our predictions, TEP during lapses was characterized by larger amplitude and slope. We further found that ReSc over the cortical surface was lower during lapses. Importantly, cortical excitability increase and response propagation decrease during lapse did not significantly differ between age groups. These results demonstrate that attentional lapses are associated with transient increase of excitability, and decrease in response propagation and effective connectivity. This pattern is similar to what is observed during sleep, suggesting that lapses reflect a sleep-like phenomenon. These findings could contribute to develop models aimed to predicting and preventing lapses in real life situations. Highlights: Cortical excitability increases during attentional lapses Brain response propagation is reduced during attentional lapses Aging does not affect the differences between normal attention and lapse periods Lapses characteristics resemble previous reports made during sleep

Study Objectives: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer’s disease. Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset. Methods: We computed whole-genome Polygenic Risk Scores (PRS) for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation and extended sleep opportunity, in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. Results: AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with large slow wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness. Conclusions: These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD. Statement of Significance: We show that the genetic liability for developing for Alzheimer’s disease (AD), as grasped over the entire genome using polygenic risk scores (PRS), is associated with sleep intensity and daytime sleepiness in healthy individuals devoid of sleep disorders and aged < 30 y, i.e. 30 to 60 years before typical onset of AD cognitive symptoms. Sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative. The findings reinforce the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD.

INTRODUCTION – Arousal during sleep are transient shifts in EEG frequency lasting at least 3 seconds that are thought to reflect poorer sleep quality. Their impact on brain function and brain structure is however not established. In addition, accumulating evidence support a strong link between sleep-wake dysfunction and the pathogenesis of Alzheimer’s disease (AD), including the abnormal accumulation of amyloid-β (Aβ) and tau protein in the brain. Here we investigated whether arousals during sleep are associated with Aβ and Tau burden in healthy aging. METHODS – Fifty-four healthy and cognitively normal older individuals (aged 51-69; mean 59 ± 5; 36 females) were tested in this study. We recorded their night time sleep in the laboratory under EEG and assessed Aβ and tau protein burden during two Positron Emission Tomography (PET) scans, respectively with 18F-flutemetamol and 18F-THK 5351 radiotracers. Automatic sleep stage scoring and arousal detection was computed on all EEG recordings. RESULTS – Generalized linear mixed models analyses revealed that the number of arousals with a concomitant increase in EMG tone was significantly associated with whole-brain tau burden (p = .009), but not with whole-brain Aβ burden (p = .30), even when correcting for age, sex, education and total sleep time. Further analyses showed that sleep macrostructure parameters such as sleep onset latency, wake after sleep onset, sleep efficiency were not significantly associated to whole-brain F18-THK 5351 or F18-flutemetamol intake values. CONCLUSION – These findings suggest that arousals during sleep are strongly linked to whole-brain AD pathophysiology, namely the accumulation of tau, but not Aβ. These results cast new light on the association between sleep and AD pathophysiology.