Cortical excitability depends on sleep-wake regulation, is central to cognition and hasbeen implicated in age-related cognitive decline. The dynamics of cortical excitability during prolonged wakefulness in aging are unknown, however. Here, we repeatedly probed cortical excitability of the frontal cortex using transcranial magnetic stimulation and electroencephalography in thirteen young and twelve older healthy participants during sleep deprivation. While overall cortical excitability did not differ between age groups, the magnitude of cortical excitability variations during prolonged wakefulness was dampened in older individuals. This age-related dampening was associated with mitigated neurobehavioural consequences of sleep loss on executive functions. Furthermore, higher cortical excitability was potentially associated with better and lower executive performance, respectively in older and younger adults. The dampening of cortical excitability dynamics found in older participants likely arises from a reduced impact of sleep homeostasis and circadian processes. It may reflect reduced brain adaptability underlying reduced cognitive flexibility in aging. Future research should confirm preliminary associations between cortical excitability and behaviour, and address whether maintaining cortical excitability dynamics can counteract agerelated cognitive decline.

While efficient treatments for Alzheimer's disease (AD) remain elusive, a growing body of research has highlighted sleep-wake regulation as a potential modifiable factor to delay disease progression. Evidence accumulated in recent years is pointing toward a tight link between sleep-wake disruption and the three main hallmarks of the pathogenesis of AD, i.e. abnormal amyloid-beta (Aβ) and tau proteins accumulation, and neurodegeneration. However, all three hallmarks are rarely considered together in the same study. In this review, we gather and discuss findings in favor of an association between sleep-wake disruption and each AD hallmarks in animal models and in humans, with a focus on the preclinical stages of the disease. We emphasize that these relationships are likely bidirectional for each of these hallmarks. Altogether, current findings provide strong support for considering sleep-wake disruption as a true risk factor in the early unfolding of AD, but more research integrating recent technical advances is needed, particularly with respect to tau protein and neurodegeneration. Interventional longitudinal studies among cognitively healthy older individuals should assess the practical use of improving sleep-wake regulation to slow down the progression of AD pathogenesis.

Sleep alteration is a hallmark of ageing and emerges as a risk factor for Alzheimer's disease (AD). While the fine-tuned coalescence of sleep microstructure elements may influence age-related cognitive trajectories, its association with AD processes is not fully established. Here, we investigated whether the coupling of spindles and slow waves is associated with early amyloid-beta (Aβ) brain burden, a hallmark of AD neuropathology, and cognitive change over 2 years in 100 healthy individuals in late-midlife (50-70y; 68 women). We found that, in contrast to other sleep metrics, earlier occurrence of spindles on slow-depolarisation slow waves is associated with higher medial prefrontal cortex Aβ burden (p=0.014, r²β*=0.06), and is predictive of greater longitudinal memory decline in a large subsample (p=0.032, r²β*=0.07, N=66). These findings unravel early links between sleep, AD-related processes and cognition and suggest that altered coupling of sleep microstructure elements, key to its mnesic function, contributes to poorer brain and cognitive trajectories in ageing.

We investigated whether cognitive fitness in late midlife is associated with physiological and psychological factors linked to increased risk of age-related cognitive decline. Eighty-one healthy late middle-aged participants (mean age: 59.4 y; range: 50-69 y) were included. Cognitive fitness consisted of a composite score known to be sensitive to early subtle cognitive change. Lifestyle factors (referenced below as cognitive reserve factors; CRF) and affective state were determined through questionnaires, and sleep-wake quality was also assessed through actimetry. Allostatic load (AL) was determined through a large range of objective health measures. Generalized linear mixed models, controlling for sex and age, revealed that higher cognitive reserve and lower allostatic load are related to better cognitive efficiency. Crystallized intelligence, sympathetic nervous system functioning and lipid metabolism were the only sub-fields of CRF and AL to be significantly associated with cognition. These results show that previous lifestyle characteristics and current physiological status are simultaneously explaining variability in cognitive abilities in late midlife. Results further encourage early multimodal prevention programs acting on both of these modifiable factors to preserve cognition during the aging process.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful col-How to cite this article: Tahmasian M, Aleman A, Andreassen OA, et al. ENIGMA-Sleep: Challenges, opportunities, and the road map.

Age-related cognitive decline arises from alterations in brain structure as well as in sleep-wake regulation. Here, we investigated whether preserved wake-dependent regulation of cortical function could represent a positive factor for cognitive fitness in aging. We quantified cortical excitability dynamics during prolonged wakefulness as a sensitive marker of age-related alteration in sleep-wake regulation in 60 healthy older individuals (50–69 y; 42 women). Brain structural integrity was assessed with amyloid-beta- and tau-PET, and with MRI. Participants’ cognition was investigated using an extensive neuropsychological task battery. We show that individuals with preserved wake-dependent cortical excitability dynamics exhibit better cognitive performance, particularly in the executive domain which is essential to successful cognitive aging. Critically, this association remained significant after accounting for brain structural integrity measures. Preserved dynamics of basic brain function during wakefulness could therefore be essential to cognitive fitness in aging, independently from age-related brain structural modifications that can ultimately lead to dementia.

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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).