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.

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.

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.

1Age-related cognitive decline is rooted in alterations in brain integrity as well as in sleep-wake 2 regulation. Here, we investigated whether preserved sleep-wake regulation of cortical function 3 during wakefulness could represent a positive factor for cognitive fitness in aging, independently 4 of early age-related alterations in brain structure associated with Alzheimer's disease 5 neuropathology. We quantified slow waves generation during sleep and cortical excitability 6 dynamics during prolonged wakefulness as sensitive markers of age-related alteration in sleep-7 wake regulation in 60 healthy late middle-aged individuals (50-69y; 42 women). We evaluated 8 brain integrity with amyloid-beta-PET and tau-PET, and with MRI. Participants' cognition was 9 extensively assessed. We first confirm that sleep slow waves generation is associated with 10 amyloid-beta burden. Although cortical excitability dynamics during wakefulness is related to 11 sleep slow waves, it is not associated with amyloid-beta nor with tau burden. We further show that 12 individuals with preserved cortical excitability dynamics showed better cognitive performance, 13 particularly in the executive domain, which is crucial for successful cognitive aging. Critically, 14 this association remained significant after accounting for brain integrity measures. Preserved 15 dynamics of basic brain function during wakefulness could be essential to cognitive fitness in 16 aging, independently from age-related brain structural deteriorations that can ultimately lead to 17 dementia. 18 19

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