Sleep arousals are associated with the polygenic risk for developing Alzheimer's disease and with cognitive decline in healthy late middle-aged individuals

Mortazavi, N.; Zubkov, M.; Chylinski, D.; Collette, F.; Bastin, C.; Maquet, P.; Vandewalle, G.; Talwar, P.

doi:10.1101/2025.11.11.687823

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bioRxiv · 10.1101/2025.11.11.687823

Sleep arousals are associated with the polygenic risk for developing Alzheimer's disease and with cognitive decline in healthy late middle-aged individuals

Mortazavi, N.·Zubkov, M.·Chylinski, D.·Collette, F.·Bastin, C.·Maquet, P.·Vandewalle, G.·Talwar, P.

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Abstract

ObjectiveSleep disturbances are increasingly recognized as early features of Alzheimers disease (AD) neuropathology. In that context, spontaneous arousals during sleep have been associated with the burden of Amyloid beta in the brain of healthy late middle-aged individuals. Whether the heterogeneity of arousals during sleep may be related to the genetic risk of developing AD in young adults is not established. Likewise, whether arousals may be associated with cognitive decline is not known. Here, we evaluated the association between arousals, the genetic risk for developing AD and cognitive performance and cognitive decline in healthy young and late-middle-aged individuals. MethodsWe classified spontaneous arousals using in-lab EEG recordings of sleep in 453 younger individuals (22+/-2.7y; 49 women) and 87 late middle-aged individuals (59.3+/-5.3y; 59 women) based on their association with sleep stage transitions and changes in muscle tone. We examined the associations between arousal types and the polygenic risk scores (PRS) for AD, cognitive performance at baseline and, in late middle-aged individuals, cognitive decline over 2 and 7 years. ResultsThe prevalence of arousals associated with sleep stage transition was higher in late middle-aged vs. younger individuals. Among these arousals, those with and without muscle tone increases were, respectively, associated with lower and higher PRS for AD in late middle-aged but not in younger individuals. In the late middle-aged individuals, transition arousals associated with and without muscle tone increases were, respectively, correlated with better and worse attentional performance at baseline, and lower and larger memory decline over 2 or 7 years. ConclusionThe heterogeneity in spontaneous arousals during sleep may reflect their physiological intensity or underlying neural activation, and may indicate vulnerability to AD in late middle-aged individuals. The findings may contribute to identifying early markers of neurodegenerative risk. Statement of SignificanceSleep arousals are typically regarded as disruptive events, yet their physiological diversity may reveal important insights into brain health. In this study, we report that distinct subtypes of spontaneous sleep arousals are differentially associated with genetic vulnerability to Alzheimers disease (AD) and with future cognitive decline in healthy late middle-aged adults. Specifically, sleep arousals linked to sleep stage transitions but lacking muscle activation were related to higher polygenic risk for AD and greater memory decline, while those accompanied by muscle tone increases showed the opposite pattern. These findings indicate that subtle variations in sleep microstructure can reflect neurobiological vulnerability to AD before clinical symptoms emerge. By identifying electrophysiological markers associated with genetic risk and cognitive trajectories, this work advances the potential for using sleep-based biomarkers to detect and monitor preclinical neurodegenerative processes.

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Mortazavi, N., Zubkov, M., Chylinski, D., Collette, F., Bastin, C., Maquet, P., Vandewalle, G., Talwar, P.. 2025-11-13. Sleep arousals are associated with the polygenic risk for developing Alzheimer's disease and with cognitive decline in healthy late middle-aged individuals. https://doi.org/10.1101/2025.11.11.687823

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