Sleep-Wake Transitions Are Impaired in the App ^NL-G-F Mouse Model of Early Onset Alzheimer’s Disease

Jan 9, 2026bioRxiv : the preprint server for biology

Sleep and Wake Changes Are Disrupted in a Mouse Model of Early Alzheimer's Disease

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Abstract

Mice with three mutations linked to early onset Alzheimer's disease exhibited partial insomnia and altered sleep patterns compared to wildtype littermates.

Mice showed more Wake and less NREM and REM sleep than wildtype mice at both 14-18 and 18-22 months of age.
A long wake/short sleep phenotype was observed during the dark phase at 14-18 months and in both phases at 18-22 months.
At 18-22 months, mice had fewer short Wake bouts and more long Wake bouts, indicating hyperactivity that may contribute to reduced sleep.
Sex differences revealed that partial insomnia was stronger in female mice, with both sexes experiencing longer Wake and REM sleep bout durations.
Female mice displayed reduced EEG spectral power in NREM sleep, while both sexes showed reduced spectral power in the theta range during REM sleep.

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Poor sleep quality and reduced sleep duration are associated with Alzheimer's disease (AD)-related β-amyloid (Aβ) pathologies. We conducted two studies of sleep/wake, activity and body temperature inmice, a strain that exhibits three mutations in the humangene associated with elevated risk for early onset AD. First,mice were compared to wildtype (WT) littermates at 14-18 and 18-22 months of age and, at both ages, were found to exhibit partial insomnia with more Wake and less NREM and REM sleep than WT littermates. This long wake/short sleep phenotype was evident during the dark phase at 14-18 months but occurred in both the light and dark phases at 18-22 months.mice had fewer short (<60 sec) and more long (>260 sec) Wake bouts and were hyperactive at 18-22 months, which undoubtedly contributed to the increased Wake/reduced sleep. Despite this partial insomnia phenotype,mice were no sleepier than WT mice and the sleep homeostat was functional in both strains. In the second study, sex differences in these parameters were assessed at 18-24 months. Partial insomnia was evident in both sexes ofmice but was clearly stronger in females. Wake and REM sleep bout durations were longer in both sexes ofmice than in WT littermates. EEG spectral power during NREM sleep was reduced in femalemice between 4.88-10.50 Hz compared to WT mice whereas, during REM sleep, both male and femalemice exhibited reduced spectral power in the theta range. These results suggest that Aβ deposition may impair state transition mechanism(s) inmice and demonstrate that, as in human AD patients, femalemice exhibit a stronger insomniac-like phenotype, thus supporting the use of this strain as a model to investigate interventions that mitigate AD burden during early disease stages. App App App App App App App App App App App NL-G-F NL-G-F NL-G-F NL-G-F NL-G-F NL-G-F NL-G-F NL-G-F NL-G-F NL-G-F

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Sleep-Wake Transitions Are Impaired in the App ^NL-G-F Mouse Model of Early Onset Alzheimer’s Disease

Abstract

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