Results suggest greater emphasis on managing sleep habits for people at risk of Alzheimer’s disease.
New research from the University of California, Irvine indicates that chemical changes within brain cells triggered by disruptions to the body’s day-night cycle may play a central role in the learning and memory decline associated with Alzheimer’s disease. The study links circadian rhythm disturbances—similar to chronic jet lag—to measurable impairments in memory and to oxidative changes in the brain.
Led by UCI biomedical engineering professor Gregory Brewer, the research used established mouse models of Alzheimer’s disease to test whether repeated shifts in light and dark periods alter cognition and brain chemistry. The findings, published in the Journal of Alzheimer’s Disease, suggest that disrupted sleep patterns may accelerate cognitive decline and that addressing sleep could be a practical strategy to help preserve memory in at-risk individuals.
Sleep and circadian disturbances are common in people with Alzheimer’s, yet it has been unclear whether those sleep problems are a consequence of neurodegeneration or a contributing factor. “The issue is whether poor sleep accelerates the development of Alzheimer’s disease or vice versa,” said Brewer, who is affiliated with UCI’s Institute for Memory Impairments and Neurological Disorders. “Our research supports the idea that disruption of sleep can act as an accelerator of memory loss.”
To examine how circadian disruption affects learning and memory, the research team exposed both young Alzheimer’s-model mice and normal control mice to an altered light-dark schedule: every three days they shortened the dark period by eight hours, producing a repeated jet-lag-like condition. This schedule produced a marked reduction in nocturnal activity in both groups.
Behavioral testing using the Morris water maze revealed that the Alzheimer’s-model mice exposed to the jet-lag condition developed significant learning impairments. In contrast, Alzheimer’s-model mice kept on a regular light-dark cycle did not show the same deficits, and normal mice subjected to the same circadian disruption had different, less severe effects on learning. Memory retention measured days after training was impaired in both genotypes after circadian disruption, indicating a broader impact on memory consolidation.
At the tissue level, circadian disruption produced consistent biochemical changes. The team observed a drop in brain levels of glutathione (GSH), a key antioxidant that protects cells from oxidative damage. Although glutathione decreased in all mice after jet-lag exposure, the reduction was more pronounced in the Alzheimer’s-model brains and correlated with poorer performance on the water maze. The study also found associated increases in NADH levels, indicating a shift in cellular redox balance.
Reduced glutathione and the resulting redox shift imply increased oxidative stress in neurons. Oxidative stress can disrupt metabolism and trigger inflammatory pathways, processes that are already implicated in Alzheimer’s pathology. According to Brewer, accelerated oxidative stress appears to be an important factor linking circadian disturbances to the cognitive deficits seen in the Alzheimer’s-model mice. These redox changes also point to potential pharmacological targets: treatments that restore glutathione levels or correct redox imbalances might help protect memory in the context of circadian disruption.
The practical takeaway from this research is straightforward: clinicians, caregivers, and individuals at elevated risk of Alzheimer’s should consider sleep hygiene and stable circadian routines as part of a comprehensive approach to brain health, alongside exercise and a healthy diet. Improving sleep quality and minimizing chronic circadian disruption could reduce oxidative stress and help preserve cognitive function.
Funding: Kelsey LeVault and Shelley Tischkau of the Southern Illinois University School of Medicine contributed to the research, which received support from the National Institutes of Health (grant R01 AG032431).
Source: Tom Vasich – UC Irvine
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Original Research: Abstract for “Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model” by LeVault, Kelsey R.; Tischkau, Shelley A. and Brewer, Gregory J. in Journal of Alzheimer’s Disease. Published online October 9 2015 doi:10.3233/JAD-150026
Abstract
Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model
To determine whether circadian disruption contributes to cognitive decline, researchers shortened the dark period by eight hours every three days (a repeated jet-lag paradigm) in a young APPSwDI NOS2–/– Alzheimer’s disease mouse model (AD-Tg) and in non-transgenic controls. While baseline activity under stable lighting showed minor differences between genotypes, the repeated jet-lag schedule greatly reduced nocturnal activity in both groups. Learning on the Morris water maze was significantly impaired only in the AD-Tg mice exposed to circadian disruption, though memory three days after training declined in both genotypes. Jet lag reduced brain glutathione (GSH), with a larger decrease in AD-Tg mice, and increased NADH in both groups. Lower GSH levels after circadian disruption correlated with worse maze performance. These results indicate that environmental circadian stress combined with latent genetic vulnerability can produce cognitive deficits that align with oxidative redox changes in the brain.
“Circadian Disruption Reveals a Correlation of an Oxidative GSH/GSSG Redox Shift with Learning and Impaired Memory in an Alzheimer’s Disease Mouse Model” by LeVault, Kelsey R.; Tischkau, Shelley A. and Brewer, Gregory J. in Journal of Alzheimer’s Disease. Published online October 9 2015 doi:10.3233/JAD-150026