Long before they forget important dates, events, or the names of their loved ones, people with Alzheimer's disease often experience changes in their sleep patterns, which may include difficulty falling asleep, waking up frequently at night, or awakening in the early morning. These changes worsen as the disease progresses and may explain at least a subset of Alzheimer’s disease cases (1).

Researchers at Harvard Medical School led by neuroscientist Ksenia Kastanenka found that stimulating specific neurons in the brain improved sleep and in turn, memory function in a mouse model of Alzheimer's disease (2). This discovery suggests that changes in sleep patterns could serve as an early predictor of Alzheimer's disease and that improving sleep might prevent disease advancement.

Kastanenka’s team generated an Alzheimer’s disease mouse model in which they could activate GABAergic interneurons using optogenetics. GABAergic interneurons generate the characteristic brain rhythms that occur during non-rapid eye movement (NREM) sleep and help reach the third stage of NREM sleep known as slow-wave activity or deep sleep, which is crucial for memory consolidation. 

The Alzheimer's disease mouse model exhibited early sleep impairments, including decreased time spent in NREM sleep and increased sleep fragmentation. Activation of GABAergic interneurons increased NREM sleep and improved slow-wave sleep. “It was specifically the GABAergic interneurons that triggered the expression of slow-wave sleep, which is a key mechanistic aspect for how sleep is related to reduction of Alzheimer's risk," said Bryce Mander, a neuroscientist at the University of California, Irvine, who was not part of the study. 

Kastanenka is interested in understanding the relationship between Alzheimer's disease and sleep. Back in the early 2010s, her group examined mouse models of Alzheimer’s disease and found profound disruptions in slow-wave activity (3). “This led to this aha moment that perhaps the reason Alzheimer's patients are not able to remember is because they don't sleep well,” she said. However, until this new study, her team had not been able to show that improving slow-wave sleep slowed down Alzheimer's disease progression. “Optogenetics was the key tool to be able to ask these causal questions.”

Monitoring brain rhythm during sleep is relatively inexpensive. It would be really promising to develop it as a biomarker for Alzheimer's disease. 
- Ksenia Kastanenka, Harvard Medical School

Restoring slow-wave sleep through optogenetic activation of GABAergic interneurons reduced memory deficits and reduced the deposition of amyloid beta, a protein implicated in Alzheimer's disease pathology. It also increased the number of microglia, the immune cells of the brain, which helped eliminate amyloid beta. 

To make a more definitive connection between improved slow-wave sleep and decelerated Alzheimer's disease progression, Kastanenka’s group sleep deprived their Alzheimer's disease mouse model and compared sleep patterns with and without optogenetic stimulation. Sleep deprivation reversed the improvement in slow-wave activity achieved with optogenetic treatment. Amyloid plaque burden remained high in the sleep deprived mice, and they showed no difference in microglia number or in the ability of microglia to clear amyloid beta.  

Kastanenka hopes that the results of this study will contribute to how Alzheimer's disease is diagnosed. “Monitoring brain rhythms during sleep is relatively inexpensive,” she said. “It would be really promising to develop it as a biomarker for Alzheimer’s disease.” Attributing sleep disturbances to Alzheimer's disease specifically will be the next challenge as sleep changes can stem from other causes. Mander added, “Understanding if these early signatures are predictive of Alzheimer's specifically is going to be an important thing to work out.”  

References:

1. Sabia, S. et al.  Association of sleep duration in middle and old age with incidence of dementia. Nat Commun  12, 2289 (2021)
2. Zhao, Q. et al. Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer’s disease model. Mol Neurodegeneration  18, 93 (2023).
3. Kastanenka, K.V. et al. Optogenetic restoration of disrupted slow oscillations halts amyloid deposition and restores calcium homeostasis in an animal model of Alzheimer's disease. PLoS One  12, e0170275 (2017).