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  • Perspective
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Linking activity dyshomeostasis and sleep disturbances in Alzheimer disease

Nature Reviews Neuroscience volume 25, pages 272–284 (2024)Cite this article

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Abstract

The presymptomatic phase of Alzheimer disease (AD) starts with the deposition of amyloid-β in the cortex and begins a decade or more before the emergence of cognitive decline. The trajectory towards dementia and neurodegeneration is shaped by the pathological load and the resilience of neural circuits to the effects of this pathology. In this Perspective, I focus on recent advances that have uncovered the vulnerability of neural circuits at early stages of AD to hyperexcitability, particularly when the brain is in a low-arousal states (such as sleep and anaesthesia). Notably, this hyperexcitability manifests before overt symptoms such as sleep and memory deficits. Using the principles of control theory, I analyse the bidirectional relationship between homeostasis of neuronal activity and sleep and propose that impaired activity homeostasis during sleep leads to hyperexcitability and subsequent sleep disturbances, whereas sleep disturbances mitigate hyperexcitability via negative feedback. Understanding the interplay among activity homeostasis, neuronal excitability and sleep is crucial for elucidating the mechanisms of vulnerability to and resilience against AD pathology and for identifying new therapeutic avenues.

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Fig. 1: Network pathophysiology in mouse models of familial Alzheimer disease.
Fig. 2: A new paradigm for the transition from presymptomatic to symptomatic phases of Alzheimer disease.

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Acknowledgements

The author thanks L. Heim for the comments on the manuscript and for help with the figures, Y. Nir for the comments on the manuscript, T. Langberg for his contribution to the initial version of the article, V. Vyazovskiy and all the laboratory members for fruitful discussions. This Perspective benefited by support from the European Research Council (CoG-724866 and AdG-101097788), the Israel Science Foundation (1663/18), The Deutsche Forschungsgemeinschaft (440813539 and 448865644), BIRAX Regenerative Medicine Initiative (46BX18TKIS) and Rosetrees Trust.

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    Inna Slutsky

  2. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Inna Slutsky

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Slutsky, I. Linking activity dyshomeostasis and sleep disturbances in Alzheimer disease. Nat. Rev. Neurosci. 25, 272–284 (2024). https://doi.org/10.1038/s41583-024-00797-y

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