Linking activity dyshomeostasis and sleep disturbances in Alzheimer disease

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. Altered network activity during sleep is observed in some individuals with Alzheimer disease and in mouse models of the disorder. In this Perspective, Inna Slutsky proposes that hyperexcitability and sleep disturbances in Alzheimer disease result from disruption of the mechanisms that maintain activity homeostasis in the brain.