Amyloid-β as a cytokine-like somnogen: Rethinking its role in sleep homeostasis and Alzheimer's disease

Abstract

Amyloid-β (Aβ) is recognized as a pathological hallmark of Alzheimer's disease, but accumulating evidence suggests that it also serves physiological roles in the healthy brain. Notably, Aβ secretion is tightly linked to neuronal activity and wakefulness, and its clearance is facilitated by sleep, raising the possibility that Aβ regulates sleep homeostasis. We propose that Aβ functions as a cytokine-like somnogen: a molecule whose accumulation during wakefulness promotes sleep onset and maintenance via synaptic and immune mechanisms. This framework reframes Aβ not as a toxic byproduct but as a key intermediary between neural activity and restorative sleep processes. We synthesize findings from molecular biology, electrophysiology, animal models, and human sleep studies, including research on AβPP processing, activity-dependent Aβ release, oligomeric signaling, and the effects of anti-amyloid therapies on sleep. Particular emphasis is placed on evidence that Aβ modulates synaptic excitability, engages glial immune pathways, and fulfills formal criteria for cytokine classification. Across multiple systems, Aβ exhibits properties consistent with homeostatic downscaling: it dampens neurotransmitter release, suppresses excitatory receptor trafficking, and activates sleep-promoting neuronal populations. Disruption of endogenous AβPP cleavage impairs sleep consolidation, while depletion of Aβ can lead to network hyperexcitability and disturbed sleep. Post-marketing reports of insomnia and abnormal dreams with plaque-clearing agents further support a physiological role. Recognizing Aβ as a somnogen offers a unifying model for sleep disruption in AD and raises caution about therapies that neutralize Aβ indiscriminately. Future interventions may benefit from preserving Aβ's homeostatic roles while mitigating its pathological aggregation.