Brain rhythm attractor breakdown in Alzheimer's disease: Functional and pathologic implications

This perspective binds emerging evidence on the bidirectional relationship between Alzheimer's disease (AD) and sleep disorders through a model of brain rhythm attractor breakdown. This approach explains behavioral-cognitive changes in AD across the sleep-wake cycle and supports a causal association between early brainstem tau pathology and subsequent cortical amyloid β accumulation. Specifically, early tau dysregulation within brainstem-hypothalamic nuclei leads to breakdown of sleep-wake attractor networks, with patients displaying an attenuated range of behavioral and electrophysiological activity patterns, a “twilight zone” of constant activity between deep rest and full alertness. This constant cortical activity promotes activity-dependent amyloid β accumulation in brain areas that modulate their activity across sleep-wake states, especially the medial prefrontal cortex. In addition, the accompanying breakdown of hippocampal–medial prefrontal cortex interplay across sleep stages could explain deficient memory consolidation through dysregulation of synaptic plasticity. Clinical implications include the potential therapeutic benefit of attractor consolidation (e.g., slow-wave sleep enhancers) in delaying AD progression.