Alzheimer's disease as a systems-level timing disorder: Circadian disruption of glial immunometabolism, brain clearance, and therapeutic responsiveness

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Alzheimer’s disease (AD) is traditionally conceptualized as a disorder of protein aggregation and neurodegeneration, yet growing evidence indicates that fundamental temporal organization of brain physiology is also disrupted. In the healthy brain, circadian clocks coordinate sleep–wake behavior, glial immunometabolism, astrocytic aquaporin-4 polarity, and glymphatic–lymphatic clearance, aligning immune readiness and proteostasis with daily activity–rest cycles. In AD, this temporal coordination progressively deteriorates, manifesting as sleep fragmentation, instability of rest–activity rhythms, vulnerability of central clock structures, and loss of circadian gating of glial and clearance pathways. These disruptions create phase-inappropriate immune and metabolic states, impair protein clearance, and alter the fate of extracellular vesicles, which may shift from mediators of waste export to facilitators of proteopathic spread. Importantly, circadian failure also constrains therapeutic delivery and biomarker interpretation by modulating blood–brain barrier transport, brain fluid dynamics, and brain-to-blood signal export. We propose that AD can be reframed as a systems-level timing disorder, in which loss of temporal coherence integrates molecular pathology, glial dysfunction, clearance failure, therapeutic inefficacy, and biomarker variability. This framework highlights chrono-pharmacology, chrono-neurotherapeutics, and circadian-informed biomarkers as essential components of precision strategies for AD prevention and treatment. • Alzheimer’s disease involves a progressive loss of temporal coordination, in which circadian timing, sleep–wake organization, and state-dependent brain physiology become uncoupled rather than simply diminished. • In the healthy brain, circadian clocks synchronize glial immunometabolism, astrocytic aquaporin-4 polarity, and sleep-dependent glymphatic–lymphatic clearance, aligning immune readiness and proteostasis with daily activity–rest cycles. • Disruption of circadian gating in Alzheimer’s disease drives maladaptive glial states, in which immune and metabolic responses become phase-inappropriate, contributing to impaired proteostasis and neuronal vulnerability. • The glymphatic–exosome axis provides a systems framework in which extracellular vesicles can mediate either clearance or proteopathic propagation depending on the integrity and timing of brain clearance pathways. • Therapeutic efficacy and biomarker readouts in Alzheimer’s disease are inherently time-dependent, implicating chrono-pharmacology, chrono-neurotherapeutics, and circadian-informed biomarkers as critical components of precision intervention.

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