Clock and the Cleaner: Circadian Rhythms and Autophagy Coupling in Alzheimer's Disease.

Alzheimer's disease (AD) continues to progress despite decades of research on protein aggregation, highlighting the need to understand upstream homeostatic failures. Among the earliest alterations in AD are disruptions of circadian rhythms and autophagy, which are mechanistically intertwined. Although circadian dysfunction and autophagic failure have been studied separately, the stage-dependent, region-specific, and cell-type-specific interplay between these systems remains poorly integrated, limiting the development of targeted interventions. In a healthy brain, the circadian clock and autophagy mutually interact, maintaining proteostasis, neuronal function, and rhythmic metabolic and immune processes. In early-stage AD, circadian rhythms show mild disruption and autophagy initiation remains active, but downstream autophagosome-lysosome fusion and lysosomal degradation are impaired, leading to the accumulation of AD pathological proteins. Dysregulation is cell-type-specific: neuronal clocks remain relatively intact, whereas astrocytic and microglial clocks exhibit altered metabolic and immune rhythms, contributing to early pathogenic events. In late-stage AD, severe circadian disruption likely uncouples circadian control from autophagy, and these dysfunctions mutually exacerbate each other, driving neuroinflammation, neuronal dysfunction, and further accumulation of pathological proteins. This review synthesizes current evidence on the circadian-autophagy axis, highlighting mechanistic insights and therapeutic opportunities, and emphasizes the importance of integrating stage-, region-, and cell-type-specific dynamics for the development of precise interventions in AD.