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

Apr 14, 2026Aging and disease

Daily Body Clocks and Cellular Cleaning Processes Linked in Alzheimer's Disease

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Abstract

Circadian rhythms are mildly disrupted in early-stage Alzheimer's disease, while autophagy initiation remains active but later fails.

Disruptions in circadian rhythms and autophagy are among the earliest changes observed in Alzheimer's disease.
In early-stage Alzheimer's, autophagosome-lysosome fusion and lysosomal degradation are impaired, leading to the accumulation of pathological proteins.
Neuronal circadian clocks remain relatively intact, while astrocytic and microglial clocks show altered metabolic and immune rhythms.
In late-stage Alzheimer's, severe circadian disruption may uncouple circadian control from autophagy, exacerbating neuroinflammation and neuronal dysfunction.

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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.

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

Abstract

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