Astrocytic timekeepers and their influence on brain waste clearance in Alzheimer's disease

Alzheimer's disease is associated with disruptions in circadian rhythmicity, yet the underlying mechanisms remain only partially understood. Developing insights suggest that astrocytes possess their own intrinsic circadian clocks, influencing multiple functions in brain homeostasis. Given the central role of astrocytes in brain waste clearance, this review investigates how the astrocytic clock mediates brain waste clearance and contributes to Alzheimer's disease pathology. By reviewing recent findings on extracellular clearance, cellular protein homeostasis, cellular detoxification/redox defence and neurotransmitter homeostasis, this review bridges research on astrocytic clock disruption with altered brain waste clearance dynamics. It further highlights the relevance of these alterations to Alzheimer's disease pathology. Interestingly, some clock-gene disruptions are associated with markers suggestive of increased autophagic activity and glymphatic-related gene expression, which may represent a compensatory response to circadian clock alteration. However, whether these changes translate into improved functional clearance in vivo, and whether they meaningfully affect Alzheimer's disease progression, remains uncertain. In contrast, similar clock-gene alterations generally impair blood-brain barrier integrity, glutamate clearance and antioxidant response, decreasing waste clearance capacity. These findings suggest a possible bidirectional relationship, in which some pathways may partially compensate for impairments in others. However, it remains unclear to what extent an imbalance in these pathways contributes to the development and/or progression of Alzheimer's disease. Altogether, the astrocytic circadian clock is positioned as an important regulator of brain waste clearance and warrants future mechanistic and therapeutic investigation.