Andrew S. P. Lim

Introduction Sleep disruption is associated with astrocyte activation and impaired cognition in model organisms. However, the relationship among sleep, astrocyte activation, and cognition in humans is uncertain. Methods We used RNA‐seq to quantify the prefrontal cortex expression of a panel of human activated astrocyte marker genes in 1076 older adults in the Religious Orders Study and Rush Memory and Aging Project, 411 of whom had multi‐day actigraphy prior to death. We related this to rest fragmentation, a proxy for sleep fragmentation, and to longitudinal cognitive function. Results Fragmentation of rest periods was associated with higher expression of activated astrocyte marker genes, which was associated with a lower level and faster decline of cognitive function. Discussion Astrocyte activation and fragmented rest are associated with each other and with accelerated cognitive decline. If experimental studies confirm a causal relationship, targeting sleep fragmentation and astrocyte activation may benefit cognition in older adults. Highlights Greater fragmentation of rest periods, a proxy for sleep fragmentation, is associated with higher composite expression of a panel of genes characteristic of activated astrocytes. Increased expression of genes characteristic of activated astrocytes was associated with a lower level and more rapid decline of cognitive function, beyond that accounted for by the burden of amyloid and neurofibrillary tangle pathology. Longitudinal and experimental studies are needed to delineate the causal relationships among sleep, astrocyte activation, and cognition.