During wakefulness, neuromodulators operate largely independently to support behavior and cognition. By contrast, sleep reorganizes their activity into a coordinated brain rhythm. During sleep, the major neuromodulators—norepinephrine, acetylcholine, serotonin, and dopamine—exhibit synchronized fluctuations with a periodicity of ~50 seconds. These oscillations appear as recurrent bursts of fast (10 to 30 hertz) electroencephalography activity and are phase-coupled to cerebrospinal fluid flow. Neuromodulators are vasoactive agents and drive slow vasomotion, which provide the mechanical force that supports glymphatic clearance of metabolic waste. Disruption of neuromodulator signaling, as seen in psychiatric disorders, cardiovascular disease, aging, or with commonly prescribed drugs, impairs clearance of neurotoxic proteins, including amyloid-β and tau.

Scheidemantel et al. address the complexity of Alzheimer’s disease by integrating comprehensive multi-omics data from over 1,300 aged individuals, revealing coordinated molecular mechanisms across brain systems. The findings provide crucial insights into age-related traits and disease pathways, paving the way for potential therapeutic strategies.