NAD⁺‒circadian rhythm coupling in dementia

The circadian rhythm system and sleep coordinate whole-body functions across the 24-h cycle, yet these rhythms progressively deteriorate with neurodegenerative diseases, including dementia. Growing evidence indicates that nicotinamide adenine dinucleotide (NAD⁺) interacts with the circadian system through multiple molecular pathways and that NAD⁺ levels decline with dementia. In this review, we synthesize current evidence on the bidirectional relationship between NAD⁺ metabolism and circadian regulation in several dementia disorders, emphasizing the key circadian pathways, the nicotinamide phosphoribosyltransferase-mediated salvage synthesis, the NAD⁺/sirtuins-dependent signaling, and the consumption of NAD⁺ by PARP1 and CD38. Finally, we also examine pharmacological and lifestyle strategies that target NAD⁺, including NAD⁺ precursors, modulators of NAD⁺ biosynthetic and depleting enzymes, timed light and activity exposure, structured exercise programs, and dietary interventions. Overall, we focus on the bidirectional interplay between NAD⁺ metabolism and circadian rhythm regulation in dementia, with particular emphasis on how this interaction influences sleep and cognitive phenotypes across different dementia subtypes. Trial Registration: ClinicalTrials.gov identifier: NCT05040321, NCT04430517, NCT06971224, NCT05500170, NCT04070378.