NAD ⁺ ‒circadian rhythm coupling in dementia

Abstract 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