NAD⁺‒circadian rhythm coupling in dementia.

Shi-Qi Zhang, Jiyeon Lee, Jun-Ping Pan, Rune Enger, Harald Hrubos-Strøm, Erik S Musiek, Evandro Fei Fang, Weidong Le

Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association 2026;22(5):e71360

PMID: 42063312

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.

Address: Key Laboratory of Liaoning Province for Research on the Pathogenic, Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.; Center for Convergence Research of Neurological Disorders, Ajou University School of Medicine, Suwon, South Korea.; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.; Letten Centre and GliaLab, Division of Anatomy, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.; Department of Neurosurgery, Oslo University Hospital, Rikshospitalet, Oslo, Norway.; K. G. Jebsen Centre for Brain Fluid Research, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.; Division of Surgery, Department of Otorhinolaryngology, Akershus University Hospital, Nordbyhagen, Norway.; Department of Neurology and Center on Biological Rhythms and Sleep, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.; Norwegian Centre on Healthy Ageing (NO-Age) and Norwegian National Anti-Alzheimer's Disease (NO-AD) Network, Oslo, Norway.; Key Laboratory of Liaoning Province for Research on the Pathogenic, Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.; Neurology Program, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

DOI: 10.1002/alz.71360

MeSH Terms: Humans, NAD, Dementia, Circadian Rhythm, Sleep, Nicotinamide Phosphoribosyltransferase

NAD+‒circadian rhythm coupling in dementia.

Abstract

NAD⁺‒circadian rhythm coupling in dementia.