Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD ⁺ ) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD ⁺ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD ⁺ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD ⁺ -induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD ⁺ -induced memory improvement in pathological Tau–bearing mice. We propose that NAD ⁺ reduces AD pathologies, at least partially, via amplification of the NAD ⁺ - EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.

ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD⁺, which in turn deacetylates acetylated-Tau174 via the NAD⁺-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.

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

Aberrant alternative splicing (ASEs) is an aging hallmark to Alzheimer’s Disease (AD). Although NAD ⁺ and related metabolites can slow down AD, NAD ⁺ on ASEs in AD remain unclear. Mouse transcriptomic data revealed NR-induced ASEs, focusing on the Eva1-C locus. AI-based algorithms predicted EVA1-C protein structures and protein-protein interactions. AD postmortem brain samples and tauopathy models including transgenic mice and worm was used for validation. NAD ⁺ abundance/metabolic status modulates ASEs and the expression of EVA1-C isoforms, which in turn regulate the interaction with BAG-1 and HSP70 proteins. Importantly, EVA1-C is dramatically reduced in 20 Braak 5/6 AD patients compared to cognitive normal humans in different brain regions. NAD ⁺ metabolism modulates abundance of specific mRNA isoforms, and that ASEs influence disease progression in model tauopathies and potentially AD. These results could facilitate future development of NAD ⁺ -based splice-switching therapeutics for AD. Teaser: Unveiling the Link Between NAD ⁺ Metabolism and Alzheimer’s Disease: Discovering the Role of Alternative RNA Splicing in Disease Progression and Potential Therapeutic Targets