Breakthrough Discovery: Boosting NAD⁺ Levels May Reverse Neurological Damage in Alzheimer’s Disease
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A new study published in Science Advances reveals a promising mechanism for combating Alzheimer’s Disease (AD), suggesting that increasing levels of the metabolite NAD⁺ can reverse neurological deficits by regulating RNA splicing – a critical process in gene expression. This discovery offers a potential pathway toward novel therapies for the devastating disease, which currently affects nearly 40 million people worldwide.
Alzheimer’s Disease, the leading cause of dementia, is characterized by a progressive loss of memory and independence. Despite decades of research, effective treatments remain elusive. A key contributor to the disease’s progression is the protein tau, which normally stabilizes neurons. However, in AD, tau becomes modified and aggregates, disrupting vital transport systems within brain cells and ultimately leading to neuronal damage.
Researchers have long suspected that bolstering NAD⁺ – a vital metabolite involved in energy metabolism and neuronal resilience – could offer protection against neurodegeneration. Preliminary studies have indicated therapeutic benefits from supplementation with NAD⁺ precursors like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) in animal models and early clinical trials, but the underlying mechanisms remained unclear.
Unlocking the RNA Splicing Pathway
The international research team, led by Associate Professor Evandro Fei Fang from the University of Oslo and Akershus University Hospital, Norway, in collaboration with researchers from China and Portugal, has now identified a previously unknown pathway through which NAD⁺ exerts its protective effects. The study centers on a protein called EVA1C, which plays a crucial role in RNA splicing.
RNA splicing is a fundamental cellular process that allows a single gene to produce multiple variations of a protein, each with potentially distinct functions. Dysregulation of this process has recently been recognized as a significant risk factor for AD. According to researchers, when NAD⁺ levels are increased, EVA1C effectively corrects errors in RNA splicing, improving the function of hundreds of genes critical for brain health and potentially reversing neurodegenerative damage caused by tau.
From Worms to Humans: Validating the Findings
To demonstrate the impact of this mechanism, the team employed a rigorous, cross-species approach. They began by identifying age-related changes in RNA splicing in a specific type of worm, finding that adding NAD⁺ could correct splicing issues induced by the toxic tau protein.
These findings were then replicated in mice with tau-related mutations. NAD⁺ supplementation improved RNA splicing, restored brain function, and enhanced memory performance. “Notably, we found when the EVA1C gene was knocked down, these benefits were lost, confirming that EVA1C is essential for NAD⁺-mediated neuroprotection,” stated Associate Professor Evandro Fei Fang-Stavem.
Further supporting these results, researchers observed significantly reduced levels of EVA1C in brain cells from individuals with early-stage AD.
AI Reveals the Molecular Connection
The team leveraged the power of artificial intelligence to further unravel how EVA1C functions. Using an AI-driven platform, they analyzed structural, sequential, and evolutionary data from millions of proteins to predict protein interactions. This analysis revealed that NAD⁺ promotes a specific form of EVA1C that efficiently binds to essential proteins involved in protein folding and clearance. This connection highlights the interplay between metabolic homeostasis, RNA splicing, and protein management – all processes critically impaired in AD.
Paving the Way for New Treatments
This study establishes a crucial link between NAD⁺ and EVA1C, laying the groundwork for the development of innovative therapies and optimized NAD⁺ augmentation strategies. “We propose that maintaining NAD⁺ levels could help preserve neuronal identity and delay cognitive decline, paving the way for combination treatments to enhance RNA splicing,” explained Alice Ruixue Ai, a researcher at the University of Oslo.
The findings offer a beacon of hope in the ongoing fight against Alzheimer’s Disease, suggesting a potential new avenue for intervention and a future where cognitive decline can be slowed or even reversed.
Source: Ai, R., et al. (2025). NAD + reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C. Science Advances. DOI: 10.1126/sciadv.ady9811. https://www.science.org/doi/10.1126/sciadv.ady9811.
