Despite decades of intensive research, no treatments have yet succeeded in halting or reversing the course of this devastating disease.
In this complex landscape, the tau protein emerges as a key factor in disease progression. In its normal state, this protein resembles "railway tracks" that guide and support the internal structure of nerve cells.
But in Alzheimer's disease, the protein undergoes abnormal changes that cause it to clump and clump together, disrupting the cellular transport system and ultimately leading to nerve cell damage and memory loss.
Now, an international research team led by Assistant Professor Evander Faye Vang from Norway has revealed a promising new mechanism. The study showed that boosting the natural metabolite NAD⁺ can protect the brain from Alzheimer’s-related degeneration through a previously unknown pathway related to RNA splicing.
The significance lies in the fact that declining NAD⁺ levels with age and in neurological diseases open the door to new therapeutic strategies. Supplements such as nicotinamide riboside (NR) have been observed to improve the condition in animal models, but the molecular mechanism remains unclear.
The new findings reveal that NAD⁺ works via the EVA1C protein, which regulates RNA splicing. When NAD⁺ levels are boosted, EVA1C corrects errors in splicing, improving the function of hundreds of genes essential for brain health.
To demonstrate this mechanism, the researchers followed a comprehensive approach that included:
Study of age-related changes in C. elegans worms
Testing the effect of NAD⁺ supplementation in genetically modified mice
Analysis of human brain samples from Alzheimer's patients
The results showed a marked improvement in RNA splicing (a precise biological process that resembles smart scissors cutting and pasting genetic material within a cell), brain function, and cognitive performance.
Most importantly, silencing the EVA1C gene eliminated these benefits, confirming its pivotal role.
Using artificial intelligence, the researchers were able to analyze the interactions between millions of proteins, revealing how NAD⁺ promotes the efficient form of EVA1C that binds to proteins responsible for protein folding and removal, vital processes that are disrupted in Alzheimer’s.
This discovery, for the first time, links three vital pathways affected in the disease: cellular metabolism, RNA splicing, and protein management. It opens the door to the development of new therapies focused on maintaining NAD⁺ levels and improving RNA splicing, potentially delaying cognitive decline and improving the ives of millions worldwide.