A sweeping new international study suggests that recharging a fundamental metabolic molecule, NAD+, could curb some of Alzheimer’s most stubborn neurological defects. And it appears to do so by restoring the brain’s ability to properly splice its own RNA.
The results, published in Science Advances, expose a previously overlooked mechanism that ties age-related NAD+ decline to the molecular chaos that defines Alzheimer’s disease. The research also hints at a startling new therapeutic target: a neuronal protein called EVA1C.
The research team, from labs scattered across Asia, Europe, and North America, tapped a rare, multi-species cross-validation pipeline powered by deep-learning structural predictions, C. elegans reporter models, mouse hippocampal transcriptomics, and even human brain tissue.
And what did they find? Alzheimer’s pathology derails the mechanics of RNA splicing. NAD+ restoration corrects that. And EVA1C rests right in the middle of this intersection.
Alzheimer’s and the Collapse of RNA Splicing
RNA splicing reverberates across nearly all human genes. But in Alzheimer’s, this apparatus breaks down. Early transcriptome studies already identified hundreds of abnormal splicing events in the brains of Alzheimer’s patients, including disruptions in Tau isoforms that seed neurofibrillary tangles.
Using 14-month-old mice, the team confirmed that dysregulated splicing is a defining feature of tauopathy. The researchers found that genes involved in spliceosome assembly and mRNA processing fell off sharply. At the same time, specific alternative splicing events shot up. RNA splicing errors also surfaced in a C. elegans Tau model, where fluorescent exon-skipping reporters revealed accelerating splicing instability with age.
The collapse, the authors insist, wasn’t random. Genes essential for mitochondrial function, synaptic communication, and neuronal plasticity all suffered the most.
The Promise of NAD+ Supplementation
Given NAD+’s broad influence on cellular metabolism, mitochondrial health, and DNA repair, the researchers wanted to find out whether restoring NAD+ could stabilize splicing. So, they fed the mice nicotinamide riboside (NR). And they responded. Hundreds of genes involved in healthy expression levels.
Perhaps most importantly, NR reversed compensatory overactivation of spliceosome genes, an unstable attempt by neurons to make up for the splicing failure.
Similar improvements appeared in C. elegans, though restricted to the earliest developmental window. And in human SH-SY5Y neuronal cells, boosting NAD+ with NMN normalized protein levels of EVA1C, which had plummeted in Tau-overexpressing cells.
Across species, NAD+ consistently restored splicing integrity.
A Molecular Linchpin
From a shortlist of nearly two dozen genes that NAD+ helped boost, EVA1C appeared to benefit the most. Research has already revealed that this immunoglobulin-superfamily protein steers axonal development, but the science has been less clear about the part it plays in neurodegeneration.
In this research project, EVA1C showed altered splicing and expression in Tau mice. And NAD+ corrected both. As a result, the authors suspected EVA1C might mediate the protein’s cognitive effects. And their tests appeared to back that up. In Tau-model worms, NR supplementation boosted memory-like performance in chemotaxis tasks.
But when the worm ortholog of EVA1C (eva-1) fell off, NR’s cognitive benefit faded. Likewise, NR extended the lifespan of Tau worms by nearly 17%. But that effect appeared only when eva-1 remained intact. This, the authors noted, suggests that EVA1C isn’t merely associated with NAD+-responsive resilience. It’s a prerequisite for it.
A Metabolic Gateway
The authors stop short of calling NAD+ a cure. But they do insist that boosting NAD+ could better regulate fundamental aspects of Alzheimer’s biology early in disease progression. By restoring RNA splicing fidelity, NAD+ might just help re-establish neuronal homeostasis, slow Tau pathology, and preserve cognition.
Most strikingly, the results suggest that metabolic therapies and splice-switching therapies may not be separate strategies, but two arms of the same system.
As clinical trials of NAD+ precursors continue, the study underscores a pretty compelling idea: tweaking RNA’s final edit might be one of the most promising ways to protect the Alzheimer’s brain.
Further Reading
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