NAD+ Restores Memory in Alzheimer’s Models by Fine-Tuning a Key Brain Protein’s Splicing
Boosting cellular energy metabolism corrects faulty RNA processing to protect neurons
NAD+ precursors have shown striking benefits across tissues—improving cardiac function in heart failure models, preserving ovarian reserve in aging females, even extending lifespan in multiple species. Now researchers have uncovered a mechanism that explains at least part of these effects: NAD+ doesn’t just fuel cells. It rewrites how genes get assembled into proteins.
Your brain assembles proteins like IKEA furniture—following genetic instructions but with room for creative interpretation. One gene can spawn multiple protein versions depending on which sections get included or skipped during assembly. When this “alternative splicing” breaks down in Alzheimer’s, neurons can’t build the proteins they need to survive. NAD+ precursors—compounds like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN)—correct this molecular editing process, particularly for a protein called EVA1C that’s essential for brain health.
“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 knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau-bearing mice.”
What’s the Big Idea?
NAD+ rescues memory deficits in Alzheimer’s-like conditions by correcting alternative splicing events (ASEs)—the molecular editing process where one gene produces multiple protein variants. The study tracked this across worms, mice engineered with mutant human Tau, and postmortem brain tissue from patients at different disease stages.
The mechanism: NAD+ normalizes splicing of EVA1C, a protein involved in axon guidance and neuronal function. When EVA1C splicing fails in Alzheimer’s, memory collapses. NAD+ promotes the protective EVA1C variant to bind heat shock protein 70 (HSP70) instead of BAG1—a switch that appears neuroprotective.
The numbers tell the story. Researchers identified 267 splicing events altered in tauopathy mice. NAD+ normalized a substantial portion, affecting genes tied to axon development, oxygen metabolism, mitochondrial positioning, and autophagy—all known contributors to Alzheimer’s pathology.
In worms, NR treatment extended lifespan by 17% and restored memory-like behaviors, but only with intact EVA1C. Knock it down, and the benefits vanished. In mice, reducing EVA1C in the hippocampus blocked NMN’s ability to improve memory and reduce pathological Tau accumulation.
Why Should You Care?
Alternative splicing dysregulation marks both aging and tauopathies. Targeting it—through NAD+ boosters or future splice-switching therapies—could address cognitive decline earlier than waiting for plaques and tangles to accumulate.
The evidence is cross-species. EVA1C levels drop in neurons across Braak stages in human brains, confirming this extends beyond rodent models. The study also showed NAD+ didn’t just tweak one pathway—it corrected a cascade of splicing errors.
Timeline matters. Supplementation overlapped the age when cognitive impairment typically emerges in these mouse models (11 to 14 months old). NAD+ prevented the expected decline rather than reversing late-stage damage.
The researchers used AI (AlphaFold 3) to predict how different EVA1C protein shapes interact with HSP70 and BAG1. The NAD+-promoted isoform binds HSP70 with higher affinity—a structural insight that could accelerate splice-switching drug design. Several such therapies already have FDA approval for other diseases (spinal muscular atrophy), making adaptation for Alzheimer’s feasible.
What’s Next on the Horizon?
Precision medicine takes center stage. Combining NAD+ precursors with targeted splicing modulators could hit tauopathies from multiple angles—metabolic support plus RNA-level correction.
Unanswered questions remain. Does EVA1C regulate splicing upstream, or is it one node in a bigger network? What about other NAD+-responsive splicing targets beyond EVA1C—could they offer additional therapeutic entry points?
The mechanistic gap matters: The study didn’t clarify whether the NAD+-splicing link operates through sirtuins, PARPs, or other NAD+-dependent enzymes. That detail affects drug development strategy.
Clinical trials are already underway. Several NAD+-related trials targeting Alzheimer’s are in progress (NCT05617508, NCT04430517), though none specifically test the splicing mechanism identified here.
Safety, Ethics, and Caveats
The study crosses species (worms, mice, human cells, postmortem tissue), but it remains preclinical. The AAV-mediated mouse model represents acute injection of mutant Tau rather than the slow accumulation in human Alzheimer’s. Translating to chronic, age-related neurodegeneration requires validation.
EVA1C’s role in non-neuronal cells (particularly oligodendrocytes, where it’s highly expressed) wasn’t fully explored. Manipulating its splicing could affect myelin or white matter—effects not captured in these experiments.
AI limitations apply. AlphaFold predictions, while validated experimentally, carry uncertainty. Binding affinity calculations assume static structures; protein interactions are dynamic in living cells.
Dosing remains unclear. The study used 6 mM in mouse drinking water (roughly 7 ml/day), which doesn’t translate directly to human doses. NAD+ precursors are already marketed as supplements, but optimal dosing, bioavailability, and long-term safety in humans aren’t settled. Over-supplementation could disrupt other NAD+-dependent processes.
Human tissue work relied on well-characterized brain banks with informed consent—ethically solid. But the sample size per Braak stage was limited (6-14 samples per group).
What This Could Mean for You
NAD+ operates as a master regulator of RNA processing in the aging brain, not just a metabolic supplement. Maintaining NAD+ levels—through diet, exercise, or supplementation—helps neurons correctly assemble the proteins they need to function.
If you’re considering NR or NMN supplementation: This adds mechanistic support, though consulting a healthcare provider remains essential. Dose and formulation matter.
Track splice-switching therapies. While experimental for Alzheimer’s, they’re advancing for other conditions. Metabolic support (NAD+) combined with precision RNA tools could define the next wave of neurodegenerative disease prevention.
The intervention window matters. In Alzheimer’s, protein misfolding and splicing errors compound over decades. Early intervention—before symptoms emerge—offers the strongest theoretical benefit.
Context: The study showed NAD+ normalizes deficiencies affecting the nervous system, oxygen metabolism, mitochondrial localization, autophagy, and behavior in tauopathy models. Translation to human healthspan awaits clinical validation, but the cross-species consistency strengthens the case.
Explore the Full Study:
Ai et al., “NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C,” Science Advances (2025). Read the full paper