The short answer is no — not yet. Despite a surge of interest in NAD+ supplements like NMN and nicotinamide riboside, no human clinical trial has demonstrated measurable cognitive improvement from taking these compounds. The supplements do raise NAD+ levels in the blood, sometimes dramatically, but that biochemical bump has not translated into better memory, sharper thinking, or slower cognitive decline in any rigorous study published to date. If you are spending $60 a month on an NMN supplement hoping to stave off dementia, the current evidence does not support that expectation.
That said, the science behind NAD+ and brain aging is far from settled, and there are reasons to keep paying attention. A landmark December 2025 mouse study achieved complete cognitive recovery in advanced Alzheimer’s models by restoring NAD+ balance — not with over-the-counter supplements, but with a targeted pharmaceutical compound called P7C3-A20. And a separate 2025 human trial found that NR supplementation reduced a key Alzheimer’s biomarker by a meaningful margin, even though participants did not report feeling any sharper. The gap between biological promise and practical results is the central tension in this field. This article walks through what NAD+ actually does in the aging brain, what the clinical trials show, where the real breakthroughs are happening, and what the safety concerns are that most supplement companies will not tell you about.
Table of Contents
- Why Does NAD+ Decline in the Aging Brain — and Does It Matter?
- What Do Human Clinical Trials Actually Show About NAD+ Supplements and Cognition?
- The Mouse Study That Changed the Conversation
- NR vs. NMN vs. P7C3-A20 — Understanding the Differences
- The Cancer Risk That Supplement Companies Do Not Advertise
- The Scale of the NAD+ Supplement Market
- Where the Science Goes From Here
- Conclusion
- Frequently Asked Questions
Why Does NAD+ Decline in the Aging Brain — and Does It Matter?
NAD+, or nicotinamide adenine dinucleotide, is a coenzyme found in every cell in the body. It plays a central role in energy metabolism, DNA repair, and the regulation of cellular stress responses. In the brain specifically, NAD+ helps mitochondria produce the enormous amount of energy that neurons require — the brain accounts for roughly 20 percent of the body’s energy consumption despite being only about 2 percent of its mass. When NAD+ levels drop, mitochondria struggle, and neurons become more vulnerable to damage, inflammation, and death. MRI-based studies in humans have shown that brain NAD+ levels decline 10 to 25 percent between young adulthood and old age, and cerebrospinal fluid measurements confirm a roughly 14 percent drop in NAD(H) in people over 45 compared to younger adults.
The systemic picture is even starker. Plasma NAD+ falls approximately 60 percent over the human lifespan, from about 50 nanomolar in adults aged 20 to 40 down to roughly 20 nanomolar in those aged 60 to 97. This decline is not just an incidental marker of aging — reduced NAD+ is directly implicated in mitochondrial dysfunction, increased susceptibility to neurodegenerative diseases, and accelerated biological aging across multiple organ systems. To put it concretely, a 70-year-old’s cells are trying to run the same biological machinery as a 30-year-old’s, but with significantly less of the fuel those processes depend on. The logical question follows: if falling NAD+ levels contribute to brain aging, can we simply top them back up? This is the premise that has launched a multibillion-dollar supplement industry. But biology is rarely that straightforward, and the distinction between raising a number on a blood test and actually improving how your brain works turns out to be enormous.
What Do Human Clinical Trials Actually Show About NAD+ Supplements and Cognition?
The supplement industry’s marketing leans heavily on a real finding: nicotinamide riboside supplementation produces an average 139 percent increase in blood NAD+ levels. That is a genuine, replicable result. NR and NMN do get absorbed, they do get converted to NAD+, and they do raise circulating levels substantially. The problem is what happens next — or more precisely, what does not happen next. In a double-blind randomized controlled trial of healthy older men aged 65 and over, NMN at 250 milligrams per day for 12 weeks raised NAD+ levels but produced no significant improvement in cognitive function as measured by the MMSE and MoCA, two standard screening tools for cognitive decline. A separate trial published in December 2025 in eClinicalMedicine, a Lancet journal, tested NR in people with long COVID. The supplement boosted NAD+ and showed some potential improvements in fatigue, sleep, and mood, but once again there were no significant between-group differences for cognitive outcomes.
The pattern is consistent across trials: the biochemistry responds, but the brain does not seem to notice. However, one result from a 2025 crossover RCT deserves careful attention. In older adults with subjective cognitive decline and mild cognitive impairment, NR at 1 gram per day for 8 weeks produced a 1.23-fold difference in phosphorylated tau-217 between treatment and placebo groups. Phosphorylated tau is one of the most reliable biomarkers for Alzheimer’s pathology, and the researchers estimated this difference could reduce the pTau217 gap between normal and MCI subjects by 39 to 72 percent. That is a meaningful biological signal. But — and this is a critical caveat — it did not translate into measurable memory improvements in the study participants. A biomarker moving in the right direction is not the same as a person thinking more clearly, and the history of Alzheimer’s research is littered with interventions that looked promising on lab work but failed to help patients.
The Mouse Study That Changed the Conversation
In December 2025, researchers at Case Western Reserve University published a study in Cell Reports Medicine that stunned even skeptics. Using a compound called P7C3-A20, they achieved complete cognitive recovery in 5xFAD mice — an aggressive Alzheimer’s model engineered to develop severe pathology. This was not a modest slowing of decline or a marginal improvement on one test. The treatment reversed tau phosphorylation, repaired blood-brain barrier deterioration, reduced oxidative stress and DNA damage, and resolved neuroinflammation. Mice with advanced-stage disease recovered fully. The mechanism matters enormously here. P7C3-A20 works by restoring NAD+ homeostasis — it brings NAD+ back to normal physiological levels without overshooting them.
This is fundamentally different from what over-the-counter NMN and NR supplements do, which is push NAD+ levels as high as possible. The Case Western researchers were explicit about this distinction: they warned that OTC NAD+ precursors can raise NAD+ to levels that may actually promote cancer growth. Cancer cells, like all rapidly dividing cells, are hungry for NAD+ to fuel their metabolism. Flooding the body with excess NAD+ may feed exactly the processes you do not want to accelerate. A separate study published in Science Advances in November 2025 added another piece to the puzzle, showing that NAD+ reverses Alzheimer’s neurological deficits by correcting errors in alternative RNA splicing of a gene called EVA1C. In tau-mutant mice, NAD+ supplementation improved RNA splicing, restored brain function, and enhanced memory. These preclinical results are genuinely exciting, but they involve precise pharmacological tools and controlled laboratory conditions — not a capsule ordered from Amazon.
NR vs. NMN vs. P7C3-A20 — Understanding the Differences
If you are wading into the NAD+ supplement space, you will encounter two main compounds: nicotinamide riboside and nicotinamide mononucleotide. Both are NAD+ precursors, meaning your body converts them into NAD+ after ingestion. NR has a longer track record in clinical research and has been used in most of the published human trials. NMN gained popularity partly due to the work of David Sinclair at Harvard, though his more extravagant claims about aging reversal remain controversial among his peers. In practice, both compounds raise blood NAD+ levels, and neither has demonstrated cognitive benefits in humans. P7C3-A20, the compound used in the Case Western mouse study, is not a supplement and is not available for purchase.
It is a synthetic neuroprotective agent that enhances the activity of NAMPT, a rate-limiting enzyme in the NAD+ salvage pathway. Rather than flooding the system with raw NAD+ precursor material, it fine-tunes the body’s own production machinery to maintain normal levels. Think of it as the difference between dumping extra fuel into an engine versus tuning the fuel injection system to run at optimal efficiency. The distinction matters because the dose-response relationship for NAD+ may not be linear — more is not necessarily better, and there appears to be a therapeutic window above which the risks may outweigh the benefits. For consumers currently spending $59 to $70 per bottle on NMN or NR supplements, this creates an uncomfortable reality. The compounds that have shown the most dramatic preclinical results are not the ones available at your local health food store, and the ones you can buy have not demonstrated the outcomes most people are hoping for.
The Cancer Risk That Supplement Companies Do Not Advertise
The most important safety concern around NAD+ supplementation is one you will rarely see on a product label. The Case Western Reserve researchers who achieved full Alzheimer’s reversal in mice went out of their way to warn that pushing NAD+ levels above normal physiological ranges — which is precisely what high-dose NR and NMN supplements do — may promote cancer. This is not a theoretical concern plucked from the air. NAD+ is essential for cellular energy production, and cancer cells are among the most energy-hungry cells in the body. Providing them with additional metabolic fuel could accelerate tumor growth. This does not mean that taking an NR supplement will give you cancer.
The research on this specific risk is still early, and the doses used in most human trials have not produced alarming safety signals over their relatively short durations of 8 to 12 weeks. But the absence of evidence of harm in short trials is not the same as evidence of safety over years of daily use. Most people who take NAD+ supplements plan to take them indefinitely, and the long-term cancer risk profile of chronically elevated NAD+ levels in humans is simply unknown. If you have a personal or family history of cancer, this is a conversation worth having with an oncologist before starting supplementation. The broader lesson is that the body’s decline in NAD+ production with age may not be purely a malfunction to be corrected. Some researchers have speculated that reduced NAD+ in older adults could be partially protective — a tradeoff that sacrifices some cellular performance to limit the metabolic resources available to precancerous cells. This is speculative, but it underscores how little we truly understand about intervening in fundamental metabolic pathways.
The Scale of the NAD+ Supplement Market
The global NAD+ products market was valued at $3.45 billion in 2024 and is projected to reach $12.19 billion by 2033, growing at a compound annual rate of 15.1 percent. The NMN market alone was valued at $372.95 million in 2025, projected to hit $410.25 million in 2026.
These are not niche products anymore — they represent a massive commercial ecosystem built largely on preclinical research and the hope that what works in mice will eventually work in humans. For context, the gap between a promising mouse study and an approved human therapy is historically about 13 years and a 95 percent failure rate. Consumers are essentially placing a very expensive bet on science that has not yet crossed the finish line.
Where the Science Goes From Here
The next few years will be pivotal. If P7C3-A20 or a similar targeted NAD+ modulator enters human clinical trials, the results could fundamentally change how we approach neurodegenerative disease. The RNA splicing mechanism discovered in late 2025 also opens new avenues — if NAD+ corrects splicing errors in specific genes associated with Alzheimer’s, it may be possible to develop interventions that target those pathways precisely rather than relying on a blunt systemic increase in NAD+ levels. For now, the honest position is one of informed patience.
The biology connecting NAD+ decline to brain aging is solid. The preclinical results are among the most exciting in Alzheimer’s research in decades. But the clinical evidence for supplements you can actually buy today does not support claims of cognitive improvement, and there are legitimate safety questions about long-term use. The most responsible approach is to follow the research closely, maintain the lifestyle factors that naturally support NAD+ metabolism — regular exercise, adequate sleep, caloric moderation — and resist the urge to treat a $60 bottle of capsules as a substitute for the targeted therapies that may eventually emerge from this science.
Conclusion
NAD+ decline in the aging brain is real, well-documented, and almost certainly contributes to cognitive vulnerability and neurodegenerative disease. The drop of 10 to 25 percent in the brain and roughly 60 percent systemically over a lifetime represents a meaningful erosion of the cellular infrastructure that keeps neurons healthy. The preclinical breakthroughs of late 2025 — particularly the full reversal of advanced Alzheimer’s in mice using P7C3-A20 — suggest that restoring NAD+ balance could eventually become a cornerstone of dementia treatment. The RNA splicing work adds mechanistic depth that makes these findings more than just another mouse study. But the supplements available today are not the therapies of tomorrow.
NR and NMN reliably raise blood NAD+ levels without producing detectable cognitive benefits in any published human trial. The gap between a rising biomarker and a sharper mind remains unbridged. Add the unresolved question of whether chronically elevated NAD+ could promote cancer, and the case for supplementation becomes difficult to make on scientific grounds alone. The most honest answer to the title’s question is: not yet, and possibly not with the tools currently on the shelf. The science is worth watching. The supplements are not yet worth the confidence the market places in them.
Frequently Asked Questions
Does NMN or NR cross the blood-brain barrier?
This remains an area of active research. NR and NMN are converted to NAD+ in the body, but how efficiently they raise NAD+ specifically in brain tissue — as opposed to blood and peripheral tissues — is not fully established in humans. The blood-brain barrier is selective, and systemic NAD+ increases do not guarantee proportional increases in the brain.
How much does NAD+ supplementation cost?
Typical NMN and NR supplements run between $59 and $70 per bottle, usually representing a one-month supply at standard dosing. Some higher-dose or combination products cost more. Over a year, that is roughly $700 to $840 for a supplement with no proven cognitive benefit in humans.
Is P7C3-A20 available as a supplement?
No. P7C3-A20 is a synthetic research compound that has only been tested in animal models. It is not available for purchase, and no human clinical trials have been conducted with it. It works by a different mechanism than OTC NAD+ precursors, restoring balance rather than pushing levels above normal.
Can lifestyle changes raise NAD+ levels without supplements?
Yes. Regular aerobic exercise, caloric restriction, and adequate sleep have all been associated with supporting NAD+ metabolism. Exercise in particular activates NAMPT, the same enzyme that P7C3-A20 targets, though to a lesser degree. These interventions also carry well-established cognitive benefits independent of their effects on NAD+.
Should I stop taking NMN or NR supplements?
That is a personal decision best made with your doctor. The supplements are not harmful in the short term based on current trial data, but they have not demonstrated cognitive benefits, and their long-term safety profile — particularly regarding cancer risk — is unknown. If you are taking them specifically for brain health, the evidence does not currently support that use.
