The Forgotten Science Of Phosphatidylserine — Approved By The Fda, Then Ignored
Quick Read Phosphatidylserine (PS) is a natural fat that your brain cells use to function properly, particularly for memory and
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NAD+ is a molecule your brain needs to produce energy and maintain healthy cells. It declines significantly as you age, which may contribute to slower thinking and brain fatigue. Recent research shows that supplements like nicotinamide riboside (NR) can actually reach your brain and raise NAD+ levels. A small clinical trial found that NR improved blood flow to the memory center of the brain in older adults with mild cognitive problems, though memory itself didn’t improve over the 12-week study period.
Research in animals and human cells suggests NAD+ helps your brain’s waste disposal system and immune cells work better. However, most of the detailed science comes from studies in mice or cells, not people. While NR supplements appear safe with few side effects, the human evidence is still limited in size and duration. The strongest case for supplementation is as a preventive measure in middle age, not as a treatment for established memory disease.
If you’re interested in NAD+ supplements based on this evidence, NR is the better-studied form, typically used at doses of 300 to 1,000mg daily. Results take time, not days. This approach works best alongside sleep, exercise, and good diet, not instead of them. Larger, longer human trials are still needed to confirm whether supplementation actually protects memory over years.
Verdict: NAD+ supplements show promising early evidence for brain health and blood flow, but human evidence remains too limited to confirm they prevent cognitive decline, making them most suitable as a preventive option rather than a proven treatment.
What if the reason you feel mentally slower, more fatigued, and less sharp in your 40s and 50s isn’t just “getting older”, but the decline of a single molecule that powers almost every cell in your body? It sounds almost too simple. But the research building around nicotinamide adenine dinucleotide, NAD+, is hard to ignore. This is a molecule your brain genuinely cannot function without, and by the time you hit middle age, you have significantly less of it than you did at 20. The question scientists are now racing to answer is: can we do something about that?
From Vitacuity’s analysis of over 1.77 million research papers, we selected the 15 most relevant studies on NAD+ and brain energy to give you the clearest picture available. Here’s what the evidence actually says.
Think of NAD+ as the molecule that keeps your cellular power stations, mitochondria, running. It acts as a kind of biological electron shuttle, picking up energy from the food you eat and converting it into a form your cells can actually use. Without enough NAD+, your mitochondria become inefficient. Energy production slows. Cellular repair mechanisms stall. And in the brain, where energy demand is extraordinarily high, that matters enormously [6].
But NAD+ does more than just fuel mitochondria. It acts as a substrate for a family of proteins called sirtuins, essentially your cells’ quality-control managers. Sirtuins regulate DNA repair, reduce inflammation, and help clear out damaged proteins through a process called autophagy (think of autophagy as your brain’s waste disposal system, it removes cellular rubbish before it accumulates into the kind of toxic plaques associated with Alzheimer’s disease) [3]. When NAD+ falls, sirtuin activity falls with it. The waste disposal slows. Damage accumulates.
There are several ways to boost NAD+ through supplementation. The two most studied are nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), both precursors that the body converts into NAD+. They work slightly differently in the body, and their relative merits are still being studied [9].
The question is: does restoring NAD+ actually translate into meaningful benefits for the ageing brain?
Before asking whether raising NAD+ helps, you first need to know whether oral supplements actually reach the brain. This isn’t as obvious as it sounds, many compounds taken by mouth never make it past the blood-brain barrier.
A 2024 study published in *Magnetic Resonance in Medicine* tested this directly in humans, using a brain-scanning technique called downfield proton MRS (magnetic resonance spectroscopy) to measure NAD+ levels inside the brain itself [14]. Participants were given a single dose of NR, and researchers measured cerebral NAD+ before and after.
The result: NR supplementation increased mean brain NAD+ levels by a statistically significant margin. This is preliminary data, the sample was small and the participants were young adults, not older individuals, but it’s a meaningful proof of concept. NAD+ precursors can actually cross into the brain and raise levels where it counts.
Evidence grade: Promising, single acute-dose study in young adults, small sample. We need longer trials in older populations. But this is encouraging early confirmation that the mechanism is real.
One of the most clinically significant findings in our research pool comes from a 2025 double-blind, randomised, placebo-controlled pilot trial, the gold standard of study design, published in *Alzheimer’s & Dementia* [5].
52 older adults with mild cognitive impairment (MCI) were randomised to receive either NR or placebo for 12 weeks. The researchers were specifically measuring two things: safety and blood flow to the hippocampus, the brain’s memory centre.
Here’s what they found:
– NR was well-tolerated with no serious adverse effects – Blood NAD+ levels increased significantly in the NR group – Hippocampal blood flow (perfusion) improved in the NR group, regardless of whether participants had underlying Alzheimer’s pathology – However, and this is important, the improvement in blood flow did not translate into measurable improvements in memory performance over this 12-week period
The researchers are calling for a larger phase III trial over a longer duration. Thirty-three of the 52 participants were female; 19 were male. Adherence was high at 85% in the NR group.
Evidence grade: Promising, this is a properly designed RCT but it’s a pilot study (52 participants, 12 weeks). The blood flow finding is genuinely exciting; the absence of memory improvement is a realistic reminder that brain changes take time.
You may not have heard of microglia, but they are your brain’s resident immune cells, a kind of internal maintenance crew that patrols for damage, clears debris, and protects neurons. As we age, microglia shift into a dysfunctional state. They become chronically activated, pro-inflammatory, and less able to do their protective job [1, 13].
A 2025 study found that NR supplementation restored microglial health in aged male mice, shifting them away from this dysfunctional “disease-associated” state and back toward normal protective function. The aged mice showed improved cognition alongside the microglial improvements.
This is significant because it points to a mechanism beyond energy metabolism alone. NAD+ decline may be contributing to brain ageing partly by degrading the brain’s own immune maintenance system. If NR can restore that, the implications for cognitive resilience are considerable.
Evidence grade: Early stage, this is mouse data. Important and mechanistically plausible, but human trials are needed before we can say this applies to people.
Two 2025 studies published in *Autophagy* and *Science Advances* respectively explored how NAD+ depletion disrupts the brain’s housekeeping processes [3, 4].
The first found that as NAD+ falls, the efficiency of autophagy, the cellular recycling system that clears damaged proteins, declines significantly in ageing and neurodegeneration. Without adequate autophagy, toxic protein aggregates accumulate. The researchers identified NAD+ precursors as a potential way to restore this clearing function.
The second study, published in *Science Advances*, linked NAD+ decline specifically to dysfunctional RNA splicing, a process that determines how genes are read and proteins are made in neurons. Errors in RNA splicing are markers of both normal ageing and Alzheimer’s disease. In hippocampal tissue and mouse models of Alzheimer’s, restoring NAD+ with precursors corrected some of these splicing errors and showed neuroprotective effects.
Evidence grade: Early stage, these are primarily animal and cellular studies, with some human tissue analysis. Mechanistically compelling. Human trials needed.
Nicotinamide mononucleotide (NMN), the other major NAD+ precursor, has been studied for its effects on brain bioenergetics. A 2019 review in *Neurochemical Research* [11] examined NMN’s multi-targeted mechanisms and found evidence for improvements across several pathways involved in brain energy metabolism: mitochondrial function, acetylation regulation, and NAD-dependent enzyme activity.
A 2024 review in *Biochemical and Biophysical Research Communications* [10] added gut microbiota as an emerging pathway, NMN may partly work by beneficially altering gut bacteria, which in turn influence brain health through the gut-brain axis.
Evidence grade: Early stage for brain-specific NMN effects, most of the mechanistic data comes from animal models. The gut microbiota angle is particularly early. Human cognitive data for NMN specifically is still thin.
A 2025 pilot trial published in the *Journal of Pharmacology and Experimental Therapeutics* looked at older adults with peripheral artery disease, a condition associated with accelerated vascular ageing and elevated risk of cognitive decline [2, 15].
NR supplementation reduced oxidative stress markers, improved endothelial function (the health of blood vessel linings), and showed signs of improved cerebrovascular health in this high-risk group. The vascular-cognitive connection matters here: healthy blood flow is essential for brain function, and vascular dysfunction is a major driver of age-related cognitive decline.
This isn’t a purely brain study, but it’s human data showing NAD+ precursors can improve the vascular infrastructure that the brain depends on.
Evidence grade: Promising, pilot trial, small sample, but human data in a relevant at-risk population with measurable vascular outcomes.
A comprehensive 2022 review in *Nutrients* [6] synthesised the evidence for NAD+ precursors across cognitive decline, dementia, diabetes, stroke, and traumatic brain injury. The overall conclusion was cautiously optimistic: NAD+ precursors, particularly NR and NMN, show genuine promise for cognitive protection, particularly when started before significant neurodegeneration has occurred.
However, a separate 2022 study in *Aging Cell* [7] introduced an important nuance. Using human-derived cells from late-onset Alzheimer’s patients, researchers found that while NR (with or without caffeine) could partially restore NAD+ levels, it did not alter the underlying dysfunctional energy metabolism pattern characteristic of Alzheimer’s disease. In other words: raising NAD+ may not be sufficient on its own to reverse established Alzheimer’s pathology.
The researchers suggested NR might still be valuable as part of a combination strategy, particularly for prevention rather than treatment of advanced disease.
Evidence grade: Conflicted, the preventive case is genuinely supported; the therapeutic case for established Alzheimer’s is much less clear. The most likely truth is that timing matters enormously: acting early, when NAD+ decline begins rather than after significant neurodegeneration has occurred, is probably where the real opportunity lies.
It’s worth being honest about the significant gaps in this research.
Most of the mechanistic work is in mice, not people. The microglial findings, the autophagy findings, the RNA splicing findings, these are all from animal or cellular models. They are important because they tell us *how* NAD+ might protect the brain, but they cannot confirm that the same effects occur in humans at the same scale [1, 3, 4].
Human trials are small and short. The most rigorous human RCT in our dataset involved just 52 participants over 12 weeks [5]. That’s a pilot study, well-designed, but far too small to draw firm conclusions about cognitive outcomes. Larger, longer trials are urgently needed.
We don’t yet know the optimal dose, form, or timing. NR and NMN appear to work differently, and different doses have been tested across different studies. The 2023 review in *Drugs & Aging* [9] notes that these precursors vary in their ability to raise NAD+ and carry differing potential side effects. The most effective protocol for brain health specifically hasn’t been established.
Brain blood flow improved but memory didn’t, at least not in 12 weeks. The 2025 pilot trial [5] found hippocampal perfusion improved with NR but memory scores didn’t change significantly. This might mean 12 weeks isn’t long enough to see cognitive benefits, or it might mean perfusion improvements don’t automatically translate into better memory. We genuinely don’t know yet.
Raising NAD+ may not be sufficient on its own for established neurodegeneration. The 2022 cell study [7] found NR couldn’t overcome the metabolic signature of late-onset Alzheimer’s. This is an important caveat, NAD+ supplementation looks most promising as a protective strategy, not necessarily a reversal strategy.
So here’s the honest, practical version of where the NAD+ science stands.
The biology is compelling. NAD+ genuinely declines with age. It genuinely matters for brain energy, DNA repair, cellular waste disposal, and immune function in the brain. And there is now direct human evidence that oral NR supplementation can raise NAD+ levels inside the brain itself [14], improve blood flow to the hippocampus in people with early cognitive impairment [5], and reduce vascular dysfunction in older adults at risk of cognitive decline [2].
What we can’t yet say with confidence is that supplementing with NR or NMN will definitely protect your memory over the long term. The human trial data simply isn’t there yet at the scale needed to make that claim. Anyone who tells you otherwise is running ahead of the evidence.
But here’s how a sensible, well-informed person should think about this:
NR and NMN supplements are water-soluble, well-tolerated, and show no serious adverse effects at typical doses in the human trials conducted so far [5, 6]. The risk of doing nothing, allowing NAD+ to continue declining through your 40s, 50s and 60s, has a plausible and increasingly well-characterised biological cost. The risk of supplementing at normal doses is, based on current evidence, low.
The evidence is strongest for prevention, not cure. If your goal is to maintain cognitive function and brain energy as you age, rather than reverse established disease, the case for NAD+ precursors is considerably more persuasive than if you’re hoping to treat significant neurodegeneration.
Practical steps, based only on what the research supports:
– If you’re in your 40s or 50s and want to act on the NAD+ research, NR is the better-studied precursor for brain-specific effects. The doses used in human trials have typically been in the 300–1,000mg range. Look for products where the dose is clearly stated. – Consistency matters, the 12-week pilot trial [5] showed blood flow improvements but not memory improvements, suggesting that benefits may require longer durations. This is not a “take it once and feel the difference” supplement. Think months, not days. – Combine with the basics first, NAD+ supplementation works within a broader context. Sleep, exercise, and diet all influence NAD+ metabolism independently. No supplement compensates for severely disrupted sleep or a sedentary lifestyle. – Watch this space, this is a genuinely active area of research. The results of larger phase III trials will substantially sharpen the picture.
The bottom line: the science is not yet definitive, but it is pointing in a consistent and intriguing direction. For anyone serious about brain health in midlife and beyond, NAD+ is one of the most scientifically grounded areas to pay attention to right now.
[1] Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice (2025). DOI: 10.1007/s11357-025-01959-1 | https://pubmed.ncbi.nlm.nih.gov/41273482/
[2] Effects of NAD+ precursor nicotinamide riboside on cerebrovascular health and cognitive function in peripheral artery disease (2025). DOI: 10.1016/j.jpet.2025.103607 | https://pubmed.ncbi.nlm.nih.gov/40479886/
[3] NAD+ decline, autophagy and neurodegeneration: NAD+ precursors in tauopathy and Alzheimer’s disease (2025). DOI: 10.1080/15548627.2025.2596679 | https://pubmed.ncbi.nlm.nih.gov/41313318/
[4] NAD+ and alternative splicing in Alzheimer’s disease and hippocampal neurodegeneration (2025). DOI: 10.1126/sciadv.ady9811 | https://pubmed.ncbi.nlm.nih.gov/41202143/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12594206/
[5] NR supplementation in mild cognitive impairment: 12-week double-blind RCT pilot study (2025). DOI: 10.1002/alz70861_108851 | https://pubmed.ncbi.nlm.nih.gov/41434050/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12724761/
[6] Supplementation with NAD+ precursors and cognitive decline: a review (2022). *Nutrients*. DOI: 10.3390/nu14153231 | https://pubmed.ncbi.nlm.nih.gov/35956406/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9370773/
[7] Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer’s disease (2022). *Aging Cell*. DOI: 10.1111/acel.13658 | https://pubmed.ncbi.nlm.nih.gov/35730144/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282847/
[8] Can nicotinamide riboside protect against cognitive impairment? (2020). DOI: 10.1097/MCO.0000000000000691 | https://pubmed.ncbi.nlm.nih.gov/32925178/
[9] Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders (2023). *Drugs & Aging*. DOI: 10.1007/s40266-022-00989-0 | https://pubmed.ncbi.nlm.nih.gov/36510042/
[10] The therapeutic perspective of NAD+ precursors and gut microbiota in ageing (2024). *Biochemical and Biophysical Research Communications*. DOI: 10.1016/j.bbrc.2024.149590 | https://pubmed.ncbi.nlm.nih.gov/38340651/
[11] Multi-targeted Effect of Nicotinamide Mononucleotide on Brain Bioenergetic Metabolism (2019). *Neurochemical Research*. DOI: 10.1007/s11064-019-02729-0 | https://pubmed.ncbi.nlm.nih.gov/30661231/
[12] Nicotinamide mononucleotide: An emerging nutraceutical against cardiac aging? (2021). DOI: 10.1016/j.coph.2021.08.006 | https://pubmed.ncbi.nlm.nih.gov/34507029/
[13] Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice (2025) [duplicate entry confirming DOI]. DOI: 10.1007/s11357-025-01959-1 | https://pubmed.ncbi.nlm.nih.gov/41273482/
[14] Acute nicotinamide riboside supplementation increases human cerebral NAD+ (2024). *Magnetic Resonance in Medicine*. DOI: 10.1002/mrm.30227 | https://pubmed.ncbi.nlm.nih.gov/39044608/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436296/
[15] Effects of NAD+ precursor NR on vascular and cerebrovascular outcomes in peripheral artery disease, pilot trial (2025). DOI: 10.1016/j.jpet.2025.103607 | https://pubmed.ncbi.nlm.nih.gov/40479886/
This article is for informational purposes only and does not constitute medical advice. Food supplements should not be used as a substitute for a varied and balanced diet and healthy lifestyle. If you are pregnant, breastfeeding, taking medication or have a medical condition, consult your doctor before taking any supplement. These statements have not been evaluated by the Food and Drug Administration (FDA) or the Medicines and Healthcare products Regulatory Agency (MHRA). This product is not intended to diagnose, treat, cure, or prevent any disease.
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