Supplements With Evidence In Mild Cognitive Impairment
Quick Read Mild cognitive impairment is a grey zone between normal age-related memory changes and dementia, and it may be
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Alzheimer’s disease may partly involve an energy crisis in the brain. A molecule called NAD+ helps cells produce energy, and levels of NAD+ decline with age and are particularly low in people with Alzheimer’s. When NAD+ runs low, brain cells struggle to produce the power they need to function, and damage accumulates.
Animal studies show that supplements that boost NAD+ (NMN and NR) protect brain cells, reduce harmful proteins, and improve memory. Two human trials with NR showed encouraging improvements in brain scans and thinking ability, though both were small and short. A study combining NAD+ with antioxidants in 50 Alzheimer’s patients found no disease worsening in over half the group, but this lacked a control group so it’s preliminary.
However, one study found that NAD+ alone cannot fully reverse the energy dysfunction in established Alzheimer’s disease, suggesting earlier prevention is more promising than treating advanced disease. Much larger human trials are underway. These supplements appear safe and affordable, but current human evidence is limited.
Verdict: NAD+ precursors like NR and NMN show strong biological promise for brain aging based on animal and limited human data, but solid proof in large-scale human trials is not yet available, and they likely work best as part of a broader brain health strategy started before symptoms appear.
What if some of what we call “Alzheimer’s disease” is, at least in part, an energy crisis? Not a metaphorical one, a literal, cellular failure to produce enough power to keep your neurons alive, connected, and functioning. It’s a provocative idea, and it’s one that a growing number of researchers are taking very seriously. Because buried inside the complex story of amyloid plaques and tau tangles, the usual suspects in Alzheimer’s, there’s another story unfolding. One about a molecule called NAD+, and what happens when your brain starts running critically low on it.
Vitacuity reviewed over 1.77 million research papers and selected the most relevant studies on this topic. What emerged is a picture that is genuinely exciting, and genuinely incomplete. Here’s what we know, what we don’t, and what it might mean for you.
NAD+ stands for nicotinamide adenine dinucleotide. Don’t let the name put you off, the concept is straightforward. NAD+ is a coenzyme, meaning it’s a helper molecule that your cells absolutely cannot function without. It sits at the heart of energy production, acting as a kind of molecular relay baton in the process your mitochondria use to generate ATP, the currency your cells spend on every biological task [12].
But NAD+ does more than keep the lights on. It also acts as a substrate, a raw material, for enzymes called sirtuins and PARPs, which are involved in DNA repair, gene expression, stress response, and inflammation management [12]. Think of NAD+ as both the fuel and part of the engine itself.
Here’s the problem: NAD+ levels decline with age. This isn’t a minor dip, research consistently shows significant depletion as we get older, and this decline appears to be particularly pronounced in people with late-onset Alzheimer’s disease [3][7]. When NAD+ falls, mitochondria struggle, energy production drops, oxidative stress rises, and neurons become vulnerable. In Alzheimer’s brains, researchers have documented decreased activity in electron transport chain complexes I, III and IV, the very machinery that NAD+ helps power, alongside reduced glucose utilisation and elevated oxidative stress [5].
The logical question follows: could restoring NAD+ levels protect the brain? That’s exactly what a new wave of research is trying to answer.
One of the most striking recent findings is that NAD+ substrate deficiency isn’t just a side effect of Alzheimer’s, it may be a contributing cause. A 2025 study published by researchers examining late-onset Alzheimer’s disease specifically characterises NAD+ deficiency as “an inherent and targetable risk factor” for the condition [3]. That language, inherent and targetable, is significant. It suggests this isn’t just incidental damage; it’s a vulnerability baked into the disease biology.
This connects to broader evidence showing that NAD+ decline is involved in multiple key disease pathways in neurodegeneration: mitochondrial dysfunction, energy deficits, loss of proteostasis (the cell’s ability to manage protein quality and clearance), and neuroinflammation [2]. When you look at Alzheimer’s through this lens, NAD+ depletion isn’t one problem among many, it’s a thread running through several of them simultaneously.
Evidence grade: Promising, there are human data and strong mechanistic evidence, but this is a rapidly evolving area with much of the causal evidence still being established.
Nicotinamide mononucleotide (NMN) is one of the most studied direct precursors to NAD+. Your body can convert NMN into NAD+ relatively efficiently, making it a practical way to top up levels.
In a 2016 study, researchers used a rat model of Alzheimer’s in which amyloid-beta oligomers, the toxic protein fragments now considered the primary neurotoxic agents in AD, were infused directly into the brain [8]. These amyloid-beta oligomers are the form of amyloid believed to do the most damage at the synapse level, disrupting communication between neurons and triggering cell death.
Treatment with NMN at 500mg/kg (intraperitoneally, meaning injected, not oral) produced several notable results: it sustained cognitive function as measured by the Morris water maze, attenuated neuronal cell death in hippocampal slice cultures, restored NAD+ and ATP levels, and reduced the accumulation of reactive oxygen species, the unstable molecules that cause oxidative damage [8]. Crucially, all of these protective effects were reversed when researchers blocked NAD+ activity, confirming that the benefits were genuinely NAD+-dependent rather than some other mechanism.
A separate 2017 study in transgenic Alzheimer’s mice found that NMN treatment significantly reduced amyloid plaque burden, decreased beta-amyloid production, reduced synaptic loss, and dampened inflammatory responses [15]. The researchers identified a specific mechanism: NMN appears to inhibit activation of JNK, a stress signalling protein that, when chronically active, accelerates multiple aspects of Alzheimer’s pathology.
An earlier 2015 study in a double transgenic Alzheimer’s mouse model (APP/PS1) confirmed that NMN could address mitochondrial respiratory deficits, essentially helping the power plants in brain cells work more efficiently, and improved mitochondrial morphology [9].
Evidence grade: Promising in animal models, results across multiple independent rodent studies are consistent and mechanistically coherent. Human trials using NMN specifically for Alzheimer’s are not yet available in the published literature [6].
Nicotinamide riboside (NR) is the other major NAD+ precursor generating significant research interest. Unlike NMN, NR has actually been tested in some human clinical trials for Alzheimer’s, a meaningful step forward.
A 2024 systematic review identified two human clinical trials showing “marked improvements in plasma and neuroimaging biomarkers, and cognitive measures” following NR supplementation in Alzheimer’s patients [6]. That’s an encouraging signal, but it’s important to be precise about what we know: the review notes that the trials were limited in number, and the authors explicitly call for further clinical studies before NR can be considered a confirmed pharmacological intervention.
A 2021 study added another dimension by examining how NR might work in Alzheimer’s brains. Researchers found that NR reduced senescence of affected cells, attenuated DNA damage, and normalised the activity of the cGAS-STING pathway, a cellular alarm system that, when overactivated, drives chronic neuroinflammation [10]. In the APP/PS1 Alzheimer’s mouse model, NR also increased mitophagy (the cellular process of clearing out damaged mitochondria) and improved both cognition and behaviour [10]. Elevated cGAS-STING activity observed in both AD mouse brains and human AD fibroblasts was normalised following NR treatment, a finding with clear implications for the neuroinflammation that accelerates disease progression.
A 2024 study exploring NR’s effects in mouse brain tissue found brain-region-specific effects on oxidative phosphorylation, fatty acid oxidation, and neurotransmitter regulation pathways, with cognitive benefits and reduced neuroinflammation occurring without any decrease in amyloid plaque burden [13]. This is a critical finding: NR doesn’t appear to clear plaques, but it seems to make the brain more resilient to them. That’s a different but potentially valuable mechanism.
Evidence grade: Promising, two human trials with positive biomarker and cognitive findings, supported by mechanistic animal data. Sample sizes remain small and trial durations short.
Most discussion of NAD+ and Alzheimer’s focuses on energy and amyloid. But two less-publicised mechanisms deserve attention.
First, autophagy, the cellular housekeeping system that clears damaged proteins and organelles. Autophagy efficiency declines with aging and neurodegeneration, and a 2025 study found that NAD+ depletion specifically impairs autophagy in ways that accelerate Alzheimer’s-related tau pathology [4]. The study used machine learning to link NAD+ precursor treatment to improvements in RNA splicing patterns and reductions in tauopathy markers, a sophisticated approach that points to NAD+ playing a role in multiple upstream regulatory processes.
Second, a 2025 study published in *Science Advances* found that dysfunctional alternative splicing events in RNA, errors in how genetic instructions are processed, are markers of both aging and Alzheimer’s disease, and that NAD+, described as “a key neuronal resilience metabolite,” plays a role in maintaining normal splicing function [1]. This is early-stage research, but it adds to the picture of NAD+ as something far more fundamental than simply a fuel molecule.
Evidence grade: Early stage, these are emerging mechanistic findings, primarily from animal and cellular models, pointing to novel pathways that require human investigation.
One of the most clinically significant pieces of research in this space comes from a 2025 pilot study involving 50 Alzheimer’s patients who received intravenous infusions of a biosupplement combination including NAD, alpha-lipoic acid, vitamin C and glutathione [5]. This was not a pure NAD+ study, it tested an antioxidant cocktail, but the results are worth noting.
After one year, 27 of the 50 patients showed no signs of deterioration, 18 showed mild cognitive improvement on MOCA and ADAS-cog scores, and only 5 showed mild deterioration. No side effects were observed [5]. This is a very small, uncontrolled study, there was no placebo group, which is a fundamental limitation, and it tested a combination of compounds rather than NAD alone. But it adds to a consistent pattern: targeting the mitochondrial energy crisis in Alzheimer’s with antioxidant and NAD-supporting compounds produces signals worth following up.
The underlying rationale is biologically sound. In Alzheimer’s, decreased electron transport chain function in mitochondrial complexes I, III and IV, combined with reduced glucose utilisation and elevated oxidative stress, creates a progressive energy deficit that ends in neuronal death [5]. NAD+ sits directly in this pathway, restoring it, at least partially, addresses the deficit at its source.
Evidence grade: Promising rationale, very early clinical data, the 50-patient study lacks a control group and tests multiple compounds simultaneously. The mechanistic basis is well-supported; the clinical evidence needs much larger, controlled trials.
Here is where intellectual honesty matters. A thoughtful 2022 study specifically examined whether NR, with or without caffeine (which increases a key NAD-producing enzyme, NMNAT2), could restore the abnormal energy metabolism seen in late-onset Alzheimer’s disease [7].
The findings were nuanced and important. In patient-derived skin cells and stem-cell-derived neural progenitors from late-onset Alzheimer’s patients, NR and caffeine did partially restore diminished NAD+ availability. They also transiently enhanced mitochondrial respiration or glycolysis in a cell-type-specific way. However, and this is the crucial finding, continued treatment led to reversed bioenergetic effects, and neither NR nor caffeine altered what the researchers describe as an “inherent LOAD-associated bioenergetic phenotype” [7].
In plain English: there may be something fundamentally different about how late-onset Alzheimer’s cells handle energy, and simply topping up NAD+ doesn’t fully fix it. The researchers concluded that NR “might still be of value in combination with other agents in preventive or therapeutic intervention strategies”, but that NAD+ alone is unlikely to be a complete solution [7].
This finding doesn’t invalidate the case for NAD+ precursors. It refines it. It suggests that earlier intervention, before the bioenergetic phenotype becomes entrenched, may be more effective, and that combination approaches may be necessary for established disease.
Evidence grade: Promising, with important limitations clearly stated, this was a sophisticated in vitro study using human-derived cells, which is more relevant than pure animal data, but not the same as a large clinical trial.
Let’s be direct about the gaps, because they matter.
The human clinical trial evidence is thin. Almost everything compelling here comes from animal models, primarily transgenic mice engineered to develop Alzheimer’s-like pathology. Mice are not humans, and multiple promising Alzheimer’s treatments have failed to translate from mice to people. The systematic review in this space found zero published human clinical trials using NMN for Alzheimer’s, and only two human trials using NR, both showing encouraging signals, but both limited by small size and short duration [6].
We don’t know the right dose or timing. Animal studies use doses that don’t directly translate to human equivalents. The two NR human trials haven’t yet established an optimal dosing protocol for cognitive outcomes specifically. Earlier intervention may be more effective, but we don’t have data defining when “earlier” means.
We don’t know whether NAD+ precursors work differently depending on stage of disease. The 2022 study suggests that in established late-onset Alzheimer’s, the bioenergetic machinery may be too compromised for NAD+ alone to fix [7]. This implies a potential window of opportunity, but where that window opens and closes is unknown.
We don’t know which precursor is best. NMN and NR both increase NAD+, but via different pathways and with potentially different tissue distributions and effects [14]. Head-to-head human trials in the context of Alzheimer’s don’t yet exist.
The mechanisms are multiple and interconnected. NAD+ affects energy, inflammation, DNA repair, autophagy, RNA splicing, and protein clearance all at once [1][2][4][12]. That complexity makes it harder, not easier, to isolate what’s doing what, and to design clean trials.
Many more clinical trials are currently underway, reflecting genuine scientific urgency in this field [2]. The next few years should tell us considerably more.
Here’s how a sensible, well-informed person should think about this.
The case for NAD+ in brain ageing is not yet proven in humans at the level of large, multi-centre randomised controlled trials. Anyone who tells you otherwise is getting ahead of the evidence. But the mechanistic case, the biological logic, is among the strongest of any supplement area in brain health. NAD+ sits at the centre of energy production, inflammation control, DNA repair, and cellular housekeeping. Its decline with age is documented. Its specific depletion in Alzheimer’s disease is documented. The animal data showing that restoring it protects neurons, reduces pathological markers, and improves cognition is consistent across multiple independent research groups [8][9][10][11][15]. And the first human signals with NR are encouraging [6].
The 2022 study that found NR couldn’t fully reverse established late-onset Alzheimer’s bioenergetics is actually, in a strange way, a useful finding for healthy people in their 40s and 50s [7]. It suggests that the time to think about NAD+ is before the energy crisis becomes entrenched, not after. Prevention logic applies here more strongly than treatment logic.
Practical steps worth taking:
1. Consider an NR or NMN supplement. Both are well-tolerated in humans, available without prescription, and affordable relative to the cost of cognitive decline. NR has the most human safety and bioavailability data. NMN has strong animal model evidence. Either is a reasonable choice at this stage of knowledge [6][14]. Both are water-soluble and cleared through normal metabolic pathways, there is no meaningful toxicity risk at standard doses.
2. Don’t think of this as a silver bullet. The 2025 review is explicit that NAD+ augmentation targets multiple disease pathways, but the field is still determining “the specific contexts in which NAD supplementation is most effective” [2]. Think of it as supporting your brain’s resilience infrastructure, not as a cure.
3. Think combination, not isolation. The research hints consistently at NAD+ working best as part of a broader strategy that addresses mitochondrial health, oxidative stress, and inflammation together [5][7]. It’s one important piece of a larger picture.
4. Earlier is probably better. If the bioenergetic hypothesis is correct, supporting NAD+ levels during healthy ageing, before the machinery shows signs of breakdown, is likely more effective than waiting for symptoms. The evidence doesn’t yet confirm this definitively, but the biological logic is sound [3][7].
5. Watch this space. Multiple clinical trials are underway [2]. This is one of the fastest-moving areas in brain health research. What we know in two years will be significantly richer than what we know today.
The story of NAD+ and Alzheimer’s is, at its heart, a story about energy, and about the possibility that we can do something meaningful to protect the brain’s power supply as we age. It’s not proven. But the direction of travel is increasingly clear.
[1] NAD+ as a key neuronal resilience metabolite and dysfunctional alternative splicing in Alzheimer’s disease (2025). DOI: 10.1126/sciadv.ady9811 | https://pubmed.ncbi.nlm.nih.gov/41202143/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12594206/
[2] NAD augmentation as a disease-modifying strategy for neurodegeneration (2025). DOI: 10.1016/j.tem.2025.03.013 | https://pubmed.ncbi.nlm.nih.gov/40287324/
[3] NAD substrate deficiency is an inherent and targetable risk factor for late-onset Alzheimer’s disease (2025). https://pubmed.ncbi.nlm.nih.gov/40879628/
[4] NAD+ precursors, autophagy, tauopathy and machine learning in Alzheimer’s disease (2025). DOI: 10.1080/15548627.2025.2596679 | https://pubmed.ncbi.nlm.nih.gov/41313318/
[5] Intravenous antioxidant biosupplement infusion therapy in Alzheimer’s disease: NAD, Alpha Lipoic Acid, Vitamin C and Glutathione (2025). DOI: 10.1002/alz70859_106341 | https://pubmed.ncbi.nlm.nih.gov/41451751/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12741796/
[6] Supplementation with NAD+ Precursors for Treating Alzheimer’s Disease: A Metabolic Approach (2024). DOI: 10.3233/JAD-231277 | https://pubmed.ncbi.nlm.nih.gov/39422945/
[7] Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer’s disease (2022). DOI: 10.1111/acel.13658 | https://pubmed.ncbi.nlm.nih.gov/35730144/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9282847/
[8] Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (2016). https://pubmed.ncbi.nlm.nih.gov/27130898/
[9] Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (2015). https://pubmed.ncbi.nlm.nih.gov/25884176/
[10] Modulation of cGAS-STING Pathway by Nicotinamide Riboside in Alzheimer’s Disease (2021). DOI: 10.1089/rej.2021.0062 | https://pubmed.ncbi.nlm.nih.gov/34694148/
[11] Can nicotinamide riboside protect against cognitive impairment? (2020). DOI: 10.1097/MCO.0000000000000691 | https://pubmed.ncbi.nlm.nih.gov/32925178/
[12] Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases (2021). DOI: 10.1080/1028415X.2019.1637504 | https://pubmed.ncbi.nlm.nih.gov/31280708/
[13] Nicotinamide riboside modulates the reactive species interactome, bioenergetic status and proteomic landscape in a brain-region-specific manner (2024). DOI: 10.1016/j.nbd.2024.106645 | https://pubmed.ncbi.nlm.nih.gov/39179121/
[14] Importance of NAD+ Anabolism in Metabolic, Cardiovascular and Neurodegenerative Disorders (2023). DOI: 10.1007/s40266-022-00989-0 | https://pubmed.ncbi.nlm.nih.gov/36510042/
[15] Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease (2017). https://pubmed.ncbi.nlm.nih.gov/28330719/
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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