Nad+ Depletion And Why Your Memory Worsens After 40

NAD+ Depletion and Why Your Memory Worsens After 40

What if the reason you walked into a room and forgot why you were there isn’t just stress, or too much on your mind, but a slow, measurable chemical decline that began in your thirties? What if the mental sharpness you took for granted in your twenties was partly powered by a molecule that your body is now producing less and less of every decade? And what if the research on how to slow that decline is further along than most people realise?

This is the story of NAD+, nicotinamide adenine dinucleotide, and why scientists increasingly believe it sits at the very centre of how our brains age. Vitacuity analysed over 1.77 million research papers and selected the most relevant for this topic. Here’s what the evidence actually says.

The Science Behind NAD+ and Your Ageing Brain

Think of NAD+ as the brain’s master switch for energy and repair. It’s a coenzyme, a helper molecule, found in every single cell in your body, and it does two essential jobs.

First, it drives energy production. Your brain consumes around 20% of your body’s total energy despite being only 2% of your body weight. That energy comes from mitochondria, tiny power plants inside your cells, and NAD+ is what keeps those power plants running efficiently. Without enough NAD+, the mitochondria begin to falter, and the energy supply to your neurons drops [5][12].

Second, NAD+ fuels a family of proteins called sirtuins, particularly SIRT1, which act as cellular maintenance crews. They repair damaged DNA, regulate inflammation, and help neurons stay healthy and connected. When NAD+ falls, these repair processes slow down, and damage begins to accumulate [11][15].

Here’s the problem: from around your mid-thirties onwards, NAD+ levels begin to decline, and they keep declining. By your sixties, you may have only around half the NAD+ you had in your twenties. This isn’t a minor dip. It’s a fundamental shift in how your brain cells generate energy, manage stress, and repair themselves [12][14].

To make things more complicated, an enzyme called CD38, which your immune system produces, especially during inflammation, actively breaks down NAD+. As we age, inflammation tends to increase (a phenomenon sometimes called “inflammaging”), and so CD38 activity rises, accelerating NAD+ depletion in a cycle that is difficult to break [14].

The result? Brain cells with less energy, more inflammation, and diminishing capacity for the repair and plasticity that underpin memory, focus, and cognitive resilience.

NAD+ Depletion Directly Disrupts Brain Energy and Memory

The brain’s dependence on NAD+ is not theoretical, it’s measurable and specific. Neurons are among the most energy-hungry cells in the body, and they rely almost entirely on glucose metabolism to generate ATP (energy). NAD+ is a critical step in that metabolic process. When NAD+ falls, glucose metabolism in neurons becomes less efficient, energy production drops, and the structural changes that underpin learning and memory, a process called synaptic plasticity, begin to suffer [5][12].

A 2024 review published in *Biomolecules* confirmed that NAD+ depletion in brain cells is directly linked to impaired mitochondrial function, increased oxidative stress, and reduced capacity for synaptic repair, all of which are associated with age-related cognitive decline [12]. The review highlighted that the brain’s NAD+ metabolism operates differently across different cell types (neurons, astrocytes, microglia), and that disrupting this balance has cascading consequences for brain health.

A 2024 review in *Neuroscience Bulletin* reinforced this picture, noting that declining NAD+ levels contribute to the development of neurodegenerative diseases including Alzheimer’s, and that targeting NAD+ metabolism is increasingly seen as a promising therapeutic direction, though human trial data remains limited [15].

Evidence grade: Promising to early stage, the mechanisms are well-established in cell and animal studies; direct human evidence for NAD+ levels predicting cognitive decline is still emerging.

The Immune Cells in Your Brain Are Ageing Too, and NAD+ Is Involved

Here’s something that surprises many people: the brain has its own immune cells, called microglia. In a healthy young brain, microglia act as vigilant, efficient maintenance workers, monitoring for threats, clearing cellular debris, and supporting the connections between neurons. In an ageing brain, microglia shift into an inflammatory, overactivated state. They stop doing their maintenance work and start causing low-level chronic inflammation instead [2].

A 2026 study published in *GeroScience* looked directly at this connection. Researchers compared young mice (6 months old) with aged mice (22 months old), and then gave a group of aged mice nicotinamide riboside (NR), a form of vitamin B3 that the body converts into NAD+, at a dose of 400 mg/kg body weight for 8 weeks [2].

The results were striking. Aged mice showed impaired performance on three cognitive tests: a nest-building task (reflecting everyday functional ability), a Y-maze test (spatial working memory), and a novel object recognition test (recognition memory). NR supplementation improved or prevented decline in all three measures. Perhaps more importantly, gene expression analysis showed that NR shifted the microglia of aged mice back towards a younger, healthier profile, reducing inflammatory signalling and suppressing the “disease-associated microglia” (DAM) patterns that are also seen in Alzheimer’s disease [2].

The honest caveat: This is mouse data. The doses involved are not directly translatable to human doses, and what works in aged mice doesn’t always translate to humans. But the mechanistic logic is compelling, and this research informs ongoing human trials.

Evidence grade: Early stage (animal study)

NMN, Another NAD+ Precursor, Shows Similar Protective Effects in Animal Models

Nicotinamide mononucleotide (NMN) is another form of vitamin B3 that raises NAD+ levels, and animal research published in 2025 in *Frontiers in Pharmacology* explored its effects in a model of accelerated ageing [11].

Researchers gave mice D-galactose, a compound that mimics ageing-related damage, for 8 weeks, then treated them with NMN orally. The NMN group showed restored locomotor activity and significantly improved spatial memory performance in the Morris water maze test compared to untreated ageing mice [11].

The mechanisms were detailed: NMN reduced markers of oxidative stress (increasing antioxidant enzymes SOD and CAT), suppressed pro-inflammatory cytokines (TNF-α, IL-6), reduced cell death in the hippocampus and cortex, and activated the SIRT1/AMPK/PGC-1α pathway, essentially switching on the cells’ own maintenance and energy-efficiency systems [11].

What’s particularly interesting is that the researchers also found NMN protected intestinal barrier integrity, a finding that connects to the emerging field of gut-brain axis research, and to the role the gut plays in NAD+ production (more on that below).

Evidence grade: Early stage (animal study)

The First Human Trials: Cautiously Interesting, Not Yet Definitive

In 2026, researchers published results from a phase-II randomised controlled trial, the most rigorous type of study design, investigating nicotinamide riboside (NR) supplementation in 42 adults with amnestic mild cognitive impairment (aMCI), a condition associated with elevated risk of Alzheimer’s disease [3].

This was a 12-week double-blind, placebo-controlled pilot study published in *Alzheimer’s & Dementia*. The NR supplementation successfully doubled blood NAD+ levels compared to placebo. That’s a meaningful biological effect, it confirmed that NR actually gets into the bloodstream and raises NAD+ [3].

However, and this is important, the study found no significant improvements in cognitive function (the primary outcome), total cerebral blood flow, or blood pressure over the 12 weeks. The researchers were honest about this. Exploratory analyses did hint at potential increases in regional cerebral blood flow, particularly in the hippocampus (the brain’s memory centre), but these were preliminary observations, not confirmed findings [3].

What does this tell us? Raising NAD+ in the blood is achievable with oral NR supplementation. Whether that translates into measurable cognitive improvement in humans, especially over short timeframes like 12 weeks, remains unproven. The researchers concluded that longer trials are needed, and that regional effects on blood flow to specific brain areas deserve further investigation.

Evidence grade: Promising (small human RCT, short duration, no significant primary outcome)

The CD38 Problem: Why NAD+ Keeps Falling as You Age

One of the most important, and underappreciated, pieces of this puzzle is an enzyme called CD38. A 2025 review in *Biochemical Pharmacology* identified CD38 as a major driver of age-related NAD+ decline [14].

CD38 is an NAD+-consuming enzyme expressed on immune cells. As we age, chronic low-grade inflammation increases, and with it, CD38 activity rises dramatically. The enzyme essentially chews through NAD+, accelerating the very decline it helps to cause. This creates a vicious cycle: lower NAD+ means less efficient cellular repair and more inflammation, which activates more CD38, which depletes NAD+ further [14].

This research suggests that simply supplementing NAD+ precursors may not be the complete answer, blocking or reducing CD38 activity is an emerging area of interest. Small-molecule CD38 inhibitors are being investigated, though this research is still at an early stage with no established human interventions yet available [14].

Evidence grade: Early stage (mechanistic research, human interventions not yet established)

Your Gut Is Making, and Destroying, Your NAD+

Here’s a finding that connects two of the most active areas of brain health research: your gut microbiome directly influences your NAD+ levels.

A 2026 review in *Frontiers in Nutrition* outlined three ways the gut microbiota affects NAD+ [1][9]:

1. Tryptophan metabolism. Gut bacteria help convert tryptophan (an amino acid found in protein-rich foods) into NAD+ precursors via what’s called the kynurenine pathway. A disrupted microbiome means this conversion is less efficient.

2. Vitamin B3 precursor availability. Gut bacteria regulate how much of the vitamin B3 metabolites (niacin, nicotinamide, NR, NMN) your body actually has available to convert into NAD+.

3. Inflammation control. A healthy microbiome keeps systemic inflammation lower, which in turn reduces CD38-driven NAD+ depletion.

Crucially, the same review noted that the gut microbiome may also influence *how well* NAD+ supplementation works. Two people taking the same NR supplement may see very different results depending on their microbiome composition. This is an emerging and important variable that most supplement studies haven’t yet accounted for [1][9].

Evidence grade: Promising (mechanistic reviews with emerging clinical support)

Exercise Is One of the Most Reliable NAD+ Boosters We Have

Before we get to supplements, it’s worth being very clear about something: physical exercise is one of the most well-supported ways to boost NAD+ biosynthesis, and it costs nothing.

The 2026 *Frontiers in Nutrition* review confirmed that exercise activates multiple pathways that increase NAD+ production, including HIF-1α-dependent adaptive responses, enhanced mitochondrial function, and upregulation of NAMPT, a key enzyme in the main NAD+ synthesis pathway [1][9]. Exercise also promotes the release of BDNF (brain-derived neurotrophic factor), which supports neuron growth and connectivity.

This is not a reason to dismiss supplementation. But it is a reason to treat exercise as non-negotiable, and to view supplements as working *alongside* an active lifestyle, not as a replacement for it.

Evidence grade: Strong for exercise’s effect on NAD+ biosynthesis (multiple mechanistic and clinical studies)

What Researchers Believe NAD+ Does in Alzheimer’s Disease

A 2021 review published in *Frontiers in Cell and Developmental Biology* systematically examined the role of NAD+ in Alzheimer’s disease animal models [13]. The findings are worth understanding.

In Alzheimer’s, two hallmark features are the accumulation of amyloid-beta plaques and tau tangles, toxic protein buildups that disrupt neuron function. The review found that raising NAD+ in animal models reduced amyloid-beta production (partly by promoting degradation of BACE-1, the enzyme that makes amyloid), reduced tau pathology, decreased neuroinflammation, improved mitochondrial function, and enhanced DNA repair in neurons [13].

A 2020 review in *Current Opinion in Clinical Nutrition and Metabolic Care* further noted that NR supplementation in Alzheimer’s mouse models reduced DNA damage, improved hippocampal synaptic plasticity, and even helped maintain blood-brain barrier integrity, the critical seal that stops harmful molecules from entering the brain [6].

Again, these are animal studies. The mechanisms are biologically plausible and the animal data is consistent, but translating this into proven human Alzheimer’s prevention or treatment is a step the research hasn’t yet completed.

Evidence grade: Early stage (consistent animal findings, human trials underway but not yet conclusive)

The Different Forms of NAD+ Precursors, Which One Matters?

Not all vitamin B3 derivatives are equal when it comes to raising NAD+. A 2022 review in *Nutrients* compared the main options: niacin (nicotinic acid), nicotinamide (NAM), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN) [7].

– Niacin is the cheapest and most studied, but causes a harmless but uncomfortable “flush” (skin reddening and tingling) at therapeutic doses, limiting adherence. – Nicotinamide (NAM) doesn’t cause the flush but at high doses may actually inhibit some of the sirtuin pathways NAD+ is supposed to activate, a paradox that’s still being investigated. – NR (nicotinamide riboside) is well-tolerated, orally bioavailable, and has the most human safety data. It’s the form used in the most human trials to date. – NMN (nicotinamide mononucleotide) is a direct precursor to NAD+ and has shown strong results in animal studies, but human trial data is still more limited than for NR [7][8].

A 2023 review in *Drugs & Aging* noted that these precursors “vary in their ability to promote NAD+ anabolism with differing adverse effects,” and that careful evaluation is warranted, particularly since NAD+ itself is not just a friend to healthy cells but may also support cellular processes in less desirable contexts (such as cancer cell metabolism) [8].

Evidence grade: Promising for NR (human safety data exists; efficacy in humans still being established); early stage for NMN in humans

What We Don’t Know Yet

Let’s be direct about the gaps, because they’re significant.

We don’t yet know whether raising NAD+ improves cognition in healthy humans. The most rigorous human trial to date, the 2026 phase-II RCT, found that NR successfully doubled blood NAD+ levels but did not produce measurable improvements in cognitive function over 12 weeks in people with mild cognitive impairment [3]. Longer trials in larger populations are urgently needed.

We don’t know the optimal dose for humans. Animal studies use doses that don’t translate directly to human equivalents. Most human trials have used 300–1,000 mg/day of NR or NMN, but the ideal dose, timing, and duration are unknown [7][8].

We don’t know if blood NAD+ levels accurately reflect brain NAD+ levels. The blood is easy to measure; the brain is not. A supplement that raises NAD+ in blood may or may not be raising it in the neurons where it matters most [4].

We don’t know how much individual variation matters. Gut microbiome composition appears to significantly influence how well NAD+ supplementation works, meaning the same supplement could produce very different results in different people [1][9].

We don’t know the long-term safety profile of sustained high-dose NAD+ precursor supplementation. Short-term trials suggest good tolerability, but studies beyond 12 weeks are rare in humans [3][8].

The CD38 question is unresolved. If inflammation-driven CD38 activity is the primary driver of NAD+ depletion, then supplementing precursors may be partially fighting a losing battle without also addressing underlying inflammation [14].

A 2026 commentary in *Trends in Endocrinology & Metabolism* captured the current state well in its title alone: *”NAD+ augmentation in brain aging: hype, hope, or emerging reality?”*, acknowledging that the field is promising but that definitive answers are still ahead [4].

The Final Takeaway

So what would a sensible, well-informed person actually *do* with all of this?

Here’s how we’d think about it, not as cautious academics, but as practical, honest friends who’ve read the research carefully.

1. Take exercise seriously as your primary NAD+ intervention. This isn’t a soft recommendation, it’s the most evidence-backed NAD+-boosting strategy available, costs nothing, and delivers benefits far beyond NAD+ alone. Aim for a mix of aerobic exercise (which drives mitochondrial adaptation) and resistance training (which supports metabolic health). Even brisk walking several times a week makes a difference [1][9].

2. Prioritise protein and vitamin B3 in your diet. Tryptophan (from protein-rich foods, eggs, fish, chicken, legumes) and vitamin B3 metabolites from food are the raw materials your body needs to produce NAD+. A diet that’s chronically low in protein accelerates the problem [1][5].

3. Consider NR or NMN supplementation if you’re over 40. Here’s the practical reasoning: NAD+ decline is real and measurable. NR is well-tolerated, orally bioavailable, and the most human-tested precursor available. It’s a form of vitamin B3, water-soluble, meaning excess is excreted rather than accumulated. Short-term human trials confirm it successfully raises blood NAD+ levels. The risk of supplementing at typical doses (300–500 mg/day of NR) is low; the potential upside, if ongoing trials confirm efficacy, is significant. You don’t need to wait for a 10-year trial to make a sensible risk-benefit decision. A typical dose of NR is safe, the mechanism is sound, and the downside of taking it while the evidence matures is minimal. If budget is a consideration, NR tends to be more widely studied than NMN at this point.

4. Support your gut microbiome. Given the emerging evidence that gut health influences NAD+ metabolism, eating a diet rich in fibre, fermented foods, and diverse plant foods is likely to improve how efficiently your body produces and uses NAD+, and may improve how well any supplementation works [1][9].

5. Manage inflammation. This means addressing the lifestyle factors that drive chronic low-grade inflammation, poor sleep, ultra-processed foods, chronic stress, physical inactivity. These aren’t separate issues from NAD+ depletion; they’re part of the same story. Reducing inflammation may slow CD38-driven NAD+ destruction [14].

6. Watch this space. The human trial data is young. Longer, larger trials are underway. If you’re over 50, the next three to five years of research in this area will be genuinely important. The science is not yet complete, but the direction of travel is clear enough to act on now.

The honest summary: NAD+ depletion is a real, measurable feature of brain ageing. The mechanisms by which it contributes to memory decline and cognitive vulnerability are increasingly well understood. The supplements exist, are safe at normal doses, and do raise NAD+ levels in humans. Whether that translates into preserved memory over years and decades is the question research is still working to answer, but it’s a question worth taking seriously.

References

[1] Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health (2026). *Frontiers in Nutrition*. DOI: 10.3389/fnut.2026.1865556 | https://pubmed.ncbi.nlm.nih.gov/42846758/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643272/

[2] Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice (2026). *GeroScience*. DOI: 10.1007/s11357-025-01959-1 | https://pubmed.ncbi.nlm.nih.gov/41273482/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601472/

[3] A phase-II randomized controlled pilot study of nicotinamide riboside supplementation in older adults with amnestic mild cognitive impairment (2026). *Alzheimer’s & Dementia*. DOI: 10.1002/alz.71605 | https://pubmed.ncbi.nlm.nih.gov/42478598/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13386481/

[4] NAD+ augmentation in brain aging: hype, hope, or emerging reality? (2026). *Trends in Endocrinology & Metabolism*. DOI: 10.1016/j.tem.2026.09.003 | https://pubmed.ncbi.nlm.nih.gov/42773035/

[5] Degradation of the Molecular Basis of Life During the Aging Process (2026). *International Journal of Molecular Sciences*. DOI: 10.3390/ijms27052419 | https://pubmed.ncbi.nlm.nih.gov/41828636/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12986144/

[6] Can nicotinamide riboside protect against cognitive impairment? (2020). *Current Opinion in Clinical Nutrition and Metabolic Care*. DOI: 10.1097/MCO.0000000000000691 | https://pubmed.ncbi.nlm.nih.gov/32925178/

[7] Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts (2022). *Nutrients*. DOI: 10.3390/nu14153231 | https://pubmed.ncbi.nlm.nih.gov/35956406/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9370773/

[8] 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/

[9] Restoring NAD+ pathways in brain aging and neurodegenerative diseases: roles of vitamin B3 metabolites, gut microbiota, and exercise in cognitive health (2026). *Frontiers in Nutrition* [second citation from same review]. DOI: 10.3389/fnut.2026.1865556 | https://pubmed.ncbi.nlm.nih.gov/42846758/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643272/

[10] Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice (2026). *GeroScience* [second citation from same study]. DOI: 10.1007/s11357-025-01959-1 | https://pubmed.ncbi.nlm.nih.gov/41273482/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601472/

[11] NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway (2025). *Frontiers in Pharmacology*. DOI: 10.3389/fphar.2025.1545585 | https://pubmed.ncbi.nlm.nih.gov/40276601/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018880/

[12] Pathobiochemistry of Aging and Neurodegeneration: Deregulation of NAD+ Metabolism in Brain Cells (2024). *Biomolecules*. DOI: 10.3390/biom14121556 | https://pubmed.ncbi.nlm.nih.gov/39766263/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11673498/

[13] NAD+ in Alzheimer’s Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo (2021). *Frontiers in Cell and Developmental Biology*. DOI: 10.3389/fcell.2021.668491 | https://pubmed.ncbi.nlm.nih.gov/34414179/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369418/

[14] NAD+ and CD38 as anti-aging regulatory targets (2025). *Biochemical Pharmacology*. DOI: 10.1016/j.bcp.2025.117050 | https://pubmed.ncbi.nlm.nih.gov/40516760/

[15] Targeting NAD Metabolism for the Therapy of Age-Related Neurodegenerative Diseases (2024). *Neuroscience Bulletin*. DOI: 10.1007/s12264-023-01072-3 | https://pubmed.ncbi.nlm.nih.gov/37253984/ | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10838897/

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.