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Nicotinamide adenine dinucleotide (NAD+) has become one of the most buzzworthy supplements on the market, thanks to its powerful neuroprotective properties and potential to boost brain health. In fact, NAD+ is not only crucial for cellular metabolism, but it also supports DNA repair and keeps oxidative stress in check, which may play a big role in protecting your brain as you get older. (1)
While many of the mechanisms behind NAD+ are still being unraveled, this article explores what the science shows so far about how NAD+ can enhance brain health, including how it works, which precursors are backed by research, and what to know about its safety and effectiveness.
The Critical Role of NAD+ in Brain Function
NAD+ plays a key role in keeping your brain cells energized and functioning properly. Neurons have especially high energy needs to support communication, signaling, and general brain activity, and NAD+ helps convert nutrients into the fuel they need to work efficiently. Without enough NAD+, energy production slows down, making your neurons much more vulnerable to damage and dysfunction. (2)
But NAD+ does much more than just fuel your brain. It also supports other essential cellular functions, like repairing DNA and regulating oxidative stress, a type of cell damage caused by harmful free radicals. Because neurons require a steady supply of energy and have a limited ability to regenerate, they're especially sensitive to changes in NAD+ levels. When NAD+ drops, they're also more likely to suffer damage, which can take a serious toll on brain function. (3)
NAD+ depletion might also be involved in the development of neurodegenerative disorders like Alzheimer's disease and Parkinson's. In fact, research suggests that NAD+ levels decline with age and during disease progression, which is linked to increased inflammation, protein buildup, and cognitive decline. (4) Lower levels of NAD+ can also contribute to mitochondrial dysfunction and limit the activation of sirtuins, important signaling proteins that help protect neurons and regulate cellular stress responses. (5, 6)
In short, NAD+ is crucial for keeping your brain healthy, and understanding how it works could be a promising path to help preserve cognitive function as you age.
Molecular Mechanisms of NAD+ Neuroprotection
So how does NAD+ protect the brain? Below, we take a closer look at the molecular mechanisms behind NAD+ neuroprotection, including its important roles in mitochondrial function, DNA repair, and regulating oxidative stress.
Mitochondrial Bioenergetics and Neuronal Survival
Compared to other types of cells, neurons have exceptionally high energy demands and rely heavily on the mitochondria to produce adenosine triphosphate (ATP), their main source of fuel. (7) This process requires a healthy balance of NADH (nicotinamide adenine dinucleotide in its reduced form) and NAD+ to drive the chemical reactions that generate energy. When this balance shifts and NAD+ levels falter, energy production slows down, which can compromise the function and survival of your neurons. On the other hand, maintaining healthy levels of NAD+ can support mitochondrial efficiency and energy metabolism to keep your neurons working efficiently, even under stress. (8)
DNA Repair and Genomic Stability
As you get older, your neurons become especially vulnerable to DNA damage and rely on your body's built-in repair systems to stay healthy. One key enzyme, poly (ADP-ribose) polymerase 1 (PARP-1), helps fix broken DNA strands, but uses up large amounts of NAD+ in the process. Excessive activation of PARP-1 (often caused by chronic stress or cell damage) can drain and deplete NAD+ levels, making it much harder for your neurons to repair damaged DNA. (9) Keeping NAD+ levels steady can support DNA repair and help keep your neurons healthy as you age. (10)
Sirtuin Activation and Cellular Stress Response
Sirtuins depend on NAD+ to function. (11) These signaling proteins are absolutely essential for protecting your neurons by activating the sirtuin-1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1Ξ±) pathway, which supports mitochondrial function and helps reduce inflammation in the brain (aka neuroinflammation).
Through this pathway, sirtuins are able to boost your cells' defenses against oxidative stress, which can damage the neurons. In turn, this helps promote cell survival and preserve brain function, especially under stressful conditions. (12) On the other hand, low levels of NAD+ can take a toll on the function of sirtuins, blocking their ability to protect neurons against oxidative stress and inflammation. (13)
Clinical Evidence for NAD+ Brain Health Benefits
Growing evidence has started to highlight the importance of NAD+ for brain aging, including its potential to boost memory, slow cognitive decline, and enhance blood flow to the brain. Here, we explore what the science really shows about NAD+ for brain health. (4)
Cognitive Function and Memory Enhancement
Brain function and memory rely on your brain's ability to regularly adapt and rewire itself, a process known as synaptic plasticity. Enhancing neuroplasticity is crucial when it comes to learning and retaining information, and some studies suggest that NAD+ might even support this process by boosting energy production, regulating key enzymes, and promoting the formation of new neural connections in your brain. (4, 14)
Several studies have explored possible NAD+ mechanisms for neurodegeneration and brain health. In one animal model, researchers found that supplementing with nicotinamide riboside (NR), a NAD+ precursor, could improve memory and learning in mice with dementia. Plus, it was also able to decrease DNA damage, neuroinflammation, and apoptosis (aka cell death) while improving synaptic plasticity in the hippocampus, the region of the brain that forms memories. It's thought to work by promoting the breakdown of an enzyme called proliferator-activated-Ξ³ coactivator 1Ξ±-mediated Ξ²-secretase 1 (BACE-1), which helps prevent the buildup of harmful proteins in the brain. (15)
According to another large review of 58 studies, NAD+ precursors like NR and nicotinamide mononucleotide (NMN) could also help support cognitive enhancement and preserve brain health, especially in those with cognitive decline and other conditions like diabetes and stroke. But while results were mostly positive, the author notes that most research is currently limited to animal models and more studies in humans are still needed. (16)
Neurodegenerative Disease Research
NAD+ levels tend to wane as you get older, upping the risk of chronic inflammation, impaired mitochondrial function, and increased DNA damage, all key contributors to brain aging. Maintaining healthy levels of NAD+ could help combat age-related changes and possibly even slow the progression of cognitive decline.
Alzheimer's Disease
A review of both animal and human studies concluded that supplementing with NAD+ precursors may support cognitive function in those with Alzheimer's disease, confirming the link between NAD+ and brain aging. (17) In fact, one animal model found that NR supplementation could increase levels of NAD+ in Alzheimer's disease and help regulate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, leading to less neuroinflammation, DNA damage, and cellular senescence, which causes cells to stop dividing. (18)
Parkinson's Disease
In a small clinical trial in people with Parkinson's disease, supplementing with NR enhanced levels of NAD+, which helped improve brain metabolism and even provided mild symptom relief. Not only that, but it also supported cellular health and lowered inflammation, making it a promising option for cognitive decline. (19)
Huntington's Disease and ALS
Neurodegenerative disorders like Huntington's disease and amyotrophic lateral sclerosis (ALS) gradually chip away at the nervous system, causing issues with cognitive function and movement down the line. Research suggests that lower levels of NAD+ may be more common in these motor neuron disorders, especially in regions of the nervous system that require more energy, like the hippocampus or spinal cord. Even though more trials in humans are still needed, some early animal studies suggest that increasing levels of NAD+ through specific pathways in the body (such as NAD+ salvage pathways) could help slow or even prevent these disorders. (20)
Vascular Cognitive Health
Research on NAD+ and cognitive function suggests that NAD+ may actually support better blood circulation in the brain. For example, one animal study in rats with chronic cerebral hypoperfusion (aka decreased blood flow in the brain) showed that daily treatment with NAD+ improved memory, decreased neuroinflammation, and prevented cell damage. These benefits were tied to the SIRT1/PGC-1Ξ± pathway, which can reduce oxidative stress and help keep your mitochondria healthy. (21)
NAD+ Precursors and Brain Bioavailability
NR and NMN are two of the most well-studied NAD+ precursors, both of which can increase NAD+ levels throughout the body, including in the brain. Taking NAD+ directly isn't very effective because it breaks down quickly and isn't able to easily enter the cells. On the other hand, NR and NMN are much more bioavailable and can cross the blood-brain barrier, making them a better option for supporting brain health. (22) But while NR and NMN can both increase NAD+ levels effectively, NR is backed by a stronger set of human studies. (17, 23, 24, 25)
Blood-Brain Barrier Considerations and Delivery Methods
The blood-brain barrier is a tightly controlled, protective membrane that carefully regulates which substances can move from the bloodstream into the brain. (26) Because it blocks most large or unfamiliar molecules from crossing (including NAD+ itself), it limits the effectiveness of supplementing with NAD+ directly. (22)
This is why most NAD+ supplements for brain health benefits feature NAD+ precursors like NR or NMN instead, which are smaller and are able to cross the blood-brain barrier a bit more easily. But even these molecules can face challenges crossing the blood-brain barrier, and oral supplements don't always deliver a dose strong enough to boost NAD+ levels in the brain. (27)
Some supplement manufacturers tackle this issue using liposomal delivery systems, which encapsulate NAD+ precursors in a tiny, fat-like bubble and deliver them directly to your tissues for more targeted support. In addition to boosting absorption, liposomal delivery boasts a few other possible perks, like fewer side effects and faster results. (28, 29)
Beyond the specific supplement you choose, the route of administration is also important. Capsules, softgels, tablets, and pills are still the easiest and most widely available option, with studies showing that oral supplementation is effective at increasing NAD+ levels in the brain. (30) NAD+ injections also offer a faster, more direct route to the bloodstream, though they're not nearly as accessible, convenient, or cost-effective. (31) Nasal delivery is another interesting new option, which could bypass the challenges of the NAD+ and blood brain barrier to deliver higher concentrations right where they're needed most. (32) Research on NAD+ nasal spray delivery has demonstrated promising neuroprotective effects in preclinical models, suggesting that alternative administration routes may offer advantages for targeting brain health specifically. Other new technologies and specialized formulations are also being developed to maximize the potential benefits of NAD+ for brain health, offering exciting new options for more personalized treatment plans in the future.
Safety Profile and Clinical Considerations
NAD+ precursors like NMN and NR have a strong safety track record in studies, with very few side effects reported, even at higher doses. (33, 34) Of course, not everyone will respond the same way to supplementation, and there are a long list of factors that can impact your results, like your age, genetics, and health status. Be sure to check with your doctor to address any concerns, especially if you have any underlying health conditions or experience any side effects.
It's also a good idea to test your NAD+ levels before and after starting a new supplement, which can help establish your baseline and keep tabs on how your body is responding. As a general rule of thumb, you should retest 30 days after any new lifestyle or supplement changes and then again every six months to help identify long-term trends. Keep in mind that finding the best NAD+ for cognitive function can take some trial and error, which is why testing can be a smart strategy to determine the best dose and supplement to fit your needs.
Conclusion
New research on the connection between NAD+ and brain health is constantly emerging, with some evidence even showing that it can reduce inflammation, enhance cognitive function, and support cellular bioenergetics in the brain. Supplements like NR and NMN are leading the way, backed by solid safety data, plus human and animal studies to support their potential benefits. Comprehensive reviews of NAD+ as a therapeutic approach for neurodegenerative diseases continue to validate its potential across multiple pathways including mitochondrial support, inflammation reduction, and synaptic protection. That being said, research is still in its early stages, and individual responses to supplementation can vary based on factors like your age, genetics, and overall health, among others. That's why it's important to approach NAD+ supplements thoughtfully and consider testing your NAD+ levels to see how your body is responding and whether any adjustments are needed to meet your goals.
