Never get Alzheimer’s Disease: The NAD Breakthrough

Okay, seriously, this new paper just blew my mind. It changed the way I think about Alzheimer's disease, and in a sneaky way that I'm going to show you. But first, it also did something more. It gave me hope. And not just hope about preventing Alzheimer's disease in myself and for my family, but hope for where the whole field of Alzheimer's research is headed. Because here's a hard truth: for decades, we've treated Alzheimer's as a problem of amyloid plaques in the brain, trying to scrape them away. With no success. Even if we're being generous, 99.6% of Alzheimer's drugs have failed completely and miserably, flushing tens of billions of dollars in research funding down the toilet because we've been barking up the wrong tree. But this new work points to something deeper. Alzheimer's disease is a problem of energy metabolism, energy trafficking in the brain. And when you fix the energy problem, something remarkable happens. We could not just prevent, but potentially even reverse Alzheimer's disease. So let's talk about how to never get Alzheimer's disease. A slow, irreversible, progressive decline. Could we defend against Alzheimer's disease? Could we maybe even reverse Alzheimer's disease? Our results, our data challenge the long-held view that Alzheimer's disease is intrinsically irreversible. The amyloid plaques are not sufficient to cause dementia. We open up a radically different new therapeutic window. If you want more details, full references, and related content, many different Alzheimer's deep dives, check out the bestselling science Stay Curious Metabolism newsletter linked below. All right, with that, let's get into it. Here's a roadmap for what we're going to cover in this video. 5 main chapters. First, we're going to meet our key player, our star, NAD+, the brain's metabolic linchpin, and why it matters in Alzheimer's. In Chapter 2, we're going to talk about the amyloid Alzheimer's paradox, how some people stay sharp and cognitively intact despite having Alzheimer's pathology. In 3, we're going to talk about lab breakthroughs. This is the meat of the video: how boosting NAD+ prevents or even reverses Alzheimer's disease in animal models. Then in Chapter 4, we're going to turn back to the human data, evidence that these same mechanisms may apply to us. And 5, the moment you've been waiting for, or will be waiting for, action steps, a dive into natural ways to support NAD+ and brain health. But with that, let's get to Chapter 1. Let's meet NAD+. To understand why this paper is so interesting and important, you need to understand this central molecule. NAD is short for nicotinamide adenine dinucleotide, and there's no quiz, I just want you to know what it stands for. NAD is a vital compound found in every single cell in our body, and it plays foundational roles in energy metabolism. Maybe you've heard of ATP, the energy currency of the cell. Well, NAD is just as essential. At its core, NAD functions as what's called an electron carrier. It shuttles high-energy particles, electrons, through processes that make life possible. Glycolysis and carb burning, beta oxidation and fat burning, the TCA cycle, Krebs cycle, oxidative phosphorylation of mitochondria— ultimately, energy production relies on NAD+. And without NAD+, cells simply don't function. Mitochondria fail. Energy production collapses. Without NAD+, you'd die faster than if you were hit by the Avada Kedavra curse from Harry Potter. Avada Kedavra! Now, jokes aside, here's the crucial point. NAD levels tend to decline with age and especially in metabolic diseases like Alzheimer's disease. And when that decline happens faster and more severely than expected with normal aging, you get pathological states, mitochondrial dysfunction, disrupted cellular signaling, and yes, Alzheimer's disease. So that brings us to Chapter 2. The Alzheimer's amyloid paradox, because there's been a fascinating and longstanding paradox in human neuroscience. The classical pathological hallmark that defines Alzheimer's disease, when you look in the brain, the way you define Alzheimer's disease is in part by these amyloid plaques, but the amyloid plaques are not sufficient to cause dementia. In fact, 20 to 50% of those human brains with high amyloid plaque burden are totally cognitively normal. No dementia. These individuals are referred to as non-demented with Alzheimer's neuropathology, speaking to the amyloid. Now, here's where this new study gets especially interesting. Because one of the defining features that distinguishes cognitively normal brains with lots of amyloid from Alzheimer's brains with lots of amyloid is this NAD molecule. Higher NAD levels appear to act— you can call it a resilience factor. It buffers neuronal function, brain function, despite the hallmarks of Alzheimer's disease. So you can see that here. Quickly, as a brief aside, you're going to notice the y-axis throughout the video are labeled NAD/NADH ratio. This is convention. If you want details, you can check out the notes in the letter. But the point is the Alzheimer's brain is characteristically depleted in this key energy molecule, NAD. So if NAD depletion is one type of energetic dysfunction truly driving Alzheimer's disease, it raises the provocative possibility, the hypothesis: if we can restore or preserve NAD levels in the brain, could we defend against Alzheimer's disease? Could we maybe even reverse Alzheimer's disease? So let's unpack what the authors tested and what they found, starting in mice. So Chapter 3: Lab Breakthroughs. The researchers first started in what's called the 5XFAD mouse. Again, the details aren't important. It's important to just know this is a commonly used and well-validated model for Alzheimer's disease. Now, As Alzheimer's pathology progressed in these animals, NAD levels steadily declined, by 30% at 6 months of age and 45% by 1 year of age. Now, what the researchers did is they restored NAD. They treated mice with a neuroprotective chemical called—ready for it?—P7C3A20. Not very creative. This compound though works by activating an enzyme known as NAMPT, which creates NAD. Now, to ease your interpretation of the graphs throughout this video, I've relabeled this P7C3A20 compound as NAD booster. Just know that that's the actual compound, an NAMPT activator, and we're going to return to that enzyme, NAMPT, later when discussing ways to boost NAD, so put a sticky note in your brain for now. But strikingly, treatment with the NAD boosting compound did prevent depletion of NAD altogether. But of course, what did this actually do? Well, at the behavioral level, the memory level, boosting NAD+ prevented and reversed deficits in spatial learning and memory as measured by several well-established tests like the Morris Water Maze test and Novel Object Recognition Test, which you can see here. The punchline is boosting NAD+ restored memory in this first Alzheimer's model. But that's not all. It also prevented and reversed impairments in motor learning and coordination, as well as anxiety anxiety-like behaviors, which are commonly seen in Alzheimer's disease. But again, that's barely the tip of the iceberg. Going deeper from behavior to neurophysiology, the researchers measured something called long-term potentiation. I know a lot of jargon, you can handle it. Basically, this is the cellular process that underlies learning and memory. What you're seeing here though is electrical activity generated by groups of neurons firing together. And what you're looking for is a level between 150%, and 200% of baseline. Now, in untreated Alzheimer's mice, the red line, long-term potentiation, the neurochemical process underlying learning, is decaying. But you can clearly see when you boosted NAD, it preserved, even restored long-term potentiation, mirroring the behavioral improvements and completely recovering this key neural process. So, in other words, Neurons, when NAD+ was boosted, retained their capacity to learn at the molecular level. But the effects didn't stop there, we're still just getting started. When the researchers examined neuropathology, they found that boosting NAD+ also reversed key hallmark features of Alzheimer's disease, including, yes, amyloid accumulation, and also, potentially more importantly, phosphorylated tau, p-tau, which creates neurofibrillary tangles inside neurons that metabolically choke them. And P-tau is a sensitive biomarker detected in the blood. What you can see very clearly is that boosting NAD obliterated phospho-tau levels. This is amazing, and it still wasn't the end of the story. Another defining feature of Alzheimer's disease is breakdown of what's called the blood-brain barrier, which in Alzheimer's becomes leaky, and this disrupts both toxin clearance and cerebral blood flow. But once again, NAD boosting prevented and reversed blood-brain barrier dysfunction, rescuing the blood-brain barrier. And finally, the researchers examined neuroinflammation, a key driver in Alzheimer's disease characterized by a shift in the activity of brain support cells— maybe you've heard of glia like astrocytes and microglia— into a pro-inflammatory state. So in Alzheimer's disease, the brain becomes inflamed, and you can use markers to look at this. And what they show here is that NAD boosting reversed inflammation in both cell types, astrocyte and glia. I'm showing you angry inflamed microglia here in red. Which is clearly fired up in the Alzheimer's brain, but boosting NAD causes these angry immune cells in the brain to calm and neuroinflammation drops. So I know I've thrown a lot at you, but stepping back, when viewed from nearly every angle—behavioral, electrophysiological, pathological, vascular, inflammatory—boosting NAD both prevented and reversed Alzheimer's disease in this first animal model. And it's worth noting, these findings were replicated in a second Alzheimer's mouse model known as PS19. Again, boosting NAD+ levels even at terminal stages of disease in these mice led to a recovery of cognitive deficits. They were able to reproduce their findings in a separate model. Now, while early intervention and prevention remain ideal strategies when it comes to chronic disease, these results directly challenge the longstanding assumption that Alzheimer's disease is fundamentally irreversible. In fact, don't just listen to me, the authors themselves write, "Our results, our data challenge the long-held view that Alzheimer's disease is intrinsically irreversible and position the restoration of brain NAD homeostasis, NAD balance, as a potentially transformative therapeutic approach." Those are the author's words. Now comes the most important and also trickiest question to tackle. Chapter 4. Do these findings translate to human beings? Well, we've already touched on the first key observation. In human Alzheimer's disease, disruption of NAD balance is a dominant feature. And I'll also point out this disruption closely correlates, maybe drives tau pathology. We mentioned tau earlier. By contrast, and this is important, individuals with a lot of amyloid pathology in their brain but totally normal cognition had much higher NAD levels. And this distinction is important because positioning NAD is the key distinguishing factor between true Alzheimer's disease and just having plaques in the brain with totally normal cognition. But to take a step further, the researchers also examined the molecular machinery that regulates NAD levels. So there are enzymes that produce NAD, and there are enzymes that consume, break down NAD. And what they found is that in true Alzheimer's disease, there was increased expression of enzymes that break down NAD and decreased expression of enzymes that make NAD+. So at a high level, what you're seeing here is a clear metabolic shift in human Alzheimer's disease where the balance is tipped towards NAD+ consumption over production, depleting NAD+ levels. But the researchers still didn't stop there, and I'm not going to get into all the nitty-gritty, but there were more parallels the researchers found in the human and mouse model data. NAD+ depletion and replenishment networks, gene expression, proteins, were conserved. At a high level, this helps to cement the case that the findings observed in the animal models, which we need to do these causal mechanistic studies, are likely relevant in human disease as well. But now, Chapter 5, comes the fun part: how do we boost NAD+ levels naturally? So, to set the stage, I just want to give you a bit of biochemical background. Don't worry, you don't need to memorize this, there's no quiz, just think about it as a conceptual framework. But there are 3 main pathways in the body to make NAD+. The first 2 are called the press-handler pathway and the novo biosynthesis pathway. They depend on dietary inputs like niacin and tryptophan. Now, these nutrients are abundant in most diets, deficiencies are uncommon, so I don't think it's prudent to just load up on these hoping to boost your NAD+ levels. That said, I know I'll get questions, so the best sources of niacin are beef liver, chicken, turkey, and fish. And tryptophan comes from basically any complete protein source. That said, these two pathways aren't where the majority of NAD+ production comes from, or I should say NAD+ recycling. The pathway you really want to care about is called the salvage pathway. And within this key salvage pathway, there's one enzyme I really want you to remember: NAMPT. NAMPT is the rate-limiting enzyme of NAD+ synthesis. Basically, it's a molecular bottleneck controlling how much NAD+ your cells produce. Remember the Easter egg from earlier? This is where it comes back into play. The compound used in this study was an NAMPT activator, that p7c3a20. Remember that? It's not a coincidence. But there are ways you can naturally increase NAMPT. One is by activating an upstream enzyme called AMPK. It's a cellular energy sensor. And you can stimulate this through exercise, fasting, and ketogenic diets. So these interventions activate AMPK, which activates NAMPT to boost NAD+ levels. Let's briefly zoom in, for example, on ketogenic diets. There are multiple lines of evidence showing that ketogenic diets increase NAD+ levels. For these and other reasons—I'm going to mention a few in a bit—I consider a ketogenic diet one of the strongest, if not the strongest dietary strategy for supporting NAD+ levels and potentially preventing Alzheimer's disease. And double-clicking on this, there are other ways ketogenic diets are neuroprotective. For example, ketones help clear misfolded proteins out of the brain—see this video for more—they can reduce neuroinflammation, and provide clean non-glucose fuel for the brain. For these reasons, I believe at least occasional bouts of ketosis either through a ketogenic diet or fasting are powerful tools to prevent Alzheimer's disease, and NAD+ is just one additional piece to that puzzle. But now let's double-click on exercise. When it comes to exercise and physical performance, both aerobic training and resistance training have been shown to increase NAMPT levels. Again, that rate-limiting enzyme for NAD+ synthesis in the salvage pathway. And importantly, in humans, NAMPT levels, they decline with age, but they remain positively associated with higher in people with higher lean body mass, so muscle mass, and VO2 max, a key marker of cardiovascular fitness and athletic capacity. So the takeaway here is exercise can boost NAD+ production directly by activating the salvage pathway enzyme, the NAMPT. Thus, improving aerobic fitness and muscle mass may be one of the most powerful and sustainable ways to support your NAD+ levels, possibly more than any supplement. As cliché as it sounds, exercise truly is brain medicine. Muscles are brain medicine. But boosting NAD+ production is only half the story. If you look back at the salvage pathway and the things I mentioned earlier, you notice there's also enzymes that consume NAD, break it down. So the goal then is not just to make more NAD, but to prevent it from being broken down rapidly, depleting it. Two enzymes I want to highlight are PARPs and CD38, and both of these are activated by oxidative stress and inflammation. Therefore, chronic inflammation and oxidative stress accelerate NAD depletion. NAD+ loss. And this brings us back to the fundamentals. You need to do what needs to be done to improve overall metabolic health, which you can associate with reduced oxidative stress and reduced inflammation. So anything that improves antioxidant capacity, reduces oxidative stress and inflammation will help preserve NAD+ and by extension support brain health. This means the boring, regular, but really important things: prioritizing sleep, regular physical activity. We already mentioned that. And a nutrient-dense, primarily whole food diet, whether or not it's ketogenic. Again, I know it's boring and unoriginal, but it bears reinforcing. And as an added tip, for individuals over about age 60, targeted antioxidant supplementation with something like astaxanthin may also be helpful. This is because endogenous natural antioxidant defenses decline with age around age 60. See this video, my conversation with Professor Michael Snyder from Stanford, for more. And then finally, there are additional dietary levers worth mentioning. Some food-derived compounds that can inhibit this CD38 NAD-consuming enzyme. Two notable examples are quercetin and apigenin. Quercetin is found in capers and red onions, and apigenin is found in chamomile tea. Now, I'm not saying a caper omelet for breakfast and chamomile tea in the evening are silver bullets to prevent Alzheimer's disease, but the point here is this isn't a game of silver bullets, it's a game of cumulative nudges. And it's worth noting You can supplement with NAD precursors. I know I'm going to get this question, so I might as well address it. There's nicotinamide riboside and nicotinamide mononucleotide. Really, you can use either, but they do increase NAD levels. So for example, in one double-blind randomized placebo-controlled trial, daily doses of 600 to 900 milligrams of NMN significantly increased NAD levels in the blood, with signals suggesting improvements in physical performance and subjective measures of overall health. Does this actually translate to prevention of Alzheimer's disease? We don't know for sure, but I think the data are promising. So I know we've covered a lot. Let me briefly review. Here's your checklist for boosting NAD+ naturally. Support NAD+ production via the salvage pathway. That means activating NAMPT. You can do this through regular exercise, both aerobic and resistance training, aiming to increase your VO2 max and your muscle mass. You can also practice intermittent fasting or time-restricted eating or a ketogenic diet to activate AMPK to activate NAMPT to make NAD+. You can, if you want, supplement with NAD+ precursors like NMN or NR. You also want to reduce NAD+ consumption. You can do this primarily by reducing chronic inflammation and oxidative stress, and consider antioxidant support if you're over age 60. You can use natural CD38 inhibitors like quercetin, found in capers and red onions, and apigenin, like in chamomile tea. Now, finally, before we really wrap up, I should highlight two other supplements I take for my brain health. As a neuroscientist who refuses to get Alzheimer's disease. The first is called lysodHA, short for lysophosphatidylcholine DHA. This is in addition to eating fatty fish regularly, which I do, but I do take 2 capsules daily of this specific omega-3 supplement enriched in the particular form of omega-3 lysodHA that readily crosses the blood-brain barrier. You can see in these graphs how lysodHA leads to particular enrichment of omega-3 in the brain as compared to standard DHA. Now, while this supplement is a high-end premium product and certainly not necessary for everyone, I, as an APOE44 carrier, a high genetic risk for Alzheimer's disease, choose to invest in it as an added layer of brain insurance. You can learn more in this dedicated content, and if you want to take the product I take, you can click the link below and use discount code STAYCURIOUS for 20% off. It's definitely a staple in my health routine. In addition, microdose lithium orotate. I take it at 5mg per day. And this might represent a relatively inexpensive and effective strategy for Alzheimer's disease prevention based on emerging and surprisingly strong data about lithium and Alzheimer's. For more on that, see this video. I use Pure Encapsulations. I have no particular affiliation with that brand. It's just what I use. Okay, wrapping up for real. Alzheimer's disease has long been viewed as a one-way street, a slow, irreversible, progressive decline. But this new research challenges that narrative in a meaningful way. By focusing not just on removing plaques but on restoring the brain's energetic foundation. Through this, we open up a radically different, new therapeutic window. NAD isn't just a molecule; it might be a gatekeeper of brain resilience. And of course, this is not a cure-all, not a silver bullet. Diseases like Alzheimer's disease are resistant to silver bullets, but these data are progress. They offer hope, not just in theory, but in practice, grounded in robust biology, reproducible results, and actionable strategies. For me, as both a scientist and an Apple Watch 4 carrier, this research doesn't just inspire curiosity, it bolsters a sense of agency and hope. And I thought that was something worth sharing. Stay curious.