Is Ezetimibe the Secret to Preventing Dementia? Surgeon Reacts to Nick Norwitz MDPhD ​

A common cholesterol drug might protect your brain from Alzheimer's — but I read the actual study, and there's a red flag nobody is talking about.

Nick Norwitz covered this story. I went further — I pulled the original paper published in Aging Biology and read every line. Here's what I found.Researchers ran a hypothesis-free screen of FDA-approved drugs to find compounds that could disrupt the 14-3-3/hexokinase protein interaction — a mechanism implicated in the protein aggregation that drives Alzheimer's disease and other dementias. 

Six drugs emerged from the screen. Ezetimibe was one of them, and it stood out for one reason: it can cross the blood-brain barrier. That's where the excitement starts. But it's also where you need to slow down. Because buried in the study design, I found something that changes everything. 

As a vascular surgeon who has spent years watching patients lose their brains — and their lives — to preventable disease, this is the kind of detail I can't ignore. It's exactly why I won't be prescribing this for dementia prevention in my practice.This video is for anyone who heard the ezetimibe-for-dementia claim and wanted the full picture — not the highlight reel.

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Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

SPEAKER_00 0:00

I am all spun up on brain health. And so today we are going to watch together a video by Nick Norwitz, who asks the question: Should we be taking acetamide to protect our brain against Alzheimer's dementia? So let's go through it together and see what Nick has to teach us about Acetamib and Alzheimer's. For those of you who don't know me, my name is Dr. Lily Johnston. I am a board certified vascular surgeon, but I specialize in cardiometabolic prevention. So hopefully you never need me as a surgeon.

SPEAKER_01 0:32

Promise I'm not pulling your leg when I say shocking research, just change my mind about this cholesterol-lowering medication. But here's the weird part. It has nothing to do with cholesterol. And even heart health. This medication is called a zetamide, and it's definitely one with which I'm quite familiar, not only because we learn about it in medical school, but because I am a patient with one in one million high levels of cholesterol, so I've had a doctor or two chew my ear off about it because they're worried about my heart. But here's the thing my heart is doing great. My arteries are clean as a whistle, but I do have a different concern. Not about what's beating in my chest, but what's happening in my brain. I'm at high genetic risk for Alzheimer's disease because I carry not one but two copies of a risk chain called Apple E4, and that is where our story really begins. These data blew me away because these data show how a zetomide might be doing something no one expected and no doctors know about, and it's happening in the brain. It's kind of like all of medicine was seeing a zetomide as Bruce Wayne, when in reality, it's also brain Batman. And today, I'm gonna show you Brain Batman. I'm gonna show you how it fights crime in your most important organ. Sorry, cardiology, I'm not talking about the heart. I'm of course talking about the brain. Let's go. People die fast with dementia, infectious misfolded proteins. This new study on acetamide in Alzheimer's disease that really caught me off guard. Not statins, not PC denial inhibitors, just acetamide. This is not a clusteral story. It's so much more than that. You don't see signals like that every day in medicine. It forces us to think about what we thought we knew. The most interesting solutions come from looking where no one's got to look. Now, as a roadmap for what we're gonna discuss today, I'm gonna review one, the essential background you need to know about a Zetamide and Alzheimer's disease. Two, I'll introduce a new fascinating study on acetamide and Alzheimer's disease that had my neurons firing me like crazy. We'll cover the mechanistic data and even some human data. Then in chapter three, I'm gonna tell you about what I'm gonna try next based on these data. Then in chapter four, I'm gonna reveal other rapid-fire high-yield tips for brain health and cognitive longevity based on what I do.

SPEAKER_00 2:30

And as so just to set the stage for you, if you're not familiar with the ApoE4 gene and the protein that it makes, we are gonna talk about that in another video coming up really soon. It is a lipid taxi, basically, inside the brain, but it's bigger than that. It is also an inflammatory and immune-regulating gene and protein. And so the impact inside the brain is profound for those who carry one or even two copies of this ApoE4 protein, but it is partially a cholesterol story. The azetamide component may not be, but partly the amyloid beta that builds up in our brain actually is trafficked through the LDL-like receptor. So there is a component of this that is absolutely related to lipid trafficking. It may not have to do with plasma levels of LDLC per se, but this story actually is very broad, and we are going to talk about this as we get into my own ABOE4 content coming up. But let's see what else Dr. Nick wants to tell us about a Zetamide and this very interesting study I'm excited to also walk through with you.

SPEAKER_01 3:38

As always, if you want all the references and more information, check out the link to the associated newsletter and related deep dives in the video description. Find out what everybody is so excited about in our Stay Curious community. Anyway, with that, chapter one. Background on acetamide and Alzheimer's diseases. I'm going to start with acetamide, these tills. This is a cholesterol-lowering medication, but the way it works is in the gut. It selectively inhibits a transporter known as NPC1L1 in the small intestines, which is responsible for absorbing dietary and biliary cholesterol, so the cholesterol your body actually puts out and then recirculates. And by blocking this pathway, acetamide reduces the amount of cholesterol delivered back to the liver from the intestines, thus prompting the liver to compensate by increasing LDL receptors to pull more LDL particles out of circulation. So, unlike statins, acetamide isn't inhibiting cholesterol synthesis and the synthesis of downstream components like coenzyme Q. And it's generally considered to be a gentler, safer, more benign cholesterol-lowering therapy. Now, that's the background on acetabybe, Alzheimer's disease. Alzheimer's disease and other forms of dementia and neurodegenerative diseases are driven in part by what's known as abnormal protein aggregation, abnormal protein folding. So you can think of analyz and tau in Alzheimer's disease or other neurodegenerative diseases like Parkinson's disease, where L alpha synuclein aggregates. When proteins clump together in the A in the brain, neurons suffer and eventually die. The brain degenerates as a result. And certain protein-protein interactions accelerate this aggregation process. One particularly intriguing interaction occurs between a scaffolding protein, boringly named 1433, yes, that's his name. Sorry I wasn't consulted at the naming phase, and another protein, an enzyme called hexokinase, which is critically involved in carbohydrate metabolism. Now, for the doctors listening, you might remember 1433s from somewhere in medical school if you have a good memory.

SPEAKER_00 5:23

In the context of specifically I do not have a good memory, so let's see.

SPEAKER_01 5:56

Now, this is how it works. Under normal circumstances, that enzyme hexokinase involved in metabolism sits happily on mitochondria, like Humpty Dumpty before the fall. But under pathological conditions, hexokinase detaches, attaches to 1433, and this aggregation contributes to greater protein aggregation at large, cellular dysfunction, and ultimately neuron death and nerve degeneration. So simply, you can think about the 1433 hexokinase binding interaction like an early domino in the chain of Alzheimer's disease, leading to protein misfolding, amyloid and tau accumulation in the brains, neuron being choked, and eventually neurons dying. Now, on to the primary study, chapter two, this new study on a zetamide in Alzheimer's disease that really caught me off guard. It was published in Aging Biology. And here's the really weird thing. The researchers weren't looking for the benefits of cholesterol-lorine drugs. Instead, the researchers performed what is known as a hypothesis naive screen, a broad sweep, an unbiased search for existing FDA-approved compounds that might interrupt the 1433 hexokinase protein interaction implicated in Alzheimer's disease and other neurodegenerative disorders. And six drugs emerged. One of them was azetamide. And the researchers chose to pursue azetamide further for a few reasons. One, it crosses the blood brain barrier, and, as compared to the other medications, it has an excellent safety profile. We're gonna get into that a little bit later. And just as another key detail, azetamide was the only cholesterol-loring drug that showed up. Not statins, not PC scaninai inhibitors, etc., just azetomide. So to reinforce a really important point, the researchers were not hunting for extra perks of cholesterol medications. They weren't chasing lipid biology at all. Instead, they were asking the question: what approved tools already in our arsenal do we have that might interrupt this neurodegenerative protein interaction in the brain, the 1433 hexagonase interaction, and a zetomybe just happened to raise its hand like Hermione in class? The authors then moved to a series of experiments using human cell lines to ask a simple but crucial question: what is acetamide actually doing to the downstream proteins that drive Alzheimer's pathology, like amyloid and tau? So, first they examined amyloid accumulation. That's shown here in green in the human cell lines. And very clearly, a zetamib significantly reduced amyloid accumulation.

SPEAKER_00 8:09

So I want you to keep in mind when we're talking about human cell lines, this means we're in a petri dish. Okay, we are not in humans, these are not human samples, these are not even mouse brain samples, this is in a petri dish. That's fine. This is useful information still, but we don't know if the concentration that they're providing in the petri dish is remotely related to what we think crosses the blood brain barrier. Even if a zetomob does cross blood brain barrier, we don't know exactly how much is in there and whether this concentration is relevant. That may be in the paper, that's something we can look into here shortly, but just keep in mind how far removed we are from inhuman data. We are very much in a lab, in a test tube, in a petri dish phase of this information right now.

SPEAKER_01 8:55

Next, they turn to Tau, which tangles inside neurons and chokes them metabolically from the inside. This is the protein responsible for these neurofibrillary tangles in Alzheimer's disease. And once again, acetomide markedly reduced tau accumulation. Now, aside from these proteins, another hallmark of Alzheimer's is failure of autophagy. You might have heard about this. This is the cell's internal recycling and cleanup system, and when it breaks down, junk accumulates. So, what they found was acetamide boosted autophagy by roughly 40% as shown by this graph. This is like mimicking fasting in the brain. But the researchers now didn't stop at cell cultures, they went on to animal models, specifically C. Basically, what they do is they bind the amyloid to something called m cherry, so it glows red. And consistent with the cell data, azetamib reduced amyloid accumulation in living organisms. Now, to be clear, and this is obvious, human cell lines and worm models have real limitations. But to the author's credit, it did not stop there. They went on to analyze existing clinical data, human data. So using an existing database, they compared 4,361 patients who were taking a zetomib with 945,000 age match controls. And the results were pretty astonishing. During follow-up, the incidence of Alzheimer's disease and related dementias was eightfold, eightfold lower among those receiving a zetomide. The authors conclude, now quoting, taken together, these findings suggest that a Zetamide confers a highly significant protection from Alzheimer's disease and related dementias in individuals with or without coronary disease. Remember, this is cholesterol-independent. And while the mechanisms warrant further investigation, these data provide compelling evidence to support the pursuit of acetomide for neuroprotection, so further research. This is a strong quote, a strong statement, and one that, if borne out, may be a real future avenue that could clinically meaningfully change how we think about a drug most of us have relegated to a cholesterol toolbox. But again, to be clear, this is not a cholesterol story. It's so much more than that. Remember Brain Batman? Now, it's essential to slow down and talk about caveats, limitations, and clarifications, what I'm saying and what I'm not saying. So, first and most important, this is not definitive proof that a Zenomide prevents Alzheimer's disease. I did not say that. There was no, is no randomized controlled trial in humans. The experimental work was limited to human cell lines, in veteral assays, animal models, worms, and a retrospective analysis of human medical records. That matters, it does. That said, these findings shouldn't be dismissed simply because they fall short of a gold standard randomized controlled trial. In fact, we will probably never have that trial, a Zetamide monotherapy for Alzheimer's prevention in an RCT. But from a mechanistic standpoint, the data are coherent and biologically plausible. And importantly, the effect size was enormous. These were not subtle changes. Amyloid and tau accumulation dropped meaningfully, autophagy increased by roughly 40%, and the observed associations with Alzheimer's risk were on the order of an eight-fold reduction.

SPEAKER_00 11:48

So even a lot of So just to be clear, if you're looking at a retrospective group of people that are on azetomide monotherapy, which is an odd drug to be on by itself in the modern era, many of us in the prevention space have patients on azetomide monotherapy, but it's not the most common approach. You have to ask yourself, how well are those patients on azetomide matched to those case controls in that retrospective association study and recognize that there is often confounding by indication. So even though the mechanism by which they are hypothesizing that azetomide reduces the tau accumulation and improves autophagy is independent of cholesterol lowering, you cannot ignore the fact that azetomide also reduces circulating levels of LDL cholesterol in ApoB. And what else is it doing? We don't know. Again, maybe that's controlled for in this in the paper. We'll go take a look at that here shortly. And you just have to know this as one study, right? That's all we have so far. What I'm curious about is what other evidence would support the use of a zetomy for neuroprotection in patients with ApoE4? And that is also something that I think you and I should look into here right after Nick's done talking. Let's let him finish up his piece here.

SPEAKER_01 13:14

Now the next clarification is about safety, because when you're determining what to do as an individual, it's all about careful risk-benefit analysis. So what are the risks? And in my opinion, generally, a zetomide is a benign medication, especially when compared to statin therapy. It's not associated, a zetomide is not associated with insulin resistance, diabetes risk, liver injury, muscle damage, etc. Personally, and obviously none of this is medical advice, don't get your medical advice off YouTube, but this is a drug that I've considered taking myself. In fact, I have tried it briefly in the past. I stopped because, quite honestly, it gave me diarrhea. Which is a common side effect experienced by a minority of users. It's not particularly dangerous, the diarrhea, just unpleasant. And as a quick aside, it wasn't nearly as bad as the diarrhea I got from David Barr. Just as our enzymes can't process the EPG fat Frankenstein that makes these bars possible, neither from my toilet process the destruction left in the wake of their consumption. That's pretty good. Anyway, that aside, I also want to be very clear about my track record when it comes to talking about cholesterol-lowering drugs. If anything, I'm known for highlighting the negative effects of pharmacotherapy targeting cholesterol. Some would say I even give statins a really hard time, and they wouldn't entirely be wrong. I've written extensively about the risks of reflexively driving cholesterol and Lveol and Apple B as low as possible without adequate attention to the physiology trade-offs in individual context.

SPEAKER_00 14:33

And as another transparent So some of you are gonna come at me in the comments for doing a reaction video to Nick Norwitz at all. I would encourage you to keep the open mind that he asks you to keep in mind. We are not here to litigate his position on APOB lowering therapies in general. We are here to learn about azetomybe, and that I think is a worthwhile pursuit. So try to uh simmer down. I can hear you already, and let's think about wrapping up the azetomybe story here. So I too, like Dr. Nick, was really interested in these findings, and I wanted to go through the paper itself and see what's here. So this is the same paper that Nick Norowitz is discussing in this video in aging biology, same authors, and the title is Zetamiva Lowers Risk of Alzheimer's and related dementias over sevenfold, reducing aggregation in model systems by inhibiting that 1433G hexokinase protein interaction that he talked about. So I think he did a great job covering the basic science portion. I'm not gonna go through that in detail. What I really want to dig into is this sevenfold reduction in dementia that they see in the clinical realm, because I think that is probably the most compelling part of this paper. And let's dig in and figure out what they see. So here in the abstract, they say mining clinical databases supports drug reduction. They don't talk a huge amount about the clinical component of this. So let's go through the methods and see how what data set they looked at, how they controlled for differences between patients, and how that works. So materials and methods. All right, see elegans, this is the worm culture data, neuronal degeneration assay, is it in my treatment of cultured human cell lines, autophagy, protein aggregates, metadata for human hippocampal tissue, proteomic analysis by mass spectrometry, immunoprecipitation, this is all the basic science stuff that they've done, structural retrieval, that's protein folding, PPI modeling, high throughput virtual screening, statistical analysis, students' t-test, results. Okay, so this is a bit of a red flag for me. I don't see anything in their methods section about the clinical database that they queried where they compared patients on a ZetomIBE to controls that they matched somehow. If you don't tell me how to do it in the methods, I don't know that I trust how you did it or that I can replicate those findings. It's it's not actually a little red flag, it's a really big red flag to have this be part of the title of your paper, this sevenfold reduction, and not tell me how you did it. Let's go find it in the results and see what they're gonna tell us about this. All right, here's all their basic science data. Great. All right. Here are some tables. There are drugs that you predict, general characteristics of populations used to calculate relative risk plus a zetomy. All right, so here are the tables. They have age controls. Uh there's a significant gender discrepancy here, which they don't talk about. Let's see. Diabetes is also significantly different. 18% versus 17%. That's statisti uh sorry, these are squared mean differences. This is not a p-value, so never mind that sex difference, although it's numerically interesting. I don't know that the squared mean difference is statistically different. Uh, but we do have difference in depression values, 4.4 versus 2.2%. Coronary disease is significantly increased in the azetomide group. Uh and then their dementia is here, 0.1 versus 0.8% in terms of absolute risk reduction. That's not uh high. And we're talking about five patients total out of 4,000. So we're looking at really small numbers here. When you're looking at really small numbers, detecting a difference is uh it's hard to know how meaningful that is, right? If this were 10 patients instead of five, that's not a huge numeric difference, but it would look as a big difference relatively speaking. Analysis and characteristics of Alzheimer's disease and related dementias, incidence among coronary RTDs. So Alzheimer's disease and related dementias. Related is an interesting term. Uh there are a lot of different kinds of dementia, some of which have the amyloid and tau as their fundamental, what we think is their mechanism, and others like vascular dementia may show some of that, but ask actually that's really more of like a microvascular stroke phenomenon, whereasetamide might be really helpful. So if we're talking about all dementias here, whether this is truly a reduction in Alzheimer's dementia, maybe it's a reduction in vascular dementia, where that cholesterol story might be more of an interesting picture. And we don't have a lot of data here about how well controlled were these patients on their hypertension and their coronary disease risks, like what stroke risk was quite different, 3% versus 1.6%. That is probably related to uh treatment of cardiovascular risk factors, whether that's the azetomide or something else. That's a big deal. Okay, so these are just the tables. Let's go down and figure out how they got these data, because I still don't know where this comes from yet. Acetomib enhances autophagy, reduced aggregation, those are the worm pictures Nick showed. Neat. All right. Okay. Acetomide significantly reduces the incidence of Alzheimer's dementia and related to dementias in normal elderly subjects and in a high-risk subset of patients with CAD. We analyzed data in the Pharmetrics Plus IQVA database comprising 2006 to 2020 clinical data. From this database, we found 4,361 patients receiving a zetomide. Is that a zetomide alone? Is that azetomide plus statins? Is that what other meds are they on? They don't say. And selected almost a million AMCs. I think they mean age-matched controls. So they're controlled for age. They don't have control for anything else, including the indication for azetomide, like hyperlipidemia or coronary artery disease. Untreated and treated groups have comparable sex ratios, 46% versus 54%. Prevalence of hypertension and diabetes. Remarkably, the incidence of Alzheimer's dementia and related dementias during follow-up differed by eightfold, 0.8% versus 0.1%, reflecting a relative risk reduction of 0.14 for those on a zetomib. They actually mean 0.86, I think. The hazard ratio will be 0.14. Using a time-dependent regression model to adjust for the observation time interval. We don't know anything about how they modeled this, what else they put in that model to adjust for confounders. That is a really important thing to report if you're gonna do regression modeling and report outcomes here. Alright, a subset of these subjects had been diagnosed with CAD, coronary artery disease. That should not surprise anybody because what would be reasons to have somebody on a zetomide? Coronary artery disease, hyperlipidemia is a pretty common one. So among those with CAD, we identified 547 patients prescribed a zetomybe and 73,000 in change, age-matched controls. In this cohort, relative risk reduction for this was 0.122 for a ZetomIB relative to controls. Taken together, these findings suggest that a ZetomIBE confers highly significant protection from all kinds of dementias to individuals with and without CAD. All right, let's go find out what's in this data set because I have strong feelings about how we try to find clinical data. All right. A newly expanded real-world data set featuring insured US patients with views into diagnosis, treatments, and associated costs. That means that what we have in here is not the medical record of these patients. What we have is what charges and diagnosis codes were given to these patients and what drugs they were either prescribed or filled at a pharmacy. So those can be a little different, and I don't know exactly how this data set captures that. Some of the health plans will tell you what was prescribed, some will tell you what was filled, some will tell you what was refilled, meaning did patients get the prescription and then get a second version of the prescription in 30 days or 90 days or whenever they ran out? Because, as you may well know, just because a doctor prescribes a medication does not mean that the patient takes it. And if they haven't refilled their drugs, just because they were prescribed it doesn't tell us anything about whether a zetomib is really doing anything for these patients or not. All right, let's see. Can we find out anything about this in here? Let's see if this has. So we get patient demographics, age, gender, race, ethnicity, zip code, and enrollment dates, diagnosis procedures, lab results and treatment patterns. Medication fills and cost metrics. So I gotta say, I'm not terribly impressed with the researchers' control of this data, meaning they didn't show me any lab data. We don't have any of that because again, that's not part of billing data sets. That is only part of a clinical medical record. All we have are diagnosis codes. So coronary disease, a diagnosis of coronary disease means anything from a positive calcium score all the way through to had a heart attack, had stencil, or had a bypass procedure. And we don't know which of those that is. You know, all we have are their diagnosis codes, their demographics, and really all that the authors in this paper tell us is that these are age-matched controls. So I don't know if they controlled for anything else when they did their regression modeling. I also don't know how they defined Alzheimer's dementia and related dementias. Did they exclude vascular dementia? That is really my key question here. If they did not exclude vascular dementia from this data set, then putting people on a cholesterol-lowering medication, which by the way, were they on other cholesterol-lowering medications, we don't know. Uh, and that should be knowable, by the way, from this data set. If you can tell me whether they're on a zetomybe, you should also be able to tell me whether they were on a statin or PCSK9 inhibitors or any other medications. And then whether they excluded the vascular dementia, because I would expect that lipid lowering therapy and possibly in conjunction with the antiplatelet therapy that often comes along with patients on lipid lowering therapy, right? Aspirin-statin is part of our guidelines for patients with peripheral arterial disease, coronary artery disease. Uh, you know, we don't know. I can't tell you whether this was aspirin-related, azetomide-related, lipid lowering related, or anything else until I know what the definitions were. So, Nick, I'm sorry, I love you, but I gotta tell you, I'm not terribly impressed with this clinical study when they're gonna show me a pretty small absolute risk reduction. Um, let's calculate what that is here for a second. Number needed to treat for an absolute risk reduction of 0.7%. Number needed to treat is approximately 143. This should be over a time frame. Somebody brought this up to me in one of the comments in my aspirin video. NNT is over a time frame. So I don't know what time frame we're talking about here. Uh, this was clinical data over many years, but we don't know what the average follow-up for these patients were. And also, by the way, the other thing we don't have from the data set is were they on a zetomide before or after they got a diagnosis of dementia? To tell me that the use of a zetomide was helpful. The use of a zetomide needs to come before the diagnosis of dementia by some reasonable time frame. I don't know, five years, 10 years, we start seeing changes in people with the ApoE4 protein as early as their 20s and 30s. The accumulation of amyloid and misfolded proteins like tau over time, again, just like atherosclerosis, this takes a long runway, years, maybe decades. So if you're gonna tell me that these patients all started on a Zetamide within six months of a diagnosis of Alzheimer's-related dementia, then I don't know that I'm impressed because that doesn't compute for me rationally. But before we give up on this entirely, let's see if there's anything else we can learn about the uh NemanPixie 1 like 1 receptor, the where the azetamib targets, and anything else that might shed light on azetomybe and brain health and protection. So you guys know I'm a huge fan of open evidence. We are gonna go to open evidence and ask whether we know anything else about this. Okay, so let's see what open evidence says. The current evidence does not support the use of acetomib as a protective agent against Alzheimer's dementia in clinical practice. This isn't a huge surprise, right? If people had come up with this before, Nick's paper wouldn't be the first time we'd heard about this, but let's just see what we know. Available data span preclinical animal studies, clinical trial safety analyses, Mendelian randomization studies, and pharmacovigilance data. The picture is mixed with no human clinical trial supporting a dementia preventive benefit. All right, so look at our clinical trial evidence, most robust human data come from our improve it trial, 15,000 patients. Now, this is symvastatin plus azetomide versus symvostatin and placebo. So this is also in the background of statin therapy, which particularly in ApoE4 carriers is a relevant thing to know about. We'll talk more about this in a video where we go over prevention strategies and what the data are for statin therapy in reducing dementia risk in ApoE4 carriers. This trial found no effect on incident neurocognitive adverse events. A 2023 American Heart Association statement concluded that RCTs of azetamib and PCS-K9 inhibitors failed to find an association between these LDL lowering therapies and dementia or impaired cognition, regardless of the LDLC achieved. Now, Nick would argue, well, this isn't really an LDL problem, this is a protein folding problem, and perhaps that's the mechanism. But again, we have randomized trials in patients with pretty good power, and we don't see a big change in cognitive outcomes in our randomized controlled trials. These are not an ApoE4-enriched population, so that would be a higher-risk population, but neither do we think that pharmaclinical data set that was in the aging biology paper, we also don't think that's an ApoE4-enriched population, although we don't know because again, that's not captured in their data set, but we don't think that that would be, you know, that should be population average. Separate meta-analysis of 20 RCTs, so now we are almost 140,000 patients, found no significant reduction in dementia or cognitive impairment with overall lipid lowering therapy. So that's not acetomide specific. Fair enough. Preclinical evidence is suggestive but limited. Okay. A mouse study demonstrated that acetamide attenuated memory deficits induced by high-fat diet or streptozocin reduced brain oxidative stress. That's a key thing that we're going to talk about because ApoE4 is a pro-inflammatory state in the brain for people who carry that allele. And lower acetylcholinesterase activity. This is attributed both to cholesterol-dependent and cholesterol-independent mechanisms. All right, great. Rat ischemic stroke models showed that a zetamide reduced neuronal aptosis via AMP-dependent autophagy activation. Okay, so this is consistent with the aging biology paper. We saw the increase in autophagy in that paper, and here we are showing the AMPA-dependent autophagy activation in ischemic stroke models, which is a little different than an Alzheimer's model, but this is consistent with the data that they've presented. Cholesterol esters have been identified as an upstream regulator of both Tau and amyloid beta in Alzheimer's disease neurons, suggesting that cholesterol metabolism is a druggable access in Alzheimer's disease. However, this work was on CYP46A1 activation rather than NPC1L1 inhibition or the Neman-Pix C1 like one receptor where acetomide acts to prevent the reabsorption of cholesterol and bile. Mendelian randomization and genetic evidence, potentially concerning. A Mendelian randomization study using variants in Neman-Pix C1 like one, acetomide target gene, weighed by LDL Associations, found no genetic support for repurposing acetamide for Alzheimer's prevention. More concerning, a separate MR analysis found that genetic inhibition of NPC 1L1 was associated with a higher risk of cognitive impairment across three independent data sets, suggesting a potential adverse cognitive effect of independent effect independent of lipid lowering. This raises the possibility that NPC 1L1 inhibition could theoretically worsen rather than improve cognitive outcomes. So this remains a genetic signal requiring clinical validation. Pharmacovigilance data. So these are data reported after drugs are on market. There is always an adverse event reporting system. So this is the FAIRS analysis. This is the database where we collect adverse events related to drugs, recognize that all adverse events are, this is a skewed data set, right? People preferentially report bad things, not good things in this data set, but this analysis found that a ZetomIP had a positive signal for amnesia, but an inverse association with memory impairment, significantly weaker amnesia signals compared to statins. These findings are hypothesis generating only and do not establish causality. I don't know that I put a lot of stock in this pharmacovigilance data necessarily. This is just independently reported without much analysis. So, in summary, the theoretical rationale linking cholesterol metabolism to AD pathogenesis, which is not what Nick talked about. His mechanism in that paper in aging biology is cholesterol independent and it's related to protein folding. But the rationale linking cholesterol metabolism is biologically plausible, and limited preclinical data suggests that a zendomy might have neuroprotective effects through antioxidative and anti-inflammatory mechanisms. We could argue that there are other tools that actually do that better, right? Antioxidation and anti-inflammatory components, but no human clinical trial has shown a reduction in Alzheimer's dementia or other dementias with azetomib, including our meta-analyses. And the Mendelian randomization studies would suggest that the NPC 101 inhibition might actually be harmful rather than helpful.

SPEAKER_01 35:02

And I don't say this to virtue signal, but to clarify my incentives. When I encounter data that are genuinely compelling or at least fascinating and underappreciated, I think it's my responsibility. I take it as my responsibility to highlight them, especially when they challenge my own confirmation bias and when they're not pandering. I don't like to pander. I like to give you my honest assessment of literature, and these data I find exciting. That brings us to chapter three, what I'm doing next. As for a Zetamide, it was something I was already considering revisiting as part of a four-arm year-long crossover experiment, examining the broader effects of different medications on my metabolic health markers. Now, this paper has made me even more interested in the idea of trying a Zetamide, but not for cholesterol management, for its potential implications on brain health. Remember, this isn't a cholesterol story, it's something way more. The main obstacle for me personally is tolerability. Yes, I do get diarrhea with Zetamide. Previously I tried a Zetamide for a few weeks at a standard dose, 10 milligrams. So this time, what I'm gonna do different is then I'm gonna start with a more conservative approach, starting at a half dose, 5 milligrams, and giving myself a full month to adapt. I'll also take it in the evening, when gut motility is slower, and with food. These are strategies that seem to reduce the gastrointestinal effects in some people. In addition, I currently take a magnesium supplement, which can compound with diarrhea, so I'm reducing my dose by half, from 400 to 200, to minimize any potential supplement drug interactions. And if I tolerate this approach, I may consider increasing my dose to five milligrams twice daily. Now, if I continue to have unacceptable side effects, the diarrhea, I'll just stop. But if I can tolerate it, my personal risk-benefit calculation now tilts more towards benefit than it did before, before I knew about these data, not because of the cardiovascular effects, but because of the potential brain effects. And there's something pretty ironic about that. And also as a quick nuanced note, I'm keeping a close eye on a medication that's currently just completed phase three clinical trials. It's a new generation CETP inhibitor known as obicetripib. I think that's how you pronounce it.

SPEAKER_00 36:52

Obacetropib.

SPEAKER_01 36:53

That's it. It has relevance for Alzheimer's disease as well, that I outline in this context, which you can check out if you're interested in that. Finally.

SPEAKER_00 37:00

I will be including the Obacetropib story in our deep dive on APOE4 as well, so stay tuned for that.

SPEAKER_01 37:07

In terms of what I'm currently doing for Alzheimer's prevention today, that brings us to chapter four, rapid fire tips for brain health. What I do. First, I take 5 milligrams of lithium or take daily. The brand I use is pure encapsulations, I have no affiliation, that's just a brand I use. For a deeper dive into that, see this video. I also take three capsules of a centrate and omega max daily. It's a brain-supporting supplement containing a specific form of omega-3, lysophosphatidylcholine DHA, which has been shown to pre-clinical models to preferentially increase levels of omega-3 in the brain. The data are genuinely fascinating, and I strongly encourage you to see this content if you're interested in protecting your brain, and especially if you know you're an apple carrier like me. And if you want to check out this product, check out the link below and use a discount code STAYCURIOUS for 20% off. But moving on. While I don't currently take any NAD boosting supplements, if I were over 40, I would likely consider therapies such as nicotinamide ribicide and nicotinamide mononucleotide, which can increase levels of an energy carrying molecule in the body called NAD that declines with age and is depleted in Alzheimer's disease. If you want to learn more about NAD, Alzheimer's disease, and supplementation, check out this content. But I want to wrap up and finish on our message of hope because I truly believe these data, taken together with everything else we learn here at the State Curious Metabolism Community, YouTube, Substack, elsewhere, they give us the tools to act today to better our brain health into the future, potentially completely prevent Alzheimer's disease, even in those with the highest genetic risk like me. I carry two copies of the ApoE4 allele. This is personal. I'm at 10 to 15 fold higher risk than your average person, but I don't think I'll ever get Alzheimer's disease. I am very optimistic because our genes for susceptibility, they are not our destiny.

SPEAKER_00 38:34

And by the I completely agree with this message of hope, and that is also going to be my take-home when we begin that ApoE4 series. ApoE4 is a marker. It is a signal that your brain does not process energy efficiently and does not traffic its lipids appropriately. It does not recycle the amyloid appropriately, and you are more prone to inflammation in your brain. But that is just a signal that you can be more prepared and honest about how to get yourself in a place because ApoE4 is our default gene. It has become less common over time, but it was the default, and it did not used to cause neurodegenerative diseases. That is a function of our modern environment. What I wish Nick had said is what he's doing for his brain health is maintaining his optimal metabolic health by eating in a way that does not reduce, that does not cause insulin resistance, that he is exercising, that he is sleeping. Because if we think about what moves the needle the most in preventing Alzheimer's disease, I don't think it's supplements. I don't even think it's gonna be a zetomide. These are all amazing tools and we should look at them, but I don't think that that's gonna be what moves the needle the most for people. It is controlling blood pressure, it is managing and eliminating insulin resistance, it is exercise and improving our brain-derived neurotrophic factor. And that is the bulk of what is protecting his brain and ours when we think about increased risk for dementia. So, yeah, supplements have a role. Absolutely. The data are very interesting. We are gonna dive into this azetomide study together, but that's really not the foundation. The foundation is the lifestyle.

SPEAKER_01 40:22

Learning and applying those lessons in your real life, I think you can set your fate. But wrapping up, this paper doesn't prove beyond a shadow of a doubt that Azetomide prevents Alzheimer's disease full stop, but it does reveal something almost as important. It forces us to think about what we thought we knew. Now, obviously, whether this signal holds up in replication studies and prospective trials remains to be seen, but uh, I believe at the very least, these data are a reminder that sometimes the most interesting answers, solutions, come from looking where no one thought to look. And that's why you know what I'm gonna say. Say it with me, out aloud in your kitchen, in your car, wherever you are, stay curious. Thanks.

SPEAKER_00 41:00

There are a number of drugs that have come to market that reduce amyloid plaque or reduce tau, and clinically, they have all been pretty uniformly a colossal disappointment. So just because we don't see as much accumulation of amyloid in the cell lines or in the worms that they study does not really impress me that much because we have drugs that do this already, and they have not been shown to be clinically helpful. But based on the accumulation of evidence, we don't really believe that azetomybe has a strong signal despite what the researchers in aging biology mentioned to us. So, taken on a whole, I don't think there's any harm in trying the azetomide. Like Nick said, it's a very safe drug. I don't know how much penetrates blood-brain barrier and what it's really doing behind the scenes there or behind the curtain, but I agree with him. I don't think it's that harmful. But I also don't think that there's necessarily as much supporting evidence for this as a brain health miracle drug as we might wish, right? Everybody wants this magic bullet for ApoE4 carriers or for people who are at high risk for dementia. Um, again, I will go back to what our foundations are for protecting our brain. And I am not gonna start prescribing this for all of my patients who are worried about dementia based on my interpretation of this evidence. But Nick, as always, a very uh inspiring and thought provoking video. Thank you for that. And until next time, guys, take really good care.