Why I’m Starting this Cholesterol Drug (For My Brain)
In this solo YouTube presentation, the host (Nick Norwitz) explores emerging evidence that the cholesterol‑lowering drug ezetimibe may have cholesterol‑independent neuroprotective effects relevant to Alzheimer’s disease (AD). He begins by outlining ezetimibe’s gut‑targeted mechanism (NPC1L1 inhibition) and the AD pathology centered on abnormal protein aggregation, especially the 14‑3‑3–hexokinase interaction that promotes amyloid and tau accumulation. He then reviews a recent hypothesis‑naive drug‑screen study published in Aging Biology that identified ezetimibe as a candidate to disrupt this interaction. The study showed that ezetimibe reduced amyloid and tau levels in human cell lines, enhanced autophagy by ~40%, lowered amyloid accumulation in C. elegans, and, in a retrospective analysis of 4,361 ezetimibe users versus 945,000 controls, was associated with an eight‑fold lower incidence of AD and related dementias. The presenter emphasizes the massive effect size while noting key limitations: lack of randomized controlled trials, reliance on in‑vitro and animal models, and potential confounding in the observational data. He discusses safety, noting ezetimibe’s generally benign profile but acknowledging his personal experience of diarrhea. He then outlines his own planned self‑experiment: starting with a low 5 mg dose taken in the evening with food, adjusting magnesium supplementation, and potentially titrating to 5 mg twice daily if tolerated. He also mentions monitoring a new CETP inhibitor (obesertropib) for future relevance. Finally, he shares rapid‑fire brain‑health practices he follows—daily lithium orotate, a specialized lysophosphatidylcholine DHA omega‑3 supplement, and, for those over 40, consideration of NAD‑boosting precursors (NR, NMN). Throughout, he stresses staying curious, acknowledges his APOE4 homozygous status (high genetic AD risk), and frames the data as a compelling, though not definitive, signal that challenges conventional thinking about cholesterol drugs.
Chapters
I promise I'm not pulling your leg when I say shocking research just changed 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 ezetimibe, 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 1 in 1 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 gene called APOE4, and that is where our story really begins. These data blew me away because these data show how ezetimibe might be doing something no one expected and no doctors know about, and it's happening in the brain. It's kind of like if all of medicine was seeing azetamide 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 ezetimibe and Alzheimer's disease that really caught me off guard. Not statins, not PCSK9 inhibitors, just ezetimibe. This is not a cholesterol 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 thought to look. Now, as a roadmap for what we're going to discuss today, I'm going to review: 1. The essential background you need to know about ezetimibe and Alzheimer's disease. 2. I'll introduce a new fascinating study on ezetimibe and Alzheimer's disease that had my neurons firing like crazy. We'll cover the mechanistic data and even some human data. Then in Chapter 3, I'm going to tell you about what I'm going to try next based on these data. Then in Chapter 4, I'm going to reveal other rapid-fire high-yield tips for brain health and cognitive longevity based on what I do. And 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 1: Background on Ezetimibe and Alzheimer's disease. I'm going to start with Ezetimibe, these pills. 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, ezetimibe 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, ezetimibe isn't inhibiting cholesterol synthesis in 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 ezetimibe. 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 amyloid and tau in Alzheimer's disease, or other neurodegenerative diseases like Parkinson's disease where alpha-synuclein aggregates. When proteins clumped together 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 its 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. In the context of specifically Creutzfeldt-Jakob disease, it's a devastating, universally fatal neurodegenerative condition that causes rapid onset dementia and then death. It's caused by prions, which are literally infectious misfolded proteins. And the 1-year survival rate is only 30%, so people die fast with dementia. Anyway, 1433 plays an important, albeit underappreciated, role in other neurodegenerative diseases like Alzheimer's and Parkinson's. 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 neurodegenerative 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, neurons being choked, and eventually neurons dying. Now, on to the primary study, Chapter 2, this new study on ezetimibe and 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-lowering 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 14-3-3 hexokinase protein interaction implicated in Alzheimer's disease and other neurodegenerative disorders. And 6 drugs emerged. One of them was ezetimibe. And the researchers chose to pursue ezetimibe 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 going to get into that a little bit later. And just as another key detail, ezetimibe was the only cholesterol-lowering drug that showed up. Not statins, not PCSK9 inhibitors, etc. Just ezetimibe. 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 hexokinase interaction? And ezetimibe 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 ezetimibe 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, ezetimibe significantly reduced amyloid accumulation. Next, they turned 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, ezetimibe 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 azetamide 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. elegans, little worms, where neurotoxic amyloid buildup can be visualized. Basically what they do is they bind the amyloid to something called mCherry so it glows red. And consistent with the cell data, ezetimibe 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 authors' 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 ezetimibe with 945,000 age-matched controls. And the results were pretty astonishing. During follow-up, the incidence of Alzheimer's disease and related dementias was 8-fold, 8-fold lower among those receiving ezetimibe. The authors conclude, now quoting, "Taken together, these findings suggest that ezetimibe 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 ezetimibe 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 ezetimibe 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 vitro 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— azetamide 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 8-fold reduction. So even allowing for some confounding, and I expect there was confounding, an effect of that magnitude is not trivial. It's astronomical. You don't see signals like that every day in medicine. 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 ezetimibe is a benign medication, especially when compared to statin therapy. It's not associated— ezetimibe 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 Bar. Just as our enzymes can't process the EPG fat Frankenstein that makes these bars possible, neither can 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 LDL and ApoB as low as possible without adequate attention to the physiology tradeoffs in individual contexts. And as another transparency tidbit, and it might be overkill, I have no relationship with pharmaceutical companies. I have turned down, literally turned down, 6-figure offers to sponsor or support my educational content. 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 the literature, and these data I find exciting. That brings us to Chapter 3: What I'm Doing Next. As for ezetimibe, it was something I was already considering revisiting as part of a 4-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 ezetimibe, 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 ezetimibe. Previously I tried ezetimibe for a few weeks at a standard dose, 10mg. So this time what I'm going to do different is I'm going to start with a more conservative approach, starting at a half dose, 5mg, 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 5mg 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 nuance note, I'm keeping a close eye on a medication that's currently just completed phase 3 clinical trials. It's a new generation CETP inhibitor known as obesertropib. I think that's how you pronounce it. It has relevance for Alzheimer's disease as well that I outline in this content, which you can check out if you're interested in that. Finally, in terms of what I'm currently doing for Alzheimer's prevention today, that brings us to Chapter 4: Rapid-fire tips for brain health. What I do. First, I take 5mg of lithium orotate daily. The brand I use is Pure Encapsulations. I have no affiliation, that's just the brand I use. For a deeper dive into that, see this video. I also take 3 capsules of Essentrate Omega Max daily. It's a brain-supporting supplement containing a specific form of omega-3, lysophosphatidylcholine DHA, which has been shown in preclinical 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 ApoE4 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 riboside 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 a message of hope because I truly believe these data, taken together with everything else we learn here at the Stay 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 are susceptibility, they are not our destiny. And by 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 ezetimibe prevents Alzheimer's disease full stop, but it does reveal something almost as important. It forces us to think about about what we thought we knew. Now, obviously, whether this signal holds up in replication studies and prospective trials remains to be seen, but 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 going to say, say it with me out loud in your kitchen, in your car, wherever you are: Stay curious. Thanks.
