In this YouTube monologue, Nick Norwitz, a PhD researcher who carries two copies of the high‑risk APOE4 allele, explains why he is no longer fearful of developing Alzheimer’s disease. He begins by describing the personal stakes of his genetic risk and the broader prevalence of APOE4. He then outlines the three APOE isoforms (2, 3, 4) and frames the central scientific question: is APOE4 a toxic poison that must be removed, or is the problem simply a lack of the protective APOE2 factor? To address this, he reviews a recent mouse study in which human APOE2 was delivered to the brains of APOE4‑expressing mice. The study showed dose‑dependent reductions in amyloid plaque burden, dampened microglial‑driven neuroinflammation, and preservation of synapses. He interprets these findings as proof‑of‑concept that adding protective ApoE2 can counteract APOE4‑related pathology, suggesting a future path for gene‑based therapies. Recognizing that such therapies are not yet clinically available, he shares three immediate, evidence‑based neuroprotective practices he follows: low‑dose lithium orotate, nutritional ketosis, and high‑dose omega‑3 fatty acids (EPA/DHA), providing dosage ranges and sources. He also lists broader lifestyle pillars—sleep, exercise, sauna, diet—supporting brain health. The video includes a sponsor message for Chapter, a Medicare navigation service, and concludes with an optimistic call to action, urging viewers to choose hope and proactive brain‑health measures regardless of genetic background.
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I'm going to be honest with you. Alzheimer's disease scares the synapses out of me. Alzheimer's disease. Alzheimer's disease. Alzheimer's disease. Alzheimer's disease. Alzheimer's disease. Now, Alzheimer's disease should be scary to anyone, but it's extra scary to me because I have not one, but two copies of the major risk gene variant for Alzheimer's, APOE4. Well, me and Chris Hemsworth. Bring me Thanos! And this increases our risk for Alzheimer's disease by 10 to 15 fold. Add on to that I have a PhD in neurodegenerative diseases to boot, and I'm highly aware and highly motivated to find out how to prevent my risk of Alzheimer's disease. I really try to stay up on the literature, and a paper I just read had me utterly thrilled and optimistic, and I want to share it with you to go beyond my selfish want, my desire, my need to prevent Alzheimer's disease in myself, because this literature gives us a sense of the future, how we can reach into our skulls modify our brain metabolism to protect our minds and long-term cognitive health. So stick around because together we're gonna do like a healthy brain and learn. That kinda sucks, to be honest. Some even think having 2 copies of APOE4 is a guarantee of developing Alzheimer's disease. We've spent billions of dollars trying to innovate solutions to Alzheimer's and it hasn't worked. This increases risk 10 to 15 fold. The future of Alzheimer's therapy is around the corner. So what is that antidote? Inflammatory snowball in the brain, brain cells are safe. That inevitability is an illusion. Let me start though with an image that I hope strikes you even if you have no idea what's going on— yet. The blue haze here represents the activity of immune cells in the brain. These are called microglia. They're the resident immune cells in the brain. These play a central role in neuroinflammation, brain inflammation, and Alzheimer's disease. And what should be obvious is that the intervention, quote unquote, whatever that is, and I'll explain what it is, causes the blue to vanish. Bottom line, this is predicted to be strongly neuroprotective, in fact literally saving brain cells and connections among neurons, synapses. But that begs the question I hope you're asking, what the heck is this miraculous intervention? So now that I have your attention, let's fill in the background a little bit more. Alzheimer's disease is the most common form of dementia. And it's utterly debilitating, and it's currently untreatable. In the history of all of medicine, few diseases, probably no diseases, have been more crippling at a population level or more resistant to a solution. We've spent billions of dollars trying to innovate solutions to Alzheimer's, and it hasn't worked. But we are taking on new approaches that I think are hopeful, and this study was one of them. But one more crucial thing you need to know is that the dominant risk factor for Alzheimer's disease is a variant in the ApoE gene called APOE4. Now, everybody carries 2 copies of the APOE gene, one from mom, one from dad. And this gene comes in 3 versions, 3 variations: APOE2, APOE3, and APOE4. This means there are 6 possible combinations you as an individual can have. APOE3 variant, it's the most common. APOE2 reduces risk, and APOE4, the one I have 2 copies of, increases risk. About 25% of people carry at least 1 copy of E4, and roughly 65% of Alzheimer's patients carry at least one copy. And then of course there are the unlucky few who really lost the genetic lottery, those 2% who have two copies of APOE4. And as I said, this increases risk 10 to 15 fold. Some even think having two copies of APOE4 is a guarantee of developing Alzheimer's disease if you live long enough. Now, that kinda sucks to be honest. But genes aside, I, Nick, am optimistic. I don't think I'll ever get Alzheimer's. And today I'm going to give you just a little glimpse into why. So now we know about ApoE2, 3, and 4. But here's a key question. To what degree is ApoE4 actively toxic in the brain versus ApoE2 protective versus ApoE3 and ApoE3 protective versus ApoE4? And this distinction really matters because if ApoE4 is just pure poison, it might be difficult to filter out. But what if the problem is simply lack of protection? That's much easier to address by adding back what's missing. Or another way to think about it, and I'm going to get more concrete in a moment, is if there's a poison dissolved in a glass of water, you can't filter that out very easily, but you can add in an antidote. So what is that antidote? And that distinction is at the heart of the study we're about to review. Sorry for the long preamble, I did think it was important. Anyway, the researchers behind this study used a mouse model carrying ApoE4, human ApoE4, to ask, what if you bathed the brain in extra ApoE2? Could you protect against, or even stop, or reverse Alzheimer's disease? So in simple terms, the researchers were testing this new method of ApoE2 delivery to the brain even against a full apparent dose, a background of ApoE4, which is presumed to be neurotoxic. Now, I'm not going to delve deeply into the how this newfangled methodology works. It's pretty cool, and if you do want those extra details and to review what makes this technology I think so promising and why I'm particularly giddy, please see the associated newsletter link below. I do explain the technology. But let's get on to the results. They were, as you probably can expect, incredibly uplifting. In a dose-dependent manner, higher ApoE2 reduced plaque accumulation in the brain. That's shown by staining here for amyloid plaques, the thio-S stain. But even more important than the plaques is how the brain reacts to them. Alzheimer's is in large part a neuroinflammatory condition, inflammation in the brain. And amyloid plaques and the associated neurofibrillary tau tangles, they promote inflammation, basically an inflammatory snowball in the brain. And this is mediated in part by the brain's resident immune cells, the microglia, which we already introduced, and ApoE4, it ramps up this inflammatory response in the brain. But prior to this study, it was unclear whether adding in ApoE2 on top of ApoE4, if you have it like me, whether it could turn down the inflammatory dial. And that brings us back to the opening image, the one I hope struck you. The blue marker represents microglia, and as you can clearly see, adding more ApoE2 on top of an ApoE4 background quiets the neuroinflammation, the downstream consequences are great. Brain cells are saved and synapses, the connection among neurons, they're preserved. So stepping back, what we see here is an image in blue and red of hope. Hope that by adding in a protective factor without the need to subtract one that is embedded into some of our genes, including mine, we might be able to save neurons in those predisposed to Alzheimer's disease. And protect people at risk. Now, to cap off this video, I'm sure many of you are wondering about the things I do today while I'm waiting for gene technology to advance to protect my brain. Well, I'll share 3 things and then link more information below. Now, quick tangent. I know we'd all love to have access to futuristic gene therapies for cognitive enhancement today. I'm really impatient for them. Unfortunately, they're not here yet, so in the rest of this video, I'm going to tell you about the pillars of cognitive enhancement and healthy brain aging that I ascribe to, but before we get to that, I want to tell you about the sponsor of this video, Chapter, my partner in the longevity space. Chapter is not a pill or a supplement. It's a practical program to help older adults navigate the complex headache and maze that is Medicare insurance. Because here's the truth: the right health insurance doesn't just save you money, although the average Chapter user saves $1,100 per year. The right coverage tailored to your unique needs can increase your chances of living longer. More details on those data here. Chapter— what Chapter is, is a fully independent organization, and their guides will get on the phone with you, human to human, and help you find the right plan that fits your needs or loved one's needs. So if you or someone you care about could benefit from the service, please call the helpline we've set up. It's 815-STAY-CURE, as in stay curious. That's 815-782-9287. Thanks for listening. Now back to your main program in brain health. First on my neuroprotection non-negotiables list: lithium. A couple months ago I made content reviewing a major Alzheimer's study out of Harvard that swept across headlines. I'd never seen quite anything like it in Alzheimer's disease in the media. But anyway, the short version is low-dose lithium, specifically lithium orotate, that specific lithium salt, appears to be neuroprotective. This is supported by both human evidence and mechanistic animal models. I found the data super compelling, and I encourage you, if you haven't seen that content, either read the newsletter or watch the video. Depending on if you prefer to read or watch, I'll link both. Personally, I take 5 to 10 milligrams of lithium orotate. Moving on to ketosis. Ketosis offers neuroprotection in multiple ways. Let me review 3. 1, energy metabolism. Ketones are an efficient fuel source for the brain, particularly valuable in people with insulin resistance or impaired glucose metabolism. Which are both hallmarks of cognitive decline. And 2, anti-inflammatory effects. Ketones dampen neuroinflammation in many different ways, which is parallel and maybe synergistic with the effects of ApoE2 that we just reviewed. And 3, protein clearance. Perhaps most fascinating, ketones appear to help the brain identify and clear misfolded proteins like amyloid and tau. These are defining features of neurodegenerative diseases in both Alzheimer's and Parkinson's. If you want to see more on this fascinating science, including hearing from the author behind the research, see this video. And then 3, omega-3s. You cannot overlook omega-3 fatty acids, especially the long forms, EPA and DHA. For brain health, they are structural building blocks of the brain. My preferred source is whole fatty fish. But for supplementation, I do have some options. I favor krill oil or a specialized product formulated with what's called lysodHA. This is engineered to cross the blood-brain barrier more efficiently. And if you want more information on this, See my prior letter. Anyway, for whole food sources, I definitely aim for fatty fish at least twice per week, often more. I emphasize smaller, lower trophic level fish. So sockeye salmon and sardines are my go-to because they carry lower mercury burden. And my benchmark is aiming for 2 grams of EPA and DHA per day as a goal. You can also get your omega-3 status measured. There are lots of services to do this, but if you want the service I use, see the newsletter again. Also there, I'm going to go over some more neuroscience non-negotiables I use routinely to protect my brain. But I do want to wrap up this video before I just spew too long. I want to emphasize the main point, which is one word: optimism. The future of Alzheimer's therapy is around the corner. Gene therapies, really promising gene therapies are in development and they do hold promise. And in the meantime, there's a lot we can do rather than just twiddle our thumbs waiting for innovations. We can optimize our diet, including supplementation and eating the right whole foods, sleep, exercise, sauna, There is so much we can do. So yeah, I'm in the 2% with a double ApoE4 dose. Some call that an inevitable path to Alzheimer's disease, but that inevitability, I believe, is an illusion. With emerging therapies on the horizon and practical steps available now, I choose optimism. I choose hope. Whatever is in your genes, ApoE4 or ApoE2, I hope you choose optimism, action, and hope too. Stay curious. And tell me if you found this interesting.
