Don't Take Omega-3s Until You Know This | Dr Nick Norwitz

Summary

Podcast Summary — The Neuro Experience with Louisa Nicola

Episode: Don’t Take Omega-3s Until You Know This | Dr. Nick Norwitz
Date: June 23, 2026
Host: Louisa Nicola
Guest: Dr. Nick Norwitz

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Overview & Main Theme

This episode dives deep into the complexities of omega-3 supplementation, particularly regarding its impact on brain health, cholesterol, and Alzheimer’s risk. Dr. Nick Norwitz, a researcher and self-experimenter with unique genetics and cholesterol levels, joins Louisa Nicola for an evidence-rich discussion on omega-3 forms, the paradoxes of lipid health, Alzheimer's risk genes (ApoE4), and why standard advice about heart disease and brain health is due for disruption. The conversation is packed with cutting-edge research, personal experiments, and practical guidance for listeners who want to make informed health decisions.

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Key Discussion Points & Insights

1. The Omega-3 Paradox: Why Do Fish Work But Not Supplements?

• Observational Evidence: Populations who eat fish have lower rates of Alzheimer’s, but clinical trials using standard omega-3 pills are not impressive.
• Trial Limitations: Trials don’t mirror real-world long-term use (30-year RCTs are unfeasible). Fish have additional nutrients (e.g., selenium) and healthy user bias (01:30).
• Nick’s Take: “Omega-3 throughout the life course is basically a non-negotiable, especially for people who are more vulnerable.” (01:56, Nick)
• Implication: Supplement form and trial design matter—whole fish may confer unique benefits.

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2. What Makes Omega-3 (DHA) Critical for the Brain?

• Fatty Acid Functions: Beyond fuel, DHA is a structural component of neural membranes, an anti-inflammatory agent, and a hormone precursor (02:41–03:32).
• Quote: “Without the DHA, there is no functional brain.” (03:26, Nick)

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3. Why the Carrier Form of DHA Matters: The Phospholipid Story

• Forms Discussed:
  • Triglyceride (standard fish oil)
  • Free fatty acid
  • Phospholipid (specifically lysophosphatidylcholine, LPC)
• Brain Delivery: Phospholipid (LPC) DHA is transported more efficiently into the brain due to a specialized transporter (06:20, Nick; MSFD2A).
• Lab Evidence: Equimolar doses of LPC-DHA accumulate more in the brain than standard fish oil (06:20–07:32).

“If you want to get the DHA concentrated in the brain, then the lysophosphatidylcholine form is the most effective, gram for gram.” (06:10, Nick)

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4. Choline, Eggs, and Brain Health Connections

• Choline as a Nutrient: Important for acetylcholine synthesis, which drops in Alzheimer’s (07:40).
• Dosage Realism: Most people get enough choline from a few eggs or animal protein; mega-dosing is unnecessary (07:40–08:30).

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5. DHA Mouse Studies: Memory & Brain Function

• Study Cited: Mice given LPC-DHA performed better on the Morris Water Maze, a memory test, compared to standard DHA (08:30–09:18).

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6. Dosing: How Much and Which Omega-3?

• General Guidance: 2g EPA + 2g DHA per day is an aggressive target for brain health, especially in those at higher risk (09:18–09:46).
• Phospholipid DHA: Lower doses may be needed due to greater brain uptake, but it’s expensive and not widely available (09:46–10:54).

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7. ApoE4 Gene & Alzheimer’s Risk

• ApoE Variants: ApoE4 is linked to higher Alzheimer’s risk; Dr. Nick is a rare double-carrier (E4/E4), as is Chris Hemsworth (14:25–16:15).
• Risk Is Not Destiny: Lifestyle matters more for ApoE4 carriers—poor sleep or metabolic health is riskier (17:01–17:31).
• Young vs. Old ApoE4 Brains: Young carriers have higher brain DHA uptake but burn through it faster; older brains are DHA-deficient (18:33–19:23).

  “I think about it like a ‘burn hot, die young’ phenomenon.” (18:07, Nick)

Actionable Guidance:

• ApoE4 Carriers: Consider a higher omega-3 intake due to faster DHA turnover. Doubling standard dosing may be prudent, though exact evidence is lacking.

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8. Women, Menopause, and DHA: Unique Vulnerabilities

• Menopausal Shift: Loss of estrogen leads to cerebral glucose intolerance—implicated in higher Alzheimer’s risk for women (21:00–21:02).
• DHA Synthesis on X Chromosome: Some women have enhanced capacity for DHA synthesis—may explain statin side effects in women and calls for DHA supplementation alongside statin therapy (22:27–24:13).

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9. Statins, Dementia, and Individual Risk

• Key Distinction: Statins may benefit metabolically unhealthy populations (hypertension, obesity), but the risk/benefit is uncertain for lean, metabolically healthy APOE4 carriers like Nick (25:59–29:27).
• Statin Side Effects: Inhibit mitochondrial function, possibly risky for Alzheimer’s-prone individuals due to mitochondrial vulnerabilities (29:27–29:56).
• Ezetimibe: Preferred cholesterol-lowering alternative for Nick, showing potential Alzheimer’s protective effects in early research (29:56–32:26).

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10. Alzheimer’s Pathways: Amyloid, Tau, and Innovation

• Shifting Targets: The research field is moving from amyloid-beta plaques to tau as the next frontier, especially for women (35:06–36:32).
• Lithium & GSK3β: Lithium orotate (low-dose, over-the-counter) is a promising tau-targeter via GSK3β inhibition. New Harvard research sparked market demand for lithium orotate supplements due to robust early results (39:42–41:25, Nick).

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11. Frontier Interventions: Gene Editing, Glymphatics, and AI

• Glymphatic System: Sleep’s role in clearing brain toxins; research ongoing into how 40 Hz light and sound therapy might enhance clearance (42:29–44:22).
• Gene Therapy: Rapid advances in technologies like CRISPR and “prime editing” could one day allow direct correction of ApoE4 genetic risk (44:43–47:58).
• Artificial Intelligence: Tools like DeepMind’s AlphaFold accelerate understanding of biochemical mechanisms for drug discovery (47:58–49:08).

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12. Cholesterol, Atherosclerosis, and the “Outlier” Case

• Nick’s Unique Case: Maintained an LDL ~700 mg/dL for 7 years with zero plaque. Destabilizes the LDL/heart disease paradigm, especially in metabolically healthy individuals (49:13–68:48).
• Key Message: “LDL and ApoB are one risk factor among many that need to be taken in the context of the individual patient.” (49:37, Nick)
• Analogy Misuse: Warning against simplistic reasoning—LDL is causal but not always important in every context (50:13–52:17).

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13. Self-Experiments and Metabolic Curiosity

• Lean Mass Hyperresponder: Nick lowered his LDL by 71% eating Oreos, demonstrating context matters (64:34).

• 1,000 Sardines Challenge: Led to unique metabolic and sensory changes (improved energy, cold tolerance, odd body odour), illustrating the hormone-like effects of omega-3s (72:10–79:09).

  “I smelled really weird...It created relationship strife...I gave off an aura.” (75:56, Nick)

• FGF21 and Metabolism: Surprising metabolic effects from unexpected diet interventions (73:31–74:42).

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14. Keto, Ketones, and Menopause

• Ketone Benefits: Especially after menopause, ketones provide crucial brain energy, help clear misfolded proteins, and reduce inflammation (79:41–82:18).
• Therapeutic Layer: Recommends intermittent fasting, exercise, and NAD precursors (nicotinamide riboside/mononucleotide) for resilience.

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15. Rapid Fire: Other Interventions for Brain Health

• Summary List (81:52–82:18):
  • High-dose omega-3s (especially LPC-DHA for ApoE4)
  • Prioritize sleep (glymphatics)
  • Lithium orotate (GSK3β inhibitor)
  • Exercise and NAD boosters
  • Intermittent fasting and periods of ketosis
  • Ezetimibe (for cholesterol, potentially brain health)

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16. Creatine for Brain Health and Depression

• Creatine Boosts Mood: New RCT shows 3g creatine plus specific probiotics improved depressive symptoms via better creatine absorption (82:21–83:41).
• Louisa: “That’s funny because I usually think I've never seen the data on a probiotic in combination...” (83:33)

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17. GLP-1 Agonists & Alzheimer's Disease

• GLP-1s (Ozempic, Mounjaro, etc.): Potential brain benefits are independent of weight loss—improve insulin sensitivity, inhibit toxic amyloid processing, and inhibit GSK3β (84:06–84:56).
• Retatrutide: Emerging drug suppresses LDL unexpectedly, possibly due to glucagon–PCSK9 interaction. Watch this space for future trials.

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18. Peptides and the Risk/Reward Balance

• BPC-157 & TB500 "Wolverine Stack": Not FDA-approved due to theoretical cancer risk from non-specific vascularization. “There are peptides I’d be excited to see approved...but none are 100% risk free.” (86:29–88:59, Nick).

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19. Why is Dr. Nick Norwitz Controversial?

• Provocative—but Moderate: Nick’s approach is scientific, evidence-based, and intentionally moderate. He challenges tribalism and refuses to “dumb things down,” which leads to social media misunderstanding and controversy (89:08–91:11).

  “The population I'm trying to serve is...the underserved population of people who are starving for nuance and are willing to...grapple with the complexities...” (90:02, Nick)
  “Everything I say, like I say things in a provocative manner, but they're precise... I'm going to do [clickbait], but...it's accurate. It's just going maybe where you didn't expect.” (91:17, Nick)

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Notable Quotes & Timestamps

• On Omega-3 Forms:
  “If you want to get the DHA concentrated in the brain, then the lysophosphatidylcholine form is the most effective, gram for gram.” (06:10, Nick)
• On ApoE4:
  “ApoE4 is a risk multiplier. Not deterministic, but you have to keep things on lock in order to, you know, reduce your risk.” (17:01, Nick)
• On high LDL and personal risk:
  “I know what an LDL of 500 means, and I'm sitting with that. I make a bet that they're wrong and I'm right, and then I end up being right.” (00:09, Nick)
• On controversy:
  “I refuse to dumb things down and I feel like I'm provocatively moderate." (89:08, Nick)

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Timestamps for Key Segments

• Omega-3 Brain Health Paradox: 00:52–02:36
• DHA Functional Roles: 02:41–03:32
• Omega-3 Formulation Deep Dive: 03:45–06:44
• ApoE4 Carrier Strategy: 13:11–21:02
• Statin, Ezetimibe, and Brain Health Discussion: 25:59–32:26
• Cholesterol Case Study and LDL Controversy: 49:13–68:48
• Sardine and Oreo Experiments: 72:10–79:09
• Keto & Women’s Brain Health: 79:09–82:18
• Creatine in Depression: 82:21–83:41
• GLP-1s and Retatrutide: 84:06–85:33
• Peptides & Safety: 86:02–88:59
• Controversy Explored: 89:08–91:11

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Memorable Moments

• Personal Experimentation:
  Nick’s “Oreo experiment” dropped LDL by 71%, demonstrating context-driven lipid variability.

• The 1,000 Sardines Month:
  “I had some really interesting responses...gave off an aura...created relationship strife.” (75:56, Nick)
  — led to insights on omega-3’s hormonal and metabolic actions.

• Challenging the Status Quo:
  Debates about lipid guideline dogma and scientific publishing inertia.
  “If you look at some of the early trials...the benefits...have dropped to zero [for healthy, non-smoking populations].” (53:00)

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Conclusion

This episode is a dense, nuanced, and highly practical exploration of omega-3 fatty acids and disruptive ideas in brain and cardiovascular health. Dr. Norwitz brings relentless curiosity, skepticism, and a willingness to self-experiment, while Louisa’s probing keeps the discussion tied to actionable insights for the public and clinicians alike. Anyone interested in optimizing brain health, understanding genetic risk, or deciphering the true science of cholesterol should not miss this conversation.

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For specific topics, refer to the provided timestamps for deep dives, and check out Nick’s social media for experiment videos and scientific threads.

Transcript

[Louise Nicola]

You published a case report that broke the Internet. Seven years of 700 cholesterol without coronary atherosclerosis. And the patient in the case report was you.

[Nick]

I know what an LDL of 500 means, and I'm sitting with that. I make a bet that they're wrong and I'm right, and then I end up being right. I carry two copies of Apoe 4. 65% of Alzheimer's patients carry a copy. How do I even exist as a patient?

[Louise Nicola]

You've done a lot of little experiments on yourself, notably the Oreo one.

[Nick]

I used Oreos to lower my cholesterol by 71%.

[Louise Nicola]

You've done one on where you ate a thousand sardines in a month. Talk to me about why you did that.

[Nick]

I had some really interesting responses.

[Louise Nicola]

You forgot one. Creatine thoughts?

[Nick]

There's a big study that came out. They used 3 grams creatine and they saw clinical improvements in human depression.

[Louise Nicola]

If high LDL and high APOB aren't the root cause of heart disease in someone who is metabolically healthy, then what is?

[Nick]

So let me first unpack.

[Louise Nicola]

I'm Louise Nicola and this is the Neuro Experience. So, Nick, there's a massive paradox happening right now in the area of brain health, and it specifically relates to omega 3 fatty acids, Epadha. Specifically, when we, you know, we know that eating fish is associated with lower rates of Alzheimer's disease. But when we run clinical trials giving People Standard Omega 3 supplements, the results are incredibly disappointing. But, but my question is, if the brain needs dha, why aren't these standard supplements working?

[Nick]

Well, you have to think about how the trials are designed and what they're powered to look for. So if we're talking about preventing cognitive decline, you ideally want to start as early as possible. I think the simplest analogy when you think about something like Alzheimer's is it's a boulder rolling down a hill, and the more inertia it has, the harder it is to stop. You ideally want to stop it when it's at the top of the hill, but before it has any momentum. The analogous trial, therefore, would be a 30 year randomized controlled trial with a high quality DHA supplement, which has just never been done. So I think it's an artifact of the fact that the trials aren't that good. I will say there are other nuances. So, for example, when you're eating whole fish, they contain things other than DHA that could be neuroprotective, like forms of selenium, which can be neuroprotective. And of course in observational data, there's going to be a little bit of healthy user bias. So I wouldn't rule that out, but I think just on first principles with respect to what we know about how the brain works and how important omega 3s are in the brain. Omega 3 throughout the life course is basically a non negotiable, especially for people who are more vulnerable. And we can get into that.

[Louise Nicola]

So let's talk about why DHA is actually important for the brain then.

[Nick]

Sure. So when you think about fatty acids, they have different natures. You can think of it as just a fuel source, obviously. Right. You break down the fatty acid via beta oxidation and burn it for energy. But you don't really want to do that with DHEA because it has so many other functions. You can turn omega 3s into hormones that have effects throughout your body. And when I say hormones, I literally do mean hormones. They circulate through your blood and cause various biological effects. They have anti inflammatory roles or they can be structural. I think DHA makes up about 40% of the unsaturated fatty acids in the brain, including key brain regions that are involved in Alzheimer's disease. So you have anti inflammatory properties, hormonal properties and structural properties. Without the dha, there is no functional brain. So that's the high level on why these things are important.

[Louise Nicola]

It's surprising to me as well when you look at supplements.

[Nick]

Right.

[Louise Nicola]

And it's just, you know, know a lot of people are taking rancid supplements. But you talk a lot about taking a DHA with a phospholipid layer, right?

[Nick]

Yeah.

[Louise Nicola]

Why is that?

[Nick]

So I mean there are multiple levels of omega 3s on the one hand. So actually probably first just good to zoom back and talk about what omega 3s are. You have fatty acids which can be saturated or unsaturated. Saturated means it has only single bonds. Unsaturated means it has double bonds. You have Omega 3, you have Omega 6. Where the double bonds are placed in the fatty acid determines basically you can think of its hormonal properties, its properties. Overall, Omega 3 is one such type of unsaturated fat. Where the Last double bond is 3 from the end, then within there there's shorter and longer chain depending on the number of carbons, ala, which you get from plants like things like walnuts, flaxseeds, Then you have the long chain omega 3s, EPA and DHA. These are the ones you get from seafood. The conventional wisdom is the long chain omega 3s are what you want for Heart and brain health. You know, I don't think walnuts are bad. I quite like walnuts. But you're not getting a lot of those long chain Omega 3s from Walnuts. And the conversion is pretty low, maybe at the most 5% conversion if you're say a vegan. But for the most part you want to target those EPA and DHA long chain omega 3s. But there's another level that I think most people don't appreciate, which is the carrier. So if you think of the Omega 3 as like a letter, you need to put it in an envelope and put some postage on it. There are different carriers. It can be in a triglyceride form, it can be as a free fatty acid, and it can have a carrier called a phospholipid. One's called lysophosphatidylcholine LPC for short. And this changes how the fatty acid is targeted throughout the body. So if you look at dose controlled studies, and most of these are from animals, because you can't really decapitate humans and then stain their brains, it's typically frowned on by ethics boards. You can try to get that IRB through. But if you take the same amount of say a lysophosphatidylcholine DHA or like a standard fish oil triglyceride dha, the triglyceride DHA will accumulate a lot more in fat tissue versus the brain. And lysophosphatidylcholine phospholipid bound will end up in the brain more so than fat tissue. Now to be clear, just because it's ending up in fat tissue is not making you fat. It has important helpful properties in fat tissue as well. So that's not bad per se. But if you want to get the DHA concentrated in the brain, then the lysophosphatidylcholine form is the most effective, gram for gram.

[Louise Nicola]

But why is that? Is it because it has a greater ability to penetrate the brain through the blood brain barrier?

[Nick]

Exactly. So the blood brain barrier is. It's like these things aren't diffusing back and forth. They have different transporters. And the lysophosphatidylcholine allows the DHA to lock onto a transporter. One's called MSF D2A and it makes basically lysophosphatidylcholine. I can't speak today. DHA more effective at penetrating the brain.

[Louise Nicola]

Yeah, so that's very interesting. I love this transporter, by the way. I speak about it a lot as it relates to the deterioration of the blood brain barrier in mild cognitive impairment patients. But I didn't. I wasn't fully aware that to cross, that it needed the lyso choline.

[Nick]

I don't know if it's 100% necessary, but probably will increase the affinity in transport. What I can speak to is that this is a specialized transporter that can transport this lysophosphatidylcholine dha. And at least in the preclinical studies in living organisms, the lysophosphatidylcholine DHA does concentrate more in the brain than in fat tissue. I guess to prove the relative transport capacity, you need tracer studies, which maybe have been done.

[Louise Nicola]

I'm not sure you've said the word choline as well.

[Nick]

Yeah.

[Louise Nicola]

So why don't we just describe what that means in this aspect?

[Nick]

I wouldn't overthink it. I think you're alluding to the fact that choline is a nutrient that is part of lysophosphatidylcholine, and you can get choline from eggs, among other food. Choline's important in a lot of things. It's also important in acetylcholine, which is diminished in Alzheimer's disease. In fact, the medications, although they're not preventative, that act to improve symptomology in Alzheimer's disease typically increase acetylcholine levels. Does eating more eggs, therefore prevent Alzheimer's disease? I don't think so. I love eggs. There is a funny study that goes around when people say, oh, look, eating eggs decreases the risk of Alzheimer's disease. But if you look at the doses, like an egg per week is like the upper balance. I'm like, maybe they're just eating better. Maybe you don't need to hyperdose eggs to get enough choline. But I think choline is an important part of a healthy diet. But if you're eating eggs or other animal protein foods, you're probably gonna get

[Louise Nicola]

enough choline back onto the dha. One of the studies that you've highlighted, researchers gave mice two different forms of dha. The standard free DHA went straight into the fat. CEL ISO went through. And when they put these mice through the water maze, what ended up happening?

[Nick]

Yeah. So there are different highly validated tests you can do to measure memory in animals with cognitive decline. One's called the Morris Water maze. Basically, you put the animal on a little pool of milky fluid. It's a little bit mean, but there's A platform that they can stand on so they don't have to just tread water. And what you want to do is test like how fast they can learn where the platform is. And if they give the mice the lysophosphatidylcholine dha, they just basically become faster at learning. So. So it's a standard learning test. There are other ones, but pretty consistently in the animal model literature, lysophosphatidylcholine DHA will improve cognitive function.

[Louise Nicola]

What gram is that? So would you need standard dose right now, and correct me if I'm wrong, for MCI patients or even just for general brain health, is around 2 grams of DHA per day. 2 grams of EPA, 2 grams of DHA. So 4 grams all up?

[Nick]

Yeah, I mean I typically hear 2 combined, but I like the more aggressive.

[Louise Nicola]

I'm more aggressive. If this one has a greater affinity to penetrate the brain, do you need less or not?

[Nick]

That is a really good point because in these studies what they're looking at is a dose equivalent. And typically if you're getting a lysophosphatidylcholine DHA supplement, the dose is going to be lower, which is a limitation. It's just very expensive to synthesize and concentrate. I take one specialized form which is a pretty high end product. I do take it on top of dietary dha and I can go over the logic there in a minute. But I can't give you a straightforward answer for like, what is the dose equivalent you would need in terms of like, efficiency of uptake. My personal approach is, I would say for your average person. We'll get into what average means in a moment. But healthy person who let's say is an apple three. Three, if you're eating a diet that is really rich in like Omega 3, you probably don't need to supplement on top of. For those who are more vulnerable, like me, I carry two copies of Apple E4. I want to go aggressive. So I will eat a fish heavy diet. But on top of that, supplement with lysophosphatidylcholine dha. Just because, you know, even if I have to pay a little bit more for my supplements, like I'm not gambling on my future of Alzheimer's.

[Louise Nicola]

I want to talk to you about today's presenting sponsor, pulsetto. I've been thinking a lot lately about the vagus nerve. It's the longest cranial nerve in the entire body and it runs down from your brain stem all the way down to your gut and it controls something that most people never think about your ability to shift out of stress and into recovery. The problem is that chronic stress keeps you locked in this fight or flight mode. And this is where your cortisol stays elevated. So then your sleep degrades and over time that chronic physiological load starts to do real damage to your brain. Pulsetto, which is what I'm holding right here, directly stimulates the vagus nerve. It's the same nerve clinicians use in hospital settings to treat mood disorders. Except you can do this in the comfort of your home in just four minutes. In a 2025 study, participants used Pulsetto twice a day for four weeks. Their cortisol dropped by 47.5%, their stress markers fell by 56% and their sleep quality improved by 41%. So this is not a supplement and it's not a meditation app. This is a measurable physiological shift. So I keep pulsetto in my routine because I understand the mechanism. And when you understand the mechanism, you use the tool consistently. Your vagus system is trainable. This is one of the most direct ways to train it. So if you want to pick up this device, go to pulsetto Tech and use code Neuro at checkout for an exclusive discount. Pulsetto Tech Code Neuro I wanna talk about. Do you mentioned you take a highly specialized one. Is that the Phoenix one?

[Nick]

Yes.

[Louise Nicola]

So they're using this exact lyso DHA technology, what they call tissue targeted omega 3.

[Nick]

Yes, I think it's patented as Lyso Vita is the product. It's funny. It is. It's a high end product, it's hard to synthesize. I've kind of like seen the back end pipeline, but it's the most economical way to get it. You can also get it through like fish roe and krill oil are very rich. But to get enough you're buying like, I mean caviar. Fish row is not cheap. So that's the product that I use by Phoenix. The product I think is Accentuate Omega Max is the exact one I use.

[Louise Nicola]

You only need one of those because I got.

[Nick]

I take three a day, the standard doses. I mean two in a serving. I take three just because for me I'm going to hedge on the more side. So it's something I don't take a ton of supplements, but it's one that I invest in because I know my risk of Alzheimer's disease and my brain's too valuable.

[Louise Nicola]

Well, let's talk about that. I think Apoe4 is getting a lot of recognition right now. I Just posted about it this week and it seemed to garner a lot of attention.

[Nick]

That was the Nell paper, right?

[Louise Nicola]

That was the Nell paper.

[Nick]

I read your newsletter.

[Louise Nicola]

Oh, I love that.

[Nick]

Thank you. That was very interesting.

[Louise Nicola]

And it was very interesting because it's, you know, Apoe 4. I don't know if you know this, you probably do, but you can get a carrier. Like if I'm a female, I'm a 3 3, but if I was a 44 and you are a 4 4, I actually have a more increased risk of getting Alzheimer's disease than what you do. You're pretty much right now at a 15x10 to 12x increase, whereas I would be at a 15x increase. And I find that so, so unfair.

[Nick]

Yeah, my mind is going a few places right now. There are sex differences between women and men. So maybe we talk about that for a minute.

[Louise Nicola]

Let's talk about that. Talk about ApoE4.

[Nick]

Okay. Yeah. We have ApoE is the gene and it comes in three flavor variants, three alleles, ApoE2, ApoE3, ApoE4. ApoE4 probably arose because acutely it's pro inflammatory. Basically you can think about it that way. And as we're evolving, that probably had certain advantages since we had a more robust inflammatory response that could probably protect us against certain infections. Our goals as a species have changed. We're not trying to optimize for having 12 babies by 45 and dropping dead. Now most of us want to maybe have two or three and we'll make assumptions and then live to a ripe old age healthily. So some of us, because of our evolutionary history, end up with this APOE 4, which increases the risk of Alzheimer's disease substantially. 25% of people carry at least one copy, but 65% of Alzheimer's patients carry a copy, so it's very enriched. In The Alzheimer's population, 2% of people carry two copies because you get one from mom, one from dad. So if you're really unlucky, like me or Chris Hemsworth is a famous example of an Apple E 4.4, then you're at somewhere between a 10 to 15 fold increased risk, which is not good. Some people even think it's deterministic. If you live long enough, which is sad. But one of the interesting things about Apple E4 is with a lot of genetic risk factors, we pretty much understand how they work. Appoe 4, we don't. It's a little bit of a black box. You were writing a newsletter and I'll double click on the question is like Loss of function versus gain of function. So is this like a functionality that's lacking in appoe 4 or is it doing something toxic to the brain? Probably a little bit of a mix of both. But it's very, very difficult to study in the brain, in the human brain, because it's such a black box. I will pause and we'll go over some actionable items for Apoe 4s in general. But I will just say the more I dig into the literature and when I first found out, I was, I was terrified. But I am increasingly optimistic both for the tools we have now, but also for how quickly the tools we are developing are coming through with, you know, therapies, including gene therapies that could target the brain I would say in the next 10 to 15 years. So if you're 65 and appleweed for maybe a little bit to worry, but if you're like, you know, south of 55 or something, I think there's a reason to be optimistic.

[Louise Nicola]

But even with that, you mentioned some statistics earlier, but then we've got like nationwide statistics to show that people living in certain parts of Africa can carry both copies and not get Alzheimer's disease.

[Nick]

It's possible. I don't think it's deterministic. I would say it's a risk multiplier. So think about things like sleep. Sleep is incredibly important for brain health long term. I would say that your average person can get away with sleep deprivation on the like you know, here and there. If you're Apoe4four like me, like chronic sleep deprivation will screw you. There is no wiggle room. So the way I think about being a risk carrier is it's not deterministic, but you have to keep things on lock in order to, you know, reduce your risk risk multiplier.

[Louise Nicola]

So then let's circle them back to why are you hedging your bets on omega 3 fatty acids? Because you're an E4E4 carrier.

[Nick]

Here is something really interesting about E4. Well, first let's go back to a high level observation. A couple actually. Did you know E4s actually tend to have higher IQs and achieve higher levels of academic attainment at the population level?

[Louise Nicola]

Is that observational though?

[Nick]

It's abs. Well, you're not going to randomize control. I can't do that because like, why

[Louise Nicola]

do you say that?

[Nick]

There are multiple studies showing this. There's a association at the population level in conjunction with, in your letter, for example, you were talking about hyperexcitability. So E4 neurons tend to be let's just say very energetically active. I think about it like a burn hot, die young phenomenon. So at a high level, there's a lot going on in the young E4 brain that might be setting the stage for decline later.

[Louise Nicola]

Like running out of like burning.

[Nick]

Yeah, burning through your energy being in your letter, talking about hyperexcitability. So if you, you know, run too hot for too long, it's like running an engine. You're just going to get damage if you're revving and revving the engine. So that's not necessarily something you want, although it might have early life advantages. Now here's another interesting paradox with Apoe 4 with respect to Omega 3, the Alzheimer's brain and the Omega 4 for brain, if you look at older people, is a little bit DHA deficient. DHA levels are low, Omega 3 levels are low. Which makes sense, right? Because DHA is important for brain function. But if you look at young APOE4s, uptake of DHA into the brain is much faster.

[Louise Nicola]

Not so it's probably starving for it and it wants it.

[Nick]

So the half life of DHA in an Apple E4 is much, much lower. If you look at the distributions in APOE 3, there's a pretty big distribution in APOE 4, it's pancake. The half life just drops dramatically. So remember we were talking about before how DHA can be used for many things. It can be burned for energy, it can be structural, it can be made into hormones. Among apoe's many functions is probably to dictate how the DHEA is used. And probably in Apoe 4 you're just burning through it as energy, which is not what you want to do. You want to preserve it for anti inflammatory function and structural function. Structural functions. So the way I interpret this from a practical perspective is if you think about like the average person targeting maybe 2 grams EPA DHA combined. Yeah. For an Apple E4, double that. I mean I have no statistics to say exactly double it. I'm just saying being more aggressive because your brain is probably burning through this a lot more quickly. So could you partially offset the effects of Apple E4 by maybe taking hyper dose Omega 3? We don't have population studies or long term controlled studies to assess this. I would hedge my bets that that would reduce risk at least somewhat. Now I do want to talk about women and omega 3 women, women in Alzheimer's disease. So two things come to mind. One is changes at menopause. So during the menopausal shift, the brain becomes a little Bit more has what's called cerebral glucose intolerance, basically brain insulin resistance because of the hormonal shift. So that could be one risk factor that predominates.

[Louise Nicola]

That's a result of loss of estrogen. Because estrogen helps.

[Nick]

Yes, yeah, yeah, yeah. So that could be one risk factor. Just to be clear, brain insulin resistance and cerebral glucose, like intolerance or poor glucose metabolism in the brain, is a hallmark of Alzheimer's disease. So potentially could have something to do with the menopausal shift, which means HRT for brain preservation is probably a good thing. I realize that's controversial and I am not a gynecologist, although my dad is. And we agree HRT is probably a good thing for cognitive preservation. Another really interesting thing is, do you know there are genes for DHA synthesis on the X chromosome? Yeah. You know, when I found this out, I read a study in Nature Communication and it was after medical school and it blew my mind. It was something that I read. I'm like, I cannot believe they do not teach this in medical school. Because it was about statins. Did you know that it's actually pretty well documented that statins have a higher risk in women than in men? Women are more likely to develop muscle issues and increased blood sugar. This is actually pretty well documented across the literature. Like if you plot out all the RCTs and the proportion of women in them, and historically there are just some with no women or very low levels of women. The more women that are in the study, the higher the risk of, like, muscle pains and dysglycemia, elevated blood glucose.

[Louise Nicola]

That's still a small proportion of people, though, as a population level who experience muscle weakness from statins.

[Nick]

Muscle weakness? Yes, yes. Dysglycemia, increased blood sugar.

[Louise Nicola]

Why would that be?

[Nick]

So it was a paper in Nature Communication. I can send it to you if you Google. If you go on Nature Communication tape and like X chromosome dosage, statin, it'll come up. But basically, one of the genes on the X chromosome is important in DHA synthesis. For those who are smarty pants right now, I'm being like, Nick, X chromosomes inactivate. Generally, a lot of the genes on the quote, unquote, extract. Chromosomal women get suppressed. So there's not too much gene dosage, but not all do. About 15% don't. Which means women have a higher gene dosage for certain genes than men. And one of them, it's just like a string of four letters and a number that is a five. I forget what it is, is involved in DHA synthesis. So what they find is that in women who are given statins and who do see, which is not all of them, but who do see increases in blood sugar, there's an inverse association between DHA and blood sugar rises. So the more DHA gets suppressed, the higher blood sugar rises. The reason this is relevant is because, well, the solution's obvious, isn't it? Take a fish oil. They haven't done that controlled trial in women, but they have done it in animals. And in animals given a statin, female animals given statins with the DHA gets suppressed. If you give a fish oil back, it actually improves the blood sugar control. So this is not me saying women shouldn't take statins. This is me saying this is one of those discoveries that I'm like, I can't believe it doesn't get talked about because the actionability is so high. And not only that, it's the thing that deserves follow up in a large controlled trial to make it standard of care.

[Louise Nicola]

So you said fish oil. Maybe it can be the downregulation of inflammatory markers from the EPA DHA that increases the.

[Nick]

I don't know the exact mediating pathway. It's possible. The question then is I start to try to piece things together in my brain and speculate what is the relevance there in Alzheimer's disease. Not making any claims, I'm just saying these are open questions which we don't have to go down this rabbit hole. But one of my qualms with the way we discuss and interpret scientific literature right now is we put kind of everything on a presumed to be even playing field. Even though there are a lot of questions that are really important for human health and scientific advancement that just don't get pursued because there's not a business model around them. It's not a conspiracy, it's not pointing fingers at anybody. But a finding like that I think deserves massive follow up, but that requires massive investment and nobody's funding it. So then you're left trying to make difficult personal medical decisions with incomplete information, which is just the reality of things.

[Louise Nicola]

It really is the reality of things.

[Nick]

Yes. And we have to be humble about that. I mean there are pros and cons with any approach, but at the individual level, I think this is the sort of data one should at least be aware of.

[Louise Nicola]

Yeah, it's interesting. I posted quite a while ago on the effectiveness of statins on all cause dementia. You know you want to. It's, it's, it's, it's tricky, right, because even if you are an Apoe 4 carrier. And we should also, you know, be mindful that APOE4 helps or ape, the APOE gene helps with cholesterol metabolism in the brain. But this comes back to obviously a lot that you know about. It's like, like what if you've got a high APOB and a high LDL and you want that down? It's like, isn't that more important than on a statin?

[Nick]

Let's dig into this because I think this is an area where we probably disagree. But what I'm guessing is we both hold our opinions relatively loosely. I don't mean to speak for you. We'll see if we get to this point. But given the limitations of literature and where we hedge is just a little bit different. So statins and dementia. This is a very tricky question. A lot of the play on the presumed increased risk comes from, I think it was a 2012 study where people with pre existing cognitive decline were taken off statins for six weeks and their cognition improved and they went back on statins and their cognition worsened. First things first, I think those are legitimate data. But that acute symptomology is very different than prevention. So then the question comes up with actual prevention. This is complicated because I would say first of all, the data are mixed. There are some studies showing no benefit. There are some studies showing benefit. The question then becomes what is the population and what is the mechanism of benefit? Because we have a population that is in general metabolically sick and statins do a lot of things. They have pleiotrophic effects so they can improve endothelial function, they can reduce inflammation. And if those are issues at baseline, I think that's probably going to be carrying the weight of any observed net benefit of statins. In fact, it's interesting if you do look at some of the meta analyses on improvements in cardiovascular outcomes with statins and look at the relationship between improvements in cardiovascular outcomes and degree of reduction of LDL. The r squared is 2.0.0 to 0.1. It's terrible. And that is not to say statins aren't working in these populations. It's saying there's a degree of misattribution because these drugs have multiple effects. The reason I'm going on a diatribe about this is because it becomes increasingly difficult to make a personal decision when your profile doesn't fit those in the populations in which the data were collected. So let me go through the exercise for myself. I'm an APOE 4 4, but I'm lean I don't have any features of metabolic syndrome. I'm not representative of the populations that have been historically studied. I don't think I'm going to get much cardiovascular benefit from APOB and LDL lowering. And we can get into this. I have reason to believe that, and I'm not. I have low inflammation. So a lot of the presumed benefits probably wouldn't apply to me. Now. Are there any risks? Well, we do have data showing that statins, for example, inhibit mitochondrial function, especially at Complex 4. What is a disease state in which mitochondrial function is impaired at Complex 4? Alzheimer's. You can see how there's a push, pull. There are risks and there are benefits at a very fundamental basic level. How those fall out in an individual is going to be based on their risk factors and their baseline metabolic health. So that's one of the reasons in me, I would say I will be wary about taking a statin in me as an individual because of some of the biochemical effects that I would think are concerning. But you can get creative. So a medication I recently started, not for lowering my LDL and apob, although it had a large effect, was Ezetimibe.

[Louise Nicola]

Yeah.

[Nick]

Because there's some really interesting data looking at how it could potentially protect against Alzheimer's. To be clear, I'm not saying this is definitive proof. I'm saying I'm working with the data available. It was a study. They were looking at an interaction between two proteins. They have very boring names. One's called hexokinase. It's involved in metabolism, usually sits on mitochondria. One's called 1433, which if there are any doctors listening, might ring a bell. It's involved in Creutzfeld Jacob disease, but

[Louise Nicola]

also an Alzheimer's devastating disease.

[Nick]

That's a devastating neurodegenerative disease. If you get it, you're like 30% survival rate within a year. But these two proteins interact. That's not a good thing in the brain. It kind of starts a domino chain of protein misfolding, which is characteristic of Alzheimer's, Parkinson's, a bunch of different neurological diseases. So what they did in this study was interesting. They weren't looking for benefits of cholesterol lowering drugs. They were in a hypothesis naive manner being like, is there anything that's FDA approved that might cross into the brain and interrupt this protein interaction to potentially protect against Alzheimer's? And Ezetimibe was the thing that popped out that crosses into the brain and interrupts the protein interaction. And in cell models it Reduces amyloid, it reduces tau and increases autophagy by 40%. It reduces tau, reduces tau, reduces amyloid and increases autophagy 40%. Again, cell models, they did do a C. Elegans worm model and then they did a retrospective patient chart review showing I think the hazards ratio was like 1.67. So an eight fold risk reduction. Again, retrospective chart review, not controlled, but there's interesting biological plausibility along with at least some signal in the human literature. And based on that alone, I'm like, okay, now my risk benefit analysis has changed and this is something that I will take for that purpose. I know it's complicated and we were talking before we got on about, well, I can imagine being overwhelmed as a listener and what I want to tell people, and this is something we were talking about before we started, is I think you and I share a passion for like respecting people's intelligence and not dumbing it down too much. If you have to listen back, okay, but like, I don't want to give you the keep it simple, stupid, lower is better. I want to give you the, hey, here is what I know, here is how I understand it, and here are the limitations of what we know. I think it's a useful exercise to see people who presumably have some degree of expertise still struggle with these issues because these are really complicated personal decisions based on a really beautiful, I'm going to call it a beautiful method biology, because these things are scary. But it's also really cool that we're unfolding, you know, the inner workings of our brain to some extent and coming up with tools that, you know, some of which have been around for a long time. Omega 3s, this medication, we can talk about others, like lithium, but that might be repurposed and really powerful ways to develop protocols to protect our brains.

[Louise Nicola]

Guys, I am a big believer in testing instead of guessing, especially when it comes to your health. And for years we've been told to wait until something goes wrong before looking at our blood work. I mean, that's, that's what the medical system is right now. You know, you break an arm and you're in the hospital, and that's great, but it never taught us how to get on track as a preventative method. And this is why I use Function Health, because when you use function, it gives you access to over 100 different biomarkers all in one place. They've got this amazing platform that you can look at everything. It tracks all of your biomarkers over time so you can start seeing your patterns. And for Me, the power is in the insight. So instead of wondering why your energy is off or your mood or your focus, or you're wondering if you're in perimenopause, you can actually see what's happening inside your body and make decisions for real data. Now, if you want to get some clarity and if you want to get your blood work done with Function health, you can. You'll get a discount if you sign [e-mail] Louisa Nicola, which is. Or go to functionhealth.com, use code NEURO100 at signup to get started. Okay. I want to give something to the men listening here or honestly, to anyone who has a man in their life. Let me tell you something. We spend so much time thinking about what we put in our bodies, but most men and women never think twice about what they're putting on their skin every single day. And a lot of those everyday products, I'm talking shampoos, body washes, contain ingredients linked to hormone disruption. This is why you or your man need to make the switch to Based Body Works. I actually introduced Based Body Works to somebody close to me, and the difference was immediate. First of all, let's talk about their shampoo. The shampoo from Based Body Works uses peppermint and argan oil. So the scalp feels clean without being stripped. And over time, the hair just looks healthier. No sulfates, no unnecessary chemicals, just ingredients that actually make sense. And you know what, guys? I know all of these products are usually made for women, but this one is made for men. So if the men in your life have been using the same products forever without thinking about what's in them and you're noticing those hormone changes in them, the easiest way to upgrade it is to change to Based Body Works. And if you want to, you can go to basedbodyworks.com use code neuro for 20% off. And guess what? They'll get a free toiletry bag when they buy a set.

[Nick]

Come on.

[Louise Nicola]

We all know that the men want that, because confidence shouldn't come at a cost of your health. My stance on amyloid versus tau has changed enormously. I'm now really on the bandwagon of Tao, especially in women. You know, we can see tauopathies across numerous different neurodegenerative diseases. But Tao is really like, I think Tao is going to be the next frontier. And attacking it from a biotech standpoint seems to be plausible.

[Nick]

Yeah. So let's double click on that. So there are two hallmarks of Alzheimer's. Two Pathological hallmarks that if you, like, open up a Alzheimer's brain, you see these two things. Amyloid plaques, tau tangles, they are interrelated. So amyloid can cause tau, tau can cause amyloid. The nuance on amyloid is it's probably early small amyloid oligomers, like little small amyloid particles that are problematic by the time the plaque is set. You're not going to like, removing the plaque is not going to help. The plaque once it's set is not really doing the major damage. Tau, though, is basically what it is, is cells have like a skeleton. It's called a cytoskeleton. Tau is a protein that normally sits on something called the microtubule. So one of the bones, you could say, and then it gets phosphorylated, it has these tags put on it, it falls off and it gets clumped together in these toxic neurofibrillary tau tangles. I do want to talk about the protein that does that because it's very important. It's called GSK3 beta and there's ways to target it.

[Louise Nicola]

Yes, no, I know.

[Nick]

We'll get to that. So tau is great. Well, I was going to say a great biomarker, because you probably know the holy grail of Alzheimer's research is figuring out a way to track whether or not interventions affect disease progression early on. Tau is now becoming that target. So there's a marker, P Tau217 that you can measure in the blood that probably can find Alzheimer's pretty early and maybe even more importantly be used in new trials to determine if a therapeutic is actually preventative, which is nothing we've had before. So take like ezetimibe or lithium. If you take people who are 50 who are Apoe 4 carriers and do a three year trial, you can now look at P Tau 217 and get a sense of is this doing something early on in the disease process before you have cognitive decline? We've never had that tool before, but now we do, which is one of the really exciting things about Tao as a biomarker.

[Louise Nicola]

Let's go back to the oligomers. Did you obviously. Do you know about the.

[Nick]

The Lesnar scientist, The fabrication of it?

[Louise Nicola]

The fabrication of it, which. Which I think just set us back, you know. Yeah, because of him. And I covered this in my episode with Sean Ryan, but because of him, it just set us back like millions, hundreds of millions of dollars and 20 years of research. But, you know, on that, you're right. You know, we've seen now, trials where you can take lecanemab, where as you can, imagab can clear out all this amyloid. But the symptoms still exist, like cognitive decline is still there. Their cognition didn't really enhance too much. Right.

[Nick]

It's marginal at best.

[Louise Nicola]

So let's go into the protein that you just mentioned for TAU, GSK3 beta. Yeah. You know that there's a strong correlation between that protein and estrogen.

[Nick]

I didn't know that. Yeah.

[Louise Nicola]

So I can send you the papers on that.

[Nick]

That's very interesting.

[Louise Nicola]

Yeah.

[Nick]

So GSK3 beta is one of these proteins that I hate why it was named. So it operates throughout the body. It's called glycogen synthase kinase 3 beta. I mentioned that because now it has a second name, Tau Kinase 1, because what it does is phosphorylates. That's what kinases do, tau in the brain. So it's become a very interesting target for Alzheimer's disease. Typically in the Alzheimer's brain, GSK3 beta levels and activity are increased, so that causes the tau to form neurofibrillary tangles. So things that block GSK3 beta could presumably reduce Alzheimer's risk. We do see this, the most famous now is lithium. Lithium is a well known GSK3 beta inhibitor. Just to quickly go over the literature there, there were lots of signals. I wrote about this even in, I think the 2021 paper you mentioned beforehand about lithium in the drinking water. I think there were studies done in Texas and also Denmark that geographies with just higher trace lithium in the drinking water associated with lower Alzheimer's rates, which is interesting. And then there were some early trials, one by Nunez et al. I think the early 2010s showing that microdose lithium. And I want to be clear, we're not talking doses for bipolar disorder. Micro doses.

[Louise Nicola]

Isn't this lithium orotate?

[Nick]

So the newer trial is. Yes, lithium orotate.

[Louise Nicola]

That's the latest one that.

[Nick]

The latest one came out last year, I think was published in. Was it Nature? Yeah, yeah, Nature out of Harvard and we'll get into. Yeah, it looked at a bunch of different lithium salts and lithium orotate was the standout. I just want to do a sidebar. I have never ever seen a supplement market basically go sell out. After that paper came out, if you went to buy lithium orate, everywhere was sold out. Of course it was. It was huge news. I've never seen that happen before. But it was a really powerful study. They did a lot of things, but they also looked in like the, the Alzheimer's brain show lithium was depleted. Not only was it depleted, but it was sequestered. What I mean by that is I think it was actually in the amyloid. The lithium was basically being like, sucked up. And you can see how that then generates a vicious cycle because as the disease is progressing, you're sucking up lithium. Lithium is neuroprotective. So you end up kind of getting a snowball effect. They did a bunch of different studies, but then they did look at 16 different lithium salts. And lithium orotate was the standout for the one that was the best overall bioavailable GSK3 beta inhibitor. I now take 5mg per day of lithium orotate. That's not 5migs elemental lithium. That's 5migs overall of the lithium orotate molecule.

[Louise Nicola]

Yeah. Which can come in a standard supplement form.

[Nick]

Yeah.

[Louise Nicola]

I think I was talking to Matt Cable and he said he's taking like, one to three.

[Nick]

One to three? Yeah. Yeah. I mean, the early. So the Nunes trial, I think I don't even know if they use lithium orotate, but they use, like, 300 micrograms. But for comparison, it's been a while since my psychiatry rotation, but I think for, like, bipolar disorder, it's like 600 milligrams or something. So you're not even approaching.

[Louise Nicola]

You're not gonna get, like, a pharmaceutical dosage. Yeah.

[Nick]

In a different form. So I just wanna be clear, like people like, oh, what about my thyroid? Or this, that and the other, like, when you learn about the side effects of, like, bipolar treatment. This is.

[Louise Nicola]

Not that you can get this over the counter, but, like, just talk to me about what it's actually doing at that level.

[Nick]

It's inhibiting GSK3 beta. So then you're not phosphorylating tau, which you, you know, is presumably very important for disease progression.

[Louise Nicola]

That's the. If I remember correctly, that's the pathway with estrogen as well, because estrogen seems to be neuroprotective on there. There must be a receptor.

[Nick]

Yeah. I didn't know about the relationship between GSK3 beta and estrogen, but that's very interesting.

[Louise Nicola]

Yeah. So I think that. Okay, so that's promising. So then what do you think? Have you gone any deeper into the biotech space? Because there is a company right now who have formulated these headsets. And these headsets are targeting through glymphatics, through 40 Hz binaural beats, but they're also doing light as well. So it's a. It's a Light and headphones at the same time. And basically it's Due to the 40 Hz oscillation, your gamma waves. You're clearing out amyloid.

[Nick]

So, yes, it's been a while since I looked at the literature, but you're referring to something called, and I've seen you write about it, glymphatics. The name comes from the term lymphatics, which is basically the trash disposal system for your body. But it's funny, your brain doesn't have a lymphatic system, which is weird when you think about it, because it's one of the most metabolically active organs. So how would you not have a waste disposal system? The reason is because your brain is so jam packed, there's no space for it. You can have blood vessels or lymphatic, and you need blood vessels. So the way it works is that when you sleep, the blood vessels constrict because you don't need to perfuse your brain as much. It's not as active. And that opens up channels along the blood vessels. These are glymphatic channels. And then your head, your head, your brain is bathed in cerebral spinal fluid. And basically it literally flushes debris out while you sleep. This is lymphatic flow. So it's a waste removal system for your brain at the macro level, just literally, you know, washing things out. So there's a lot of interest in, are there ways to enhance glymphatic flow? Basically, like, you know, turning up the water pressure on the hose that's spraying stuff off of the brain. Basically, anything that is going to increase deep sleep should increase glymphatic flow. And there is some science behind certain frequencies of sound and light, I think even particular blue light frequencies that might enhance glymphatic flow. So developing some sort of tech that can in some way change your brain activity to increase lymphatics. I haven't looked at the literature on that in at least 18 to 24 months. So I don't know if it's advanced, but I do think it's very promising. I think it's definitely a target to address, especially for people who are terrible sleepers like me.

[Louise Nicola]

Yeah, it's. You're a terrible sleep.

[Nick]

I'm a terror. I've always. My whole life I've been a terrible sleeper.

[Louise Nicola]

Wow.

[Nick]

So my. My Achilles heel.

[Louise Nicola]

Is there anything else on the. On the towel front that you think that we should address? It's just so interesting to me. I don't know if you're following Anything Silicon Valley and, and biotech right now. But I know there's a number of people trying to get IRBs to study like even getting, getting this in a

[Nick]

molecule form to look at a Tau GSK3 beta inhibitor. Yeah, I'm not too caught up on advancements in pharmaceutical grade GSK3 beta inhibitors in production. So a no on that. There are some very innovative other therapies though with respect to especially targeting lipid metabolism in the brain. Apoe4 so you know ways to potentially express the complement apoe2. There was one study that was done in animals where basically one of the issues is targeting like getting it exactly where you need in the brain is really hard. They showed if you basically can just literally bathe the brain in it so you can express it from like into the ventricles. That was therapeutic. There are also ways to potentially. Honestly this is going to sound scary but gene modify APOE4 to APOE2 with some advanced prime editing. So if you think of crispr, CRISPR is amazing. It does have a higher risk of off target effects and incorrect repairs because what you do is you break the whole DNA strand and then repair it. Prime editing is more like a word processor for the brain. You actually break one strand and it's a lot more precise. So it's basically the next evolution of crispr. Bear in mind when was CRISPR won the Nobel Prize? A few years ago is recent. So just to be clear, like this technology is advancing so so quickly. So we already have the next evolution.

[Louise Nicola]

Jennifer Doudna.

[Nick]

I met her at Oxford. I asked her. She's brilliant and she's also really nice.

[Louise Nicola]

Yeah, she's a dream guest of mine.

[Nick]

Oh yeah, yeah, you can get her. Yeah, I remember we were, I was in the Sherrington Building at Oxford and somebody's like Jennifer Doudna is down the hall giving a lecture. I'm like what do you mean she's down the hall?

[Louise Nicola]

Oh my gosh.

[Nick]

I didn't even know she was coming. And I'm like. And I booked it and then just sat in the front row with my hand up the whole time. But she was one of those people that you meet her and there's no arrogance there. Despite she hadn't won the Nobel prize yet. But everybody knew it was going to happen anyway. But she didn't answer my question about Apple E4. What was the question I asked do you think we'll be Gene editing Apple We4 within the next 10 years? And she.

[Louise Nicola]

It's funny because they've done Huntington's they have.

[Nick]

Yeah, I think, I think one thing I credit her for is she's very one diplomatic but careful about the ethics. She's not someone who's like I invented this thing, now let's use it wildly. Like she's very involved and conservative about gene editing ethics. So. But anyway, we are seeing advancements in technology. Really the challenge right now is targeting the brain. But I think that is going to be a breakthrough that happens in the next several years and then also building in backup safety systems. So there are ways you can create safety systems so you don't get like unwanted target effects. Basically ways that like this machinery can get deactivated in cells. You don't want it. It's very sophisticated. It would be a whole different thing to go into. But bottom line is I do think that these advanced therapeutics for gene therapy potentially in a very safe way could emerge in the next 10 to 15 years. I mean we could technically do it now. It's just not going to be safe, which obviously we can't do it now.

[Louise Nicola]

I'm very interested in DeepMind and we're going off track now but like seeing how Demis Hassabis is going to I guess cure diseases through artificial general intelligence, I think that that's going to be a frontier in Alzheimer's disease. I'm excited about that.

[Nick]

But no, I agree. I mean the technology in so many sectors is advancing so fast. As a related tangent, there was a paper that came out earlier this year about we were talking about muscle pains and statins and it was like just like single, like it was a deep molecular like cryo em where they were showing a new mechanism by which like three atorvastatin molecules form a triad around or ianodyne receptor and like how that changes calcium signaling. The point is not the side effect. The point is like if you think about drug development over the years it's been very just like let's throw a thing at a thing and see what happens. Now we have like really incredible imaging where we can see at the deepest level. We have AI that can help us like you know, design more targeted, safe therapeutics. So I think it's a very exciting time to be alive.

[Louise Nicola]

Well, let's stick on the, the, the cholesterol.

[Nick]

Yeah.

[Louise Nicola]

Okay. Because we're talking a lot about statins. In May 2026 you published a case report that broke the Internet in my opinion. It was titled 7 Years of 700 Cholesterol Without. With a 700 Cholesterol Without Coronary. Coronary Atherosclerosis and the Patient in the case report was you?

[Nick]

Yes.

[Louise Nicola]

What? Like why? Why?

[Nick]

Aside from being professional provocateur? In all seriousness, people who understand my position on lipids is actually incredibly moderate. And I will sum it up as LDL and APOB are one risk factor among many that need to be taken within the context of an individual patient, which I think is a pretty reasonable.

[Louise Nicola]

Don't you share this same opinion as Saladino, Paul?

[Nick]

What exactly is his position?

[Louise Nicola]

Oh, I believe his position is LDL cholesterol isn't as bad and atherosclerotic as we believe.

[Nick]

Yes, with caveats. I think we'll get to my case in a minute. I actually want to double click on a word that comes up a lot. I know you've heard it. It's causality. This is going to sound funny, but I think that singular word and its abuse is a large part of why we can't make progress in this discussion. And I'll explain why. So it often comes down to people saying LDL is or APOB is or is not causal for cardiovascular disease. Factually and technically speaking, it is. It is part of the causal pathway. Therefore it is causal. But people conflate causality with importance. Causal does not mean important. Actually, I found it kind of funny because in his 2018 podcast with Dave Feldman, when Peter Attia was describing this relationship, it's necessary, sufficient causal. A lot of terminology, but basically what came up was oxygen and fire, where the idea is, well, oxygen is necessary and causal for a fire, right? It's not sufficient for the fire. Just because you have oxygen doesn't mean that we fire. Just because you have LDL doesn't mean to be atherosclerosis. The reason I find this funny is because the analogy exposes the error in logic. If you want to lower the risk of a fire, you could lower the causal variable. You could go lower with it and lower with it and lower with it. And if you lower oxygen to zero, you know, my risk then of breathing the air with no oxygen around me, of my lungs spontaneously bursting into flames, has gone down in an absolute sense. But I've also suffocated and died. You can go through other analogies. You know, a male's equipment is causal for him getting a lot of STDs. It doesn't mean the treatment is removing the causal variable that's typically doing more harm than good. So that word causal, I think, is misused. But you do have, you know, LDL and APOB as part of the Causal pathway, therefore it's. You can target it. But what is the risk benefit? Like what is the benefit of lowering it? And in who. And I think that. And in who is so, so important.

[Louise Nicola]

I do too.

[Nick]

Yeah.

[Louise Nicola]

Because we. I've seen papers, I don't know if you're aware. Oh, I don't know if you are for this, but papers on Apoe 4 carriers and lowering their LDL to below

[Nick]

70 for the outcome of

[Louise Nicola]

enhancing brain health outcomes.

[Nick]

Brain health. Is there actual data on improving brain health outcomes that is likely lowering.

[Louise Nicola]

You know, the stance is if you're an Apoe 4 carrier and you're over the age of 65, then being on any form of statin to lower that down to a 70 is going to help you stave off Alzheimer's disease.

[Nick]

I'd be interested in that paper and I'd also ask the question, how do you know it's not being misattributed to say anti inflammatory effects of statins.

[Louise Nicola]

Exactly.

[Nick]

So these are complicated questions, but I would say I actually, this is a discussion I get into with people in my social circles, a lot of whom are like medical residents a lot. Because I think there's a tendency to want to speak to the population average, which I don't always do. I'm not saying for most people, most of the time I'm trying to dissect, hey, if you have hypertension and obesity and metabolic syndrome, yeah, you're probably going to get a net benefit from a statin. I'll say it, I've never denied that, and that's most people. But what if you're actually a healthy person with high LDL and apob. Did the data say you're going to benefit? And I would say no. In fact, if you look at some of the early trials, some of the landmark trials that made statins standard of care, like 4s. If you look at the 4s trial and you just partition people out by just the highest and lowest quartiles of HDL and triglycerides. So just two biomarkers. If you have high isH HDL and lowish triglycerides, the benefits in this landmark trial, which were showing massive benefits of statins, have dropped to zero. And the funny thing about this trial, I was going back and looking at it as a 2001 study where they did a reanalysis in circulation and it's been caveated that this is the metabolically healthy population is not benefiting based on two biomarkers. And then you go to look at the population Statistics. And I remember looking at the table and it said non smoking percent, 31% non smoking, 69% smokers. And there still wasn't a significant benefit. So we can go to other studies as well, but extrapolate from that. If you're someone who is actually metabolically healthy, no signs of metabolic syndrome, which again is not most people, what is the literature that you're actually going to benefit from? Aggressive lipid lowering therapy? And I would say minimal to non existent. And I don't even know if I want to. Well, one of the issues I have with science, the way it's communicated and the way it's done, is there is a very strong inertia of the status quo that nobody's willing to challenge. I can tell you from having submitted papers that are very robust. For example, we had a meta analysis of randomized control trials that ended up going to one of the. We submitted it to one of the top medical journals in the world, top three impact factor journals, and we actually got decent reviews. You know what happened to it? The editor ghosted us for seven months. They just would not reply until we withdrew. I don't think the editor changed and I just don't think they like the conclusions. They gave no rebuttal.

[Louise Nicola]

That would kill me.

[Nick]

And the opposite thing happens as well. So recently did you see the outcome from the EasyPave trial on aggressive lowering?

[Louise Nicola]

Yeah.

[Nick]

So this came out. This is an interesting trial. They were looking at conventional targeting of lipids to less than 70 versus less than 55. And the headline was lower is better because people who were aggressively targeted had lower major adverse cardiovascular events. Sounds fantastic issue. First of all, the difference between the groups was 10mg per deciliter LDL, which is not big. And they were saying there's a 33% reduction in major adverse cardiovascular events, which just not proportional. Side note. And we'll get back to why this is relevant. If you actually look at the data, the hazards ratio for women, which is a smaller proportion of the population, but there were women involved, was 1.22, which means lower than one is good, higher than one is bad. It was non significant, but there wasn't even a trend towards benefit in women. So there's already like, you know, little things in the data. You know, women aren't benefiting. Okay, interesting. The effect size is gargantuan relative to the LDL reduction. Doesn't even make. It's not biologically plausible. And then you look at what the primary outcome was. I don't know if you noticed. But you can do this thing called a composite endpoint where basically you take a bunch of different things and mush them together. The mushed together things were heart attack, stroke, death from cardiovascular disease, and something called revascularization. Very easy to look over that because it's some medical jargon. What does it even mean, revascularization?

[Louise Nicola]

It funny you're saying revascular. This is how I put this on a recent reel that went absolutely gangbusters viral because I suppose about in the context of peptides. So every time you say it, it's, it's, it's bringing up the memory.

[Nick]

We have to go to your, your PTS peptides reel in a minute because peptides is something that's very interesting. I want to maybe talk about that for a sec. But anyway, on the study. So revascularization is, is if you think about heart attack, biological event. Revascularization is not a biological event. It is if you send someone to get like a stent or coronary RD bypass. It's a clinical judgment. Why does this matter? This was not a blinded trial. It was open label. So now you're taking a variable that is a clinical judgment in an open label trial. You're introducing a source of bias and then you're putting it into this composite metric where everything's mushed together. So if you have a benefit on this composite, people then conclude, oh, heart attack risk went down. Which it didn't. That isn't even the issue for me. The issue is then how do people respond when you point this out? I'm not even saying that there is no benefit. I'm just saying the benefit's being overstated. There's this biasing error that wasn't appropriately flagged. You'd be surprised at the amount of vulgarity and pushback I got by even raising that topic. But it gets worse. We did what I think is a responsible thing and wrote a letter to the editor. I didn't one off this. I know how science politics work. So I co authored it with an MD PhD colleague who's a full professor. And I don't know if you know Ronald Kraus.

[Louise Nicola]

Yes.

[Nick]

Highly respected lipidologist. He agreed with us. He was on the letter to the editor. We sent it in. After a little while, we got a response from the New England Journal. You know what they told us?

[Louise Nicola]

What?

[Nick]

Thanks, but no thanks. They gave no rebuttal on any of our points.

[Louise Nicola]

What is their incentive to do that?

[Nick]

So in fairness to them, what they said was we get a lot of letters and we just need to use our judgment on whether or not we publish all of them. And we don't want to publish a letter is effectively what they said. So they didn't have any issue with any of our points. And the one I just raised was only one of them, not even the main point. It remains to be seen, and I will eat my hat if they do come out with letters that actually represent our point of view. They haven't published any letters yet. And for the record, they have a three week window in which you're allowed to submit and the letter has to be 150 words or less. So there's like restrictions. They haven't published any letters yet. If I'm giving my honest opinion, I think they didn't like that it was actually a big issue in the paper that threw a wrench into what is a popular mantra and the status quo. Lower is better. And they didn't want to represent that point of view. That is my opinion. If they publish letters representing our argument, then great. But. But I do think that there is an issue where the status quo just snowballs and people don't look at the data rigorously.

[Louise Nicola]

Hello. Hello. It's, you know, we're inundated with these 90 second reels on Instagram trying to teach you an entire lesson from somebody who's doesn't even have a university undergraduate degree, let alone know how to go deep in mechanism. So yes, I agree with you on that one.

[Nick]

Well, but also, I mean, most clinicians don't read these papers or know how to assess them, and that becomes difficult because I think sometimes clinical experience gets conflated with ability to process, you know, emerging literature in the field.

[Louise Nicola]

And time.

[Nick]

And time. And time's a restriction.

[Louise Nicola]

Yeah, I think so.

[Nick]

How do we create an intellectual ecosystem that is like authentic and nuanced?

[Louise Nicola]

One of the best ways to improve brain energy metabolism is to make sure that you have adequate ketones circulating in your body. This is why I ingest ketone iq. I'm obsessed with ketones. They're one of the brain's most efficient energy sources, especially as we age and glucose handling changes. I use it for deep work or for long days when I want to focus without caffeine or crashes. But I also use it just in my day to day to make sure that I am neurologically adequately fueled. If you haven't tried ketones, you, you must. These ones taste great and you can get 30% off your [e-mail] neuro/ get a free gift with your second shipment team. One thing people underestimate is how much the liver affects the brain, especially after stress, poor sleep or even alcohol, which none of you should be drinking by the way. When alcohol leaves your system, your brain actually goes into a rebound state which is why you feel anxious, foggy, or you need a huge burger the next day. And at the same time your liver is working to clear those toxic byproducts out. And by the way, if you're in your mid-40s and you're having just one glass of wine, this really does affect you. So I want to introduce you to this supplement called Cheese Health. It's a formula designed to support these toxic byproducts and getting rid of them after a big day. They're like a hangover pills. I don't know if you guys have heard of them, but they help metabolize alcohol more efficiently while also supporting liver function and reducing that next day cognitive dip. It's also built around compounds like DHM and cysteine which work overnight. So the idea is you wake up feeling more like yourself. So for a limited time you can get 20% off your order by using code [e-mail] if you are going to have a big night out, you need to have these supplements. Chishealth.com code neuro Look, I, you know, PhD, I just did my, I just did a meta analysis and let me tell you, there's around 10,000 articles that we screened. Like more than that I think. And I'm just, it's like to have all that knowledge, it ends up compounding. Right. I've been assessing literature for, for quite a number of years but what I know today, I didn't know five or six years ago. It's a compound interest thing. But if you don't have time nowadays people are just putting it into chat. GPT.

[Nick]

Yeah, I think you need to like basically make it, I mean kind of as we have like your career is like I'm going to be the person who is reading and trying to understand and communicate these things. I think that's actually going to be part of new medicine, you know, medicine, when my parents were going into it, it was very much like, and to some degree it still is. Go to the doctor, they're omniscient, they're going to tell you what to do. Now with the amount of information that's coming out and the empowerment of patient population which yes, social media has its downsides, but I think it's a net positive. I think you are Going to have people in my generation and future generations of medicine who subspecialize in being the medical communicators, even if you're not in clinical practice. Because we need that, like the sport of medicine is evolving and we need new players to fill new positions.

[Louise Nicola]

You mentioned smoking earlier and you recently put a thread actually on X challenging the idea that living with high apob was like smoking. You used your own zero plaque scan as the counter evidence. So my question is, hang on. If high LDL and high APOB aren't the root cause of heart disease in someone who is metabolically healthy, then what is?

[Nick]

So let me first unpack. We actually haven't talked about my case report fully because I wouldn't rest my argument on that, the issue with that argument. So I, when I have my case report, basically, I've lived with extremely high cholesterol for a long time and there's no signs of plaque soft or calcified. And I will get into why hereditary high cholesterol.

[Louise Nicola]

You said you've been living with high

[Nick]

cholesterol for seven years. It's. I have a, a manifestation, a phenotype called the lean mass hyper responder. So my LDL bounces around like crazy depending on lifestyle factors. I don't know if you know about my Oreo experiment. So everyone. That was my, my. Yeah, basically short of it was I used Oreos to like lower my cholesterol by 71% as a metabolic demonstration to the fact that in me, I can modify my ldl, my apob, my total cholesterol very rapidly because of the underlying cause. So I don't have familial hypercholesterolemia. This is something that's unique that we're studying. We can get into that in a moment. Let me just complete the idea on the smoking analogy, people. This is very common for people to go to. Well, not all smokers get cancer, but smoking causes cancer. So isn't it dumb to just not treat high apob just like it's dumb to, you know, not quit smoking? I don't like that analogy for two reasons. One is it equates not smoking to taking a pharmaceutical, which are not equivalent things. The risk of not smoking to your health is basically negligible. The risk of taking a lot of pharmaceuticals. There are risks that are both known and unknown. So that's where the analogy first fails. And second, cancer is basically a binary event. You have cancer, you don't have cancer. Having a heart attack is a binary event. Having atherosclerosis isn't so if I have lived for seven years with a cholesterol of 700 and on advanced scanning for soft and calcified plaque quantified by experts and ii there is 0 millimeters cubed of plaque plaque, then it's not like not having cancer. There's no sign that I'm even on the spectrum of disease. So I think it's just a failed analogy. Now to round up the story a little bit more, people often come to well, are you too young for this to be meaningful? First of all, I'll re emphasize this is not a coronary artery calcium scan. This is a coronary CT angiogram looking at soft and calcified plaque. Notably, historically the only comparable group with LDL levels as high is familial hypercholesterolemia, specifically in the homozygous form, typically can cause heart attacks and death in children as young as 8 or 10. They develop plaque in a year or two before they're toddlers. So if it was just all high, LDL was equal. I should be having heart attacks left and right. Additionally, there are more young people getting these scans and being public about the results including and I, I will bring it up and name him just because he has voluntarily made it public. I don't know if you know, Simon Hill released his results. Yes, he made it public on yeah, 61.3 millimeters cubed. I have zero.

[Louise Nicola]

He's plant based as well.

[Nick]

He's been, yeah, so he's 39. I'm 30 admittedly. But he's been hardcore lowering his LDL for about nine years. So since he was my age. So either he had progression while he was hardcore lowering his LDL implant based or when we were age. I'm not saying that's the thing, I'm just saying like if he's actually a reasonable it's N to n equals 1 and n equals 1. So like take that with what you will. But the bottom line, the argument I'm trying to make here is not only him, but other young people in their 20s or 30s. This technology can measure plaque. I have none and I think that is notable. I will be clear about two things. One, I'm not alone. We're studying people like this and this appears to be a reproducible phenomenon even in older people. One person who also is public about it, I don't know if you know Jen unwin in the UK but her LDL is around 600 and she has no plaque either and she's 60. And the other point I want to make is when I share my story. It is never do what I do. In fact, a lot of times I'm resistant from sharing exactly what my routine is because I'm like, look, I'm me. You're. You don't do what I do. So, you know, this isn't an excuse because Nick did it. You should live with your LDL of 700. I have thought about this. I continue to think about this. I continue to update my opinions. However, I do think we are very, very tied to this idea that LDL is, you know, the devil biomolecule and it is treated. I will tell you from my experience going through medical training and medical school that it is treated almost like the disease. Like Vera. Having ILDL is basically like having cardiovascular disease. To the extent that a patient like me should not exist. I just, I shouldn't.

[Louise Nicola]

Oh yeah. 700 is insane.

[Nick]

Yeah, no apob. Oh. And it was. I mean sometimes it can't be detected so high, but like above 350 it can be. Gee, Jesus Christ. I will Note on ezetimibe, 10mg monotherapy, 56% reduction both in LDL and Applebee. So it hits hard. I can actually explain why that was very predictable. But that aside, a case like me shouldn't exist. So then what do you do when that patient arises? And you can say, okay, it's just an outlier. Doesn't apply to most people. Or you can say, as a proper scientist, always learn the most from studying the outliers. In fact, homozygous familial hypercholesterolemia, a study of which won a Nobel Prize. There were like four or five kids originally studied. It is a one in one million genetic disease. And there are many people like me. So the reason I put my story out there, the reason I will write a case report is to provoke interest in this. Because how do I even exist as a patient? And stepping back for a moment, I want everybody to put themselves in my shoes as a 23 year old. So at 23 is when I started a ketogenic diet. I did it. We didn't get into this. But to treat inflammatory bowel disease, like I was very, very sick. This is the only thing that put me into remission. Then my LDL shoots through the roof. At this point, you know, like I starting medical school, my families are doctors. I know what an LDL of 500 means. And I'm sitting with that. I'm sitting with that with the deepest respect of the medical profession. A full awareness that the ideas being thrust upon me have been built over decades with billions of dollars of research funding by people who have been studying the field longer than I've been alive. And despite all that, I make a bet effectively that they're wrong and I'm right, and then I end up being right. I didn't have a magic eight ball to say this would turn out this way in seven years, but I did make a bet. And I was right. Maybe I was lucky, or maybe there's something here to study and discuss. And that is literally where I want to leave things. Well, not leave things where I want things to start, but basically in terms of my claims, I'm like, explain to me how I exist as a person without heart disease. Because hidden within that answer is something that will help us understand not just me, people like me, there are a lot of people like me. What is maybe to your question, the root cause, especially in healthy people? Because like it or not, at a high level, we have been barking up this tree for over half a century, invested billions of dollars in it, and made pretty marginal headway, if at all. I mean, emergency medicine advanced, so death rates have decreased because if you have a heart attack, they can stop you from dying. But like you have to admit, the progress has been pretty abysmal in lowering the overall burden of cardiovascular disease. So can't we just like say, what are we missing? And then take opportunities of outliers, myself included, to say, what is it in my biology that makes me unique? And how can we find the nugget of generalizable wisdom in that? To actually stop heart disease?

[Louise Nicola]

Yeah, because there'd be others around the world.

[Nick]

There are. Well, our research on this is pretty controversial, highly misunderstood. However, I will say we have studied 100 people like me in a prospective study. There is no relationship between APOB and LDL in people like me. And it overall tends to be a low risk group. We could have a three hour podcast on the controversies around that study, but those are findings that are robust.

[Louise Nicola]

Well, actually you've done a lot of little experiments on yourself. The notably the Oreo one you've done one on where you ate a thousand sardines in a month. Now this really interests me. I love sardines. We're going back to the EPA dha, but talk to me about why you did that.

[Nick]

So. So there's this thing where if a trend comes up on the Internet, I think a tendency is to be like, this is a goofy fad diet. Sometimes it is, but sometimes there's also a Nugget of brilliant insight. That is true there. I'll give you an example before I get to sardines. Remember the sugar diet? No, this is the thing. I heard about it from Mark Bell, but people were smashing Google sugar diet. And when I say sugar I mean syrup. Gummy bears, like soda.

[Louise Nicola]

What was this in the 50s?

[Nick]

No, no, last year this was a big trend. People can Google it. And people were saying their performance is improving and they're losing body fat. And I'm like this is nonsense.

[Louise Nicola]

What are they eliminating?

[Nick]

No, no, no, they were actually like I saw people's diet plans like Sour Patch Kids, Skittles. It would be like a short term thing. The reason I'm bringing it up is I then actually found A set of three human controlled trials showing that protein restriction below 9% kcal, at least in lean men, increases energy expenditure by 600 calories per day on average. I'll send you the paper. It was in Nature Metabolism.

[Louise Nicola]

What?

[Nick]

It was in Nature Nature metabolism.

[Louise Nicola]

Why is that though?

[Nick]

So what they were seeing is an increase in a hormone called FGF21. FGF21 can increase fat cell metabolism. So what's probably happening is changes in fat cell metabolism. I know there's more studies ongoing with this, but it was one of those things. And I'm bringing this up in an example but okay, okay, sugar diet, not a good idea. But they might have actually been inadvertently boosting the metabolic rate through this FGF21 boosting approach to double click on that. I actually have a letter on this and we'll have a video on it. But there was a follow up study that came out in Nature Proper. So Nature metabolism, Nature, there's really good journals where they were looking at changes in the microbiome with low protein diets. And so they're probably changes in the microbiome that are also mediating increased energy expenditure. Something that's interesting and injustice in metabolism is different people have different basically thermogenic capacity of fat. We have this thing called beige fat which produces heat. Some people, if you put them on scans, you can see them light up, they burn off heat, other people don't. And this changes energy expenditure.

[Louise Nicola]

That's me.

[Nick]

So you'll find this study interesting, I can send it to you. What they then did is they picked out the people with a lot of high brown beige fat activity and went to their microbiomes and said what's unique about them? They then developed a minimum consortium of microbes to potentially mimic the effect. They called it HU4 and made it into a probiotic that they gave to mice and could increase their metabolic rate. So maybe a probiotic to boost thermogenesis. Assistant calorie. I can send you the. The letter and. And the. The video when we're done, but, yeah, it's pretty freaking cool.

[Louise Nicola]

I thought it was cool because you. You started this cascade of, like, sardines. I. I'm telling you, sardines would have gone through the roof in sales after that.

[Nick]

Yeah. So, okay, back to the sardine thing. So this is another thing where I was seeing trends, actually, to credit Dom d', Agostino, who I think we both know, really smart guy, he was talking about on Tim Ferriss. Then I heard other people doing, like, sardine die. And I'm like, all right, full send. Let me just do it and see what happens. More is a capture and report, like, what would happen if. And I had some really interesting responses. You know, I felt really energized. I smelled really weird. And when I say smelled weird, I don't mean my. I don't mean my breath. I didn't smell like sardines exactly. I gave off an aura.

[Louise Nicola]

Was it a fish aura?

[Nick]

No, it wasn't. It was. It smelled terrible. It created relationship strife. I kid you not. I. This was a problem. In fact, if you watch my sardine video, it was the first time my girlfriend ever featured. She's blurred out, but it's because I'm like, I swear, if you complain about my scent one more time, I am videotaping this for the video.

[Louise Nicola]

If you were laying next to me and your sweat smelled of sardines, I'd kick you out.

[Nick]

Well, we made it through the month, but bottom line. And I'm gonna tie this back, it's actually, like, really interesting and relevant. And I was asking, like, professionals about it, like Professor William Harris, who's a big guy in the Omega 3 space. He's like, like, interesting. And then I also had a phenomenon of cold resistance.

[Louise Nicola]

Okay.

[Nick]

I did this in the Boston, the winter, and I just, like, stopped feeling cold. Like, I could go out in the blizzard, and it didn't feel like anything. Go, like, shovel my driveway in a blizzard. So let's try to piece the puzzle together, what might be going on here. This actually ties back to what we were talking about earlier with hormones. Omega 3s make hormones in your body. One is called 12 Hepe. It's made from EPA, I think. And this boosts thermogenic capacity, at least in animals and presumably in humans as well. It's Just that to maybe have the effect in humans, you need to have crazy amounts of Omega 3, like if you're having a thousand sardines in a month. So I was just like, you know, burning off heat energy potentially because the Omega 3s I was eating was boosting 12 HPE. The interesting thing about 12 HPE is we know what it does. Increase metabolic rate, increase thermogenesis. But for a while we didn't know how it works. Worked. Its receptor was not well known. And then a paper came out after, after I did the sardine diet. I believe it was in cell and it found the hormone, sorry, the receptor for the hormone called OLFR110. I remember that because my mnemonic is it is oily fish reeks 110. It's not what it stands for, it's just how I remember it. But the really interesting thing about this is it's a smell receptor. It's a smell receptor which is wild because it's like everything in the body, when I step back and think about it, is so interconnected. So what happened here is this is a smell receptor, but it's also expressed in your liver, in your brain and in brown fat. So I mean, it's maybe a little bit meta. But when we think about like human metabolism, human physiology, everything is connected. We. Now here's another. We're one of the most complex animals. Arguably our genomes are small. Like there are worms and plants with larger genomes than us, more genes. We have 20,000 genes. So how do we become so complex? It's because everything in the body is repurposed somehow. So machinery in the body gets repurposed. I think our inner ear bones come originally from shark jawbones. Everything gets toggled, shuffled around, repurposed in different tissues. So the fact that a smell receptor could be mediating, you know, the effect of, you know, maybe a sardine hormone on increase in thermogenesis, but also maybe something to do with smell is just like a beautiful demonstration of how interconnected our physiology is. Maybe people. I'm losing people here. I find it really awe inspiring. But I do these experiments sometimes more as like capture and report. And what can we discover or try to understand even about our physiology by just being observant and delving into the science?

[Louise Nicola]

Well, I think it's interesting, but I actually want to toggle a bit more on keto. Right. Yeah, I've, I've especially been loving a lot of the data that's coming out around, you know, women's brains and adopting a not a ketogenic lifestyle or a ketogenic diet more. So what could we do to enhance brain glucose metabolism or brain energetics in that perimenopausal state? Right. What would happen if we gave a bolus of ketones to the brain? Would these brains perform better?

[Nick]

I think so. If I had to speculate, I would say especially for women after menopause, at least some bouts of ketosis. And that doesn't mean you're keto 24 7. It could mean you're generally low carb and you do some intermittent fasting.

[Louise Nicola]

Is that just because the neurons can

[Nick]

uptake the ketones the after menopause? At least if you're not on hrt, brain glucose metabolism starts to fail. Ketone metabolism does not. So you're giving an alternative fuel substrate to the brain. Very interestingly, and I forget what journal the paper was in, I think it was a 2024 study. But ketones, in addition to being good fuel molecules for the brain, somehow they appear to target misfolded proteins and clear them out. Specifically misfolded proteins. I spoke with the first author of the paper and I'll send you the paper. But it's almost like if your brain was in a messy apartment. Ketones have a way of like finding and identifying the trash and then dumping it out. And then you need the glymphatics to obviously like take out the trash. But there is something to ketone bodies, the molecules themselves helping to target and clear out misfolded proteins. So BHP specifically, I think it's BHP specifically. So there are multiple elements where it improves energetics in the brain, it reduces inflammation in the brain. It probably helps clear out misfolded proteins. If I had to give a rapid fire, I want to do this because I figure we're probably getting close to the time the next person needs to come in here. But on like what to do for cognitive preservation and we can hit on anything deeper that that we haven't hit on. I would say omega 3s, high dose omega 3s, maybe lysophosphatidylcholine, DHA if you're Apoe 4, good sleep. We could talk about boosting lymphatics with some of these 40 Hz devices. Lithium as a GSK3 beta inhibitor, lithium orotate specifically. NAD is interesting. We haven't touched on this. I do think there is something to nicotinamide riboside, nicotinamide mononucleotide for boosting nad, because an interesting feature of Alzheimer's disease is it's Characterized by low levels of this energy molecule nad, which is absolutely critical to energy metabolism at mitochondria. In fact, interestingly, if you look in brains that don't have cognitive decline but have a lot of amyloid, they're characterized by high nad. So you can think about it as a resilience factor in the brain. If you don't want to take that supplement, how do you increase NAD levels? Exercise will do it. So exercise is a non negotiable. And then I do think some degree of intermittent fasting and occasional bouts of ketosis will be helpful. And if you want to do lipid lowering therapy, I think ezetimibe is interesting.

[Louise Nicola]

You forgot one. Creatine.

[Nick]

That's true. Creatine, yes.

[Louise Nicola]

Thoughts?

[Nick]

Yeah. So I mean creatine obviously originally the space of bodybuilders, people trying to improve performance in the gym. Creatine is absolutely essential in brain function as well in terms of practicalities. So creatine also helps with energy metabolism. The common knowledge was you need higher levels to get to the brain. Like 5 grams for like your muscles and like 15, 20 grams for your brain. I'm not sure about that anymore. I don't know if you remember seeing. There's a paper that came out earlier

[Louise Nicola]

this year, the pilot study on the 20 grams a day.

[Nick]

No, no, it was the depression study.

[Louise Nicola]

Oh yeah.

[Nick]

So there was, there was a study looking at depression and basically what they found was that creatine uptake was impaired in depression and that giving creatine with a probiotic that helped to increase creatine absorption improved depression. It's a human study. They had animals data and human data. This is a big study that came out. The interesting thing about it was they used three grams. Three grams. It was combined with a probiotic to improve creatine uptake. But it was 3 grams of creatine and they saw clinical improvements in human depression.

[Louise Nicola]

That's funny because I usually think I've never seen the data on a probiotic in combination. I've seen it in with an electrolyte combination to increase absorption.

[Nick]

Yeah, I mean I can find, I can pull my phone and find the paper but it was, it was, it was seller. I think it was one of the cell press journals.

[Louise Nicola]

Yes. Insulin is a life saving drug. So I'm not talking about that when I talk about peptides. Yes. GLP1's. I'm all for them. I think that they're doing remarkable things especially for Alzheimer's disease patients. I think we're going to even find more Evidence on that correlation when rotatrutide gets eventually when it comes to market.

[Nick]

Let me hit two things before we go into peptides that you will love. One GLP1s. I am very for GLP1s for the brain, totally weight independent effects. Two things they do. One thing is improved insulin sensitivity in the brain and that actually leads to GSK3 beta inhibition. So converging.

[Louise Nicola]

Isn't that just from not eating?

[Nick]

No, I think there are independent effects of GLP1s in the brain also amyloid processing. So they found that GLP1. Basically what happens is you have an amyloid precursor protein and it can go down one of two paths. The amylogenic toxic path or the non amelogenic path. The amylogenic toxic path has a protein called beta secretase or base and GLP1 inhibits that. So it actually skews amyloid processing towards the non amylogenic path. So that's completely weight independent. So I would say GLP1s for the brain. Yes.

[Louise Nicola]

I didn't know that.

[Nick]

Yes. And retatrutide, why are they taking so long? I don't know. But did you know it has been. I think it has a PCSK9 inhibitor activity. So what happened? I did a month long experiment with Retta and I thought it would increase my LDL and Applebee because if I lose weight it goes up because of my physiology and it went down. I'm like, well that's weird. Why is this? Turns out glucagon suppresses PCSK9 and that's the third component of Reta. So it'd be really interesting to see like a tirzepatide vs reta like RCT even just for like lipid outcomes. But keep an eye on that with your community. See if people are seeing LDL and Apple B go down with Retta and just look up glucagon pcsk9.

[Louise Nicola]

But I don't think it's going to get approved for another two years.

[Nick]

So people are gonna get it.

[Louise Nicola]

Okay, so this was my stance on BPC157TB500, also known as the Wolverine stack that a lot of people are taking. And okay, rightfully so, correct me if I'm wrong. When we're looking at body protection compound 157, we know that it primarily heals, you know, if you're going to inject it somewhere, let's say the Achilles tendon, wherever you want that that help to go via vascularization.

[Nick]

That's one mechanism.

[Louise Nicola]

That's one mechanism, yes. Now in Terms of that there is a reason why this is not FDA approved, which people hate that I say that because they think I'm some sort of pharmacial. When I say, well, this is, it's not, you know, they didn't pass the phase three trials for a reason. But not just that. It's my understanding that it doesn't know the difference between a muscle cell per se or a cancer cell. And causing vascularization around that cancer cell can in fact probably accelerate tumor cell growth.

[Nick]

Yeah, it's a theoretical concern. Remains to be determined if it bears out, I will say, in the peptide space, I mean, there's like so many peptides. Like there are ones that I think probably should get approved kind of soon. Like what MOT C I think is amazing. Yeah, it's basically a mitochondrial hormone. So MOT C your body normally produces, your mitochondria produce it. They have their own genome. And we used to think there were 13 dinky little genes on there. But there are like, like hidden instructions called open reading frames and basically they produce mitokines, mitochondrial hormones. MOTC is one that appears to improve a lot of elements of function and performance. There's a really cool study. This is all preclinical. But they took animals and they can put these mice on a treadmill running test and at baseline, 16.6% of the mice could max out the test. Given the mossy 100%, every single mouse max out the test. So you're thinking about like, you know, bonafide exercise, mimetics, things that our bodies actually produce. I think there are some and others that have been studied longer. Some of the ones out of like Russia, like Pinealon, epitalon. So peptides, I say is very broad and we can have that discussion probably another time. BBC 157, I would say the concern you raise is theoretically legitimate. My position is analogous to like the analogy I use is if you go to a college campus and you try to just say, you know, practice contraception through abstinence, just gonna get a lot of pregnancies, people are gonna get these peptides. I think it's gonna happen. So I don't try to pass judgment on if you use it or don't. It's a matter of like communicating what are the risks potentially if you had pre existing cancer cells, angiogenesis around them because of BBC 157 is a concern. Do I think it's a promising compound? Do I think that it really helps some people? I think that as well, but I don't think it's 100% risk free.

[Louise Nicola]

That's nothing really is.

[Nick]

There's other applications too. Like there's the oral form for GI health that with Larazotide, kpv. And some of these things are really well studied. So take another one. Tesamorelin. There are multiple like double blinded RCTs for tesamorellin reducing visceral fat. Fat is originally studied in patients with HIV associated lipodystrophy because the drugs increase visceral fat. So bottom line on peptides, very broad. Some of them are really well studied. I am excited to see where they go. But to your point, there are risks that at least should be talked about even if they're not like prohibited as compounds.

[Louise Nicola]

Last question. Why do you think you're so controversial?

[Nick]

I refuse to dumb things down and I feel like I'm provocatively moderate. I'm sure not everybody would agree, but there's so much extremism and tribalism and I really try to play the devil's advocate as much as I can, but when I do that, I don't control what gets amplified. So I'll do one video on really interesting benefits of fiber, inulin fiber and what it can do to like, you know, immunize you against sugar and then another one covering like RCT data out of Stanford about how high doses can harm your liver. And I, I make a big effort not to pander. But then I think there's a negative selection bias where certain things get elevated in echo chambers and it leads to creating caricatures of my position. And I kind of lean into that because I don't mind being a little bit of a provocateur and, and in leveraging those moments of conflict to elevate discussions. And I feel while some people who don't take the time to really process what I'm saying or are intimidated by the nuances, including clinicians, can get ticked off. The population I'm trying to serve is, I think the underserved population of people who are starving for nuance and are willing to be like, I want to put the effort in because I can't do that for you. Grapple with the complexities and, you know, continue to in an authentic way evolve our positions with open minds. I think there's a need for that. And I think we just live in a very dogmatic, calcified time. I think is also a function of who I am. One of the reasons I took the path I'm taking is I really got upset with the hierarchy in medicine. And because I have strong opinions and I don't think people are always open to having a discussion about them. If I were a medical resident, I would get destroyed. Now I can't. So people will still get ticked off of my opinions. If they want to sit and have a debate. I'm almost always up for it. Most of the time they don't. They make a snarky remark and run. And thankfully I'm developing thick skin, so I just have fun with it.

[Louise Nicola]

Yeah. And the good thing is because I follow all of your disagreements, you're able to back yourself up.

[Nick]

So everything I say, like I say things in a provocative manner, but they're precise. So people get like tick off about clickbait. We live in an engagement ecosystem. I'm going to do that, but I'm not. It's accurate. It's just going maybe where you didn't expect.

[Louise Nicola]

So I'm excited for the future experiments. Thank you Nick for being on the podcast.

[Nick]

Thank you for having me. This episode is brought to you by Google Health. Stop chasing someone else's definition of health. What matters is what's healthy for you. Google Health offers a new kind of coach built with Gemini for effortless tracking, sleep insights and holistic coaching tailored to you. Visit googlestore.com to learn more and start a new relationship with your health. Requires Google Account, Google Health app, Internet and Google Health Premium subscriptions. Features subject to change, availability and results vary. Not intended for medical purposes. Works independently of Gemini Apps. Check responses for accuracy. Have no Fear.

[Louise Nicola]

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