New Therapy for Alzheimer’s Prevention: An ApoE2 “Bath”

1/5) My Alzheimer's risk is 10-15x higher than average because I'm in the ~2% of the population that carries two copies of the ApoE4 gene, the dominant genetic risk factor for Alzheimer's.

Some consider this a near guarantee of developing the disease if you live long enough.

But I'm optimistic.

A study just published in Molecular Therapy demonstrates a potential "antidote" that gives me, and many others, a reason for hope. It’s not a cure. Not a silver bullet… but a glimpse of what’s coming…

In today’s letter (🔗 at the end), I break down these data and tell you what I do today to protect my ‘future me’ brain. (2/5) One core question has always been: Is ApoE4 actively "toxic," or is the problem a lack of functionality, functionality better provided by the most common “ApoE3” variant of the ApoE gene or protective ApoE2 variant.

If it's primarily a lack of functionality, the solution is simpler: add back what's missing.

That's exactly what this study tested. Researchers used a humanized mouse model carrying the ApoE4 gene to see if they could literally bathe the brain in extra ApoE2 to protect against Alzheimer’s pathology.

They developed a clever new gene therapy method to do to make this happen…

Stress Can Biologically Age Your Body and Brain. But How You Respond to Stress Matters More (🔗 in 7/7)

1/7) We often talk about stress metaphorically — "that job is aging me." But what if this is a literal biological truth?

A study published in Nature Aging provides a chilling mechanism, linking chronic psychosocial stress directly to accelerated biological aging.

The culprit? Stress is creating "zombie cells" (cellular senescence), especially in your most critical organ: your brain…

Are you surprised? And, how old do you think I am (biologically speaking)? 2/7) To test this, researchers used a robust model of chronic subordination stress in mice.

This isn't just "feeling stressed" — it's designed to simulate chronic social defeat. Think of it as the biological equivalent of a persistent bully at school or an aggressive, abusive boss with unchecked power.

Each day, the test mouse was exposed to a larger, aggressive mouse and physically subdued, creating a state of chronic, inescapable social stress.

Creatine Mini-Masterclass
💪How is Really Work?
💪How Do You Maximize Benefits?
🔗 in 8/8

1/8) Creatine is one of the most extensively studied performance-enhancing supplements in the world of exercise science and nutrition.

For examples, a recent meta-analysis of RCTs examined the effects of full-body resistance training programs, with and without creatine supplementation.
The key findings:

💪Compared to resistance training alone, creatine supplementation significantly increased lean body mass by 2.5 lbs (1.14 kg).

💪Creatine also led to reductions in body fat percentage by 0.88% and total fat mass by 1.6 lbs (0.73 kg).

And yet, despite its popularity, few people truly understand how it works or what its full range of effects might be.

So... what is Creatine and How Does It Work? 2/8) Creatine is a naturally occurring compound made up of three amino acids: arginine, glycine, and methionine. Your body produces it in small amounts, and you also get some from food—especially meat and fish.

Creatine is primarily stored in muscle tissue, where it plays a critical role in cellular energy metabolism. Its main function? Helping to rapidly regenerate a molecule called ATP—the primary energy currency of your cells.

How to Hack the Black Hole of Sugar Cravings

(1/7) Why does one person politely decline dessert while another feels irresistibly pulled toward it, as if by a "gustatory black hole?" 🍰

It's NOT a failure of willpower. It's metabolic wiring.

A fascinating paper just published in Nature Microbiology uncovers a precise gut-to-brain pathway that modulates our biological preference for sugar. 2/7) Before we get to the rest of the thread, a quick reminder. This is DAY 1 of the Nuance November Promotion at 👉 StayCuriousMetabolism.com

Link to this letter: staycuriousmetabolism.substack.com/p/the-metaboli…

Now, ONWARD!

Measuring Insulin Resistance: Your Potato-to-Grape Ratio?! 🥔🍇 (link at the end)

1/5) Your potato-to-grape ratio might predict your insulin resistance.

A 2025 study from @Stanford Snyder Lab (@SnyderShot) published in @NatureMedicine is challenging one-size-fits-all nutrition, and the findings on personalized blood sugar spikes are fascinating. 2/5) Researchers studied 55 individuals, giving them seven standardized 50g carb test meals (white rice, bread, potatoes, pasta, beans, berries, and grapes).

They tracked everyone's individual glycemic response to each meal using CGMs.

One striking finding?

🚨Quoting the paper: "for each individual, different meals produced the highest glycemic response."

Someone might spike most from bread, another from grapes, someone else from potatoes.

But the patterns weren't random.

Why Lp(a) May Not Be as Dangerous as You Think—If This One Metric Is Low (🔗 in 8/8)

1/8) A new study offers real hope for those with high Lp(a), a genetic risk for heart disease. While you can’t change your genes, the risk of high Lp(a) appears to be conditional on a modifiable factor: your waist-to-hip ratio. 2/8) For context, Lp(a) is a cardiovascular boogeyman. Unlike LDL, its unique apolipoprotein(a) tail makes it "sticky," more likely to promote blood clotting, and more atherogenic on a per-particle basis.

Your Lp(a) level is largely genetically determined, a fact that has been frustratingly difficult to address as few effective, proven therapies currently exist that lower Lp(a) and lower cardiovascular risk.

1/6) How Fructose Hijacks the Liver to Fuel Cancer (Link in 6/6)

Quote: “In all cases, diets supplemented with high-fructose corn syrup resulted in faster tumor growth compared with control diets.”

This includes melanoma, breast, and cervical cancers. What’s going on is ‘sneakier’ than you might think? Let’s break it down 🧵👇 2/6) Cancer is a master hijacker. In this case, it co-opts the liver. When the liver gets fructose, it turns it into molecules that cancer cells repurpose into specific phosphatidylcholines—key building blocks for cell membranes.

Fructose → liver → raw materials for cancer’s construction project.

DON'T DRINK Again Until Your Read THIS 🍺🍷🧠

(1/8) Sleep Deprivation Mimics Drunkenness on a Molecular Level — Here’s What That Really Means (Link in 8/8)

A paper in PNAS that provides a stunningly deep dive into how a lack of sleep and alcohol hijack the brain through the exact same pathway.

Stick with me. I'll break down why society's acceptance of "burning the midnight oil" is so dangerous. (2/8) When I first opened this paper, I was struck by a simple thought: we socially accept exhaustion but demonize drunkenness.

We praise the all-nighter but would be horrified if a surgeon showed up to the OR after a few drinks. The data in this paper reveals just how backward that thinking is.

It turns out that both states flip the very same master “dimmer switch” in the brain. This switch is governed by a key molecule called adenosine, and it explains why the cognitive impairment from sleep loss is so severe.

Cholesterol Confessions of an MD PhD Lean Mass Hyper-Responder. (link at the end)

1/7) I gave my cardiologist a heart attack. Well—not literally. But when a cardiologist sees an LDL cholesterol of 574 mg/dL, their eyes bug out like they’re a human-sized fruit fly.

And I understand why.

That number is higher than anything most doctors have seen in their entire careers. And it’s scary. It is.

It rivals levels found in “homozygous familial hypercholesterolemia,” a rare genetic disorder—occurring in ~1 in a million—that can cause fatal heart attacks in children as young as eight.

But I don’t have familial hypercholesterolemia.
Something very different is going on inside my body… 2/7) Today’s letter is an overdue ~3000-word essay on:
🩸My lipid levels
🩸Background on people like me
🩸Disclosure on my personal choices
🩸What I'm doing next
staycuriousmetabolism.substack.com/p/im-a-harvard…

Warning: It’s intense. And it’s only the beginning.

Caution: Please do not take this as medical advice or even the suggestion of such. Instead, my purpose is providing discloses it to reveal how I think, not what to think.

Note: The back half of the letter is currently only available for premium subscribers. For now, I’m reserving the most complex and intense details for a smaller, highly committed audience. Call it an intellectual stress test.

🚨Low-Carb Gaslighting: How THIS Became “Keto” Science (link at the end)

1/8) What if you could live on a diet of Reese’s Peanut Butter Cups, lose body fat, and improve your health?
It sounds absurd—and it is.

But the absurdity of that thought experiment highlights a persistent misunderstanding about ketogenic and low-carb diets.

In today’s letter, I step through four shocking examples of low-carb and keto gaslighting—ultimately building to answer the question: why are these diets so grossly misunderstood.

@AKoutnik @janellison @realDaveFeldman @metcoalition @Metabolic_Mind @bschermd @TuitNutrition @BiggestComeback @BenBikmanPhD @thelowcarb_rd 2/8) Study 1: Skews the Truth with “Scores”

Take as our first example, recent study that was touted as “proof” online that low-carbohydrate diets don’t help—or can even exacerbate—diabetes.

At first, the headlines seem compelling, if for no other reason than the American Diabetes Association “seal of approval.”

But what did the researchers actually measure? What did they call “low-carb?”

This was a nutritional epidemiology study based on food-frequency questionnaires. Participants self-reported their diets, and researchers divided them into quintiles (fifths) according to carbohydrate intake. They then assigned each group a “low-carbohydrate score” relative to the others.

Food is Medicine. Why Are We Poisoning Patients?

1/4) This is a plate of food at the hospital.

They say a picture is worth a thousand words. But I’d argue the fact that a wealthy, advanced Western society feeds its sick like this says more than all the words in the English language.

So, we must ask: Why do we do this?

And, how do we dig ourselves out of this sticky situation? 2/4) Honestly, the “why” is simple can be summed up in a words: ignorance.

I don’t believe those trays of food are driven by malice. I think it’s a genuine lack of understanding about just how harmful meals like these can be—especially for the metabolically vulnerable.

We toss around and consume misleading terms “empty calories,” phrases that distort biological reality.

On this example, nutrients that calories – carbohydrates (fructose, glucose), fats (stearic acid, linoleic acid, butyric acid), etc. – aren’t just passive carriers of vitamins and minerals; they are active biological signals with direct effects on your metabolism, mitochondria, and immune system.

The Gut Molecule Makes Blood Less “Clotty” (New Research) 🔗 in 8/8

1/8) Imagine your blood as a river, delivering life to every organ downstream. A heart attack is a dam—a single clot that blocks that river, starving your heart or brain until it begins to die.

A new paper in @NatureCVR (PMID: 40217125) has identified a key molecule from our gut that keeps this river flowing.

Stick with me. I’ll break down these data. 2/8) Researchers compared patients with coronary artery disease (CAD) to healthy controls and found a stark deficiency.

The CAD patients had significantly lower levels of a particular bile acid called Deoxycholic Acid (DCA).

They also had fewer of the specific gut microbes responsible for producing it, revealing a potential link between a missing microbe and a missing protective molecule.

We Just Discovered a Fructose “Vaccine” — and It's at the Grocery Store (🔗 in 8/8)

1/8) When I read this new paper in Nature Metabolism (PMID: 38862620), I started with a smirk and ended with a sigh of relief. “FINALLY!” I thought. “A fiber paper that’s not fluff.”

I have a bone to pick with how fiber is discussed: hand-wavy "more is better" claims. It's like evangelizing "eating is fantastic" without differentiating salmon from a breadstick coma at the Olive Garden.

This paper is different. It shows how one specific fiber can immunize against fructose. Stick with me.

Authors note regrind 'vaccine.' Yes, that's called a hook. Congrats. Give you the definition of the word, it's "a biological preparation that provides active immunity to a particular infectious disease" ... and, honestly, I could easily argue that applies here. 2/8) First, some background. Metabolic dysfunction-associated Steatohepatitis (MASH)—fatty liver—is a serious risk, worsening cardiovascular health and increasing cancer risk. One dietary driver can be fructose, which uniquely enhances de novo lipogenesis: the synthesis of new fat in the liver.

Crucially, this can be uncoupled from weight gain. In controlled experiments, mice fed high-fructose corn syrup don't always gain weight, but they gain fat, lose lean mass, and develop a fatty liver.

The simple answer is "eat less fructose," but if that's all you wanted, you wouldn't be here.

Statins Harm Mitochondria (Human Trial)💊❤️‍🔥

1/5) Even at very low concentrations, and without symptoms, statins can impair mitochondrial function. (link at the end)

In this study, patients were treated with atorvastatin daily for eight weeks. The results included:
👉Decrease in mitochondrial respiratory capacity
👉Decreased skeletal muscle oxidative capacity
👉“Striking” inhibition of mitochondrial complex IV. 2/5) The researchers in this study noted that the statin therapy caused a 23% reduction in the rate constant of muscle recovery. To quote the authors, this “indicates a decrease in muscle oxidative capacity.”

In simpler terms, statins impaired a functional metric of muscles metabolism. How? …

The Oldest Woman (117) Had “High” Cholesterol 🩸— Here’s What That Really Means🤔(Link 🔗 in 8/8)

1/8) The world’s oldest woman just died. Before she passed, she pleaded, “Please study me.”

A new paper in Cell Reports Medicine (PMID: 39322234) just published provides a deep dive into her genes, metabolism and microbiome. What made this 117-year-old such a supercentenarian?

As a metabolism scientist, this is the kind of data I’d die for (figuratively speaking). Stick with me. I’ll break down what her biology really tells us about aging, and why we might be obsessed with the wrong biomarkers. 2/8) When I first read the paper, I noticed something odd.

The authors detailed her lipid profile (HDL, VLDL-TG, etc.) but her LDL-C and ApoB—the numbers most doctors obsess over—was nowhere in the main text.

I had to go hunting in the supplementary data. There it was, buried in a single line of Supplemental Figure 8B: elevated, and in the “red.” -- Granted, it wasn’t super high… but it wasn’t low either.

So what gives? Why was it not mentioned in the main text. I provide thoughts (not conspiracy theories) in the letter. But now I know I have your attention…

cc @realDaveFeldman @AdrianSotoMota

Tylenol and Autism: Let’s put Science Over Politics

1/8) I’m not surprised today’s mini letter is getting spirited comments. But this needs to be my favorite. Why?

Because Certainty is the Coffin of Science.

Science doesn’t operate in absolutes and medicine is the art of making life-altering choices with imperfect information.

With the said, please hear me out before jumping to conclusions… 2/8) First, a promise: There are many ways I could respond to the present moment — but I’m going to try to choose compassion and understanding. By that I mean I’m not going to point fingers or make fun. This moment calls for less fighting, less politics, and more humility.
Full letter here: staycuriousmetabolism.substack.com/p/tylenol-and-…

🤯The INSANE Mitochondrial Economy in Your Body that could save your Heart 🫀! (🔗 in 7/7)

1/7) Sometimes I read a paper that literally gives me goosebumps—not because it gave me the answer to a question I’ve been seeking, but because it blindsided me with an idea I couldn’t have imagined. This is one of those times. And my challenge in this letter will be communicating in text why I’m so excited.

Let me not make you wait any longer and get to the punchline: mitochondria—the powerhouse of the cell—aren’t just little engines, but part of a complex signaling network whereby cells and organs can trade mitochondria as part of a systematic energy economy throughout the body.

If you want the full story, skip to the end and click the link to the full letter. If you want to wade in, continue… 2/7) The first paper of a triad that gave me the goosebumps was published in Cell Metabolism and found, now paraphrasing: Fat cells and immune cells employ intercellular mitochondria transfer as a mechanism of crosstalk that regulates metabolic homeostasis and is impaired in obesity.”

What you’re looking at below is a time-lapse image of a mitochondrion (arrow), released from fat cells, being taken up by an immune cell (the red blob). That we can visualize this mitochondrial transfer event in living mammals is quite a feat of engineering!

Stress Makes Sugar (Literally!) - New Study Blew my Mind...(🔗 at the end)

1/8) Groundbreaking research just published in @Nature shows that stress can trigger brain circuits with a direct hotline to the liver to make new sugar.

🚨TL; DR Stress can Make Sugar, even independent of eating carbs.

This newly discovered brain-liver axis bypasses the usual hormonal regulators of blood sugar—like cortisol, adrenaline, insulin—and instead sends a direct signal that forces the liver to make and dump sugar into the bloodstream.

Let’s break it down… 2/8) Let me start with an analogy: Imagine if I told you that I could instantly communicate with a friend on the other side of the world. You wouldn’t be shocked—you know I have access to email and a phone. But if I clarified, “No, I’ve invented telepathy,” and could somehow prove it to you, is it fair to say you’d be impressed? That’s analogous to distinction we’re dealing with here: an entirely new and direct line of communication between the brain and liver to influence blood sugar.

Four Subtypes of Diabetes: Groundbreaking Research Out of Stanford (🔗in 7/8 and 8/8)

1/8) Overview:
👉New technologies reveal four subtypes of diabetes
👉Knowing your ‘flavor’ of diabetes (or prediabetes) can guide lifestyle and medical treatment
👉Combining bio-monitoring with big data and machine learning will bring forth a revolution in diabetes care and personalized medicine

*I’m releasing this letter early because the data it covers was conducted by one of my scientific heroes, Stanford’s Professor Michael Snyder @SnyderShot, who happens to be the guest on today’s @hubermanlab podcast episode.

*In fact, Professor Snyder is the only person I’ve pestered Andrew to have on his show, although I suspect the conversation would have happened anyway.

*My two-part interview with Professor Snyder, where we dig into some of his specific studies (Sub-phenotypes of diabetes, personalized medicine, and the famous two peaks of aging) will release part one later this week.

But first, let’s dig into these data! 2/8) The most common form of diabetes — Type 2, often associated with obesity and adult onset — isn’t one disease. It’s actually four different underlying pathologies, showing up in different proportions in different people.

Here’s a metaphor that might help: Imagine a dish made from bread, vegetables, and cheese. The general ingredients stay the same — but their ratios define what you’re eating.

Pile on the vegetables, go easy on the bread, toss in some protein — and you’ve got a Caesar salad with croutons. Flip the script: make bread the base, add a smear of sauce and some melted cheese — and now you’ve got a pizza.

Now imagine if we called both dishes the same thing. That’s what we’ve been doing with Type 2 diabetes.

Can Visceral Fat Cause Depression? (🔗at the end)

1/7) New data reveals how molecular packages called extracellular vesicles (EVs) can travel from visceral fat in the abdominal cavity, through the bloodstream, and into the brain, where they alter the function of specific brain areas and promote depression.

This is no joke. It's (literally) mind-bending science. Let's dig in... 2/7) First, some human context: depression and obesity are highly 'co-morbid'—meaning they often occur together.

Individuals with obesity are twice as likely to experience depression as those with a healthy weight.

Moreover, those diagnosed with depression are similarly at (58%) higher risk of developing obesity down the line, in part due to the adverse effects of certain antidepressant medications.

This can establish a vicious cycle between obesity and depression—a descending spiral with social, psychological, pharmacological, and metabolic components.

But one big question remains unanswered: How does fat tissue contribute to depression?

This is a very difficult question to answer in humans. You can’t perform controlled trials, and the social baggage of living with obesity introduces many psychosocial confounders. So, we turn to animal models.

We return to the human story in the letter—but first, let’s get murine and mechanistic.

Causality is Overrated” – A Respectful Rebuttal to Dr @PeterAttiaMD cc @hubermanlab (🔗at the end)

This thread is about one word: causality.

1/8) People are obsessed with it. But first, let me identify the causal stimulus for this nibble: the quotes Huberman podcast clip @HLPClips (posted yesterday on X) in which Peter Attia expounds upon his “obsession” with causality.

To quote Peter: “Causality is an obsession of mine. Most of the day, on some level, I sit around thinking about causality.”

In this thread I’m going to make the case, respectfully, that Peter misses a big-picture point. This isn’t to ‘mic drop’ or puts points up on some imagined. This is not to end a discussion – it’s to reopen one that is desperately needed.

cc @realDaveFeldman @AdrianSotoMota 2/8) The first three minutes of the clip are devoted to lung cancer, where Peter uses the Socratic method with Andrew to examine the causal relationship between smoking and lung cancer. He ultimately lands on the point:

“If you believe smoking is causally related to lung cancer, then smoking cessation reduces the probability of lung cancer. That is a logical equivalency. There can be no debate about that.”

He then pivots, replacing smoking with ApoB and lung cancer with atherosclerosis, stating: “There is no ambiguity that ApoB is causally related to atherosclerosis.”

Peter even goes so far as to argue that not treating elevated ApoB—even if the a person’s overall major adverse cardiovascular event score is low—is “as idiotic” as permitting someone to smoke.

But here’s where I think Peter is wrong because causality is not the same as importance.