As you’ll remember, on July 1st I made a trip down to Boca Raton, Florida, to have extensive Alzheimer’s biomarker testing done at RetainMed, an Alzheimer’s prevention clinic created under the leadership of Dr. Richard Isaacson, a pioneering neurologist in Alzheimer’s prevention.

The results are in!

I’m not going to pretend the wait for my results wasn’t fraught with some very real anxiety and trepidation. I’m sure those of you who have had p-tau and other biomarkers tested know exactly what I’m talking about.

After implementing a multimodal Alzheimer’s prevention strategy for more than eight years—one I largely built on the teachings of trailblazers like Dr. Dale Bredesen, Dr. David Perlmutter, Dr. Heather Sandison, Drs. Dean and Ayesha Sherzai, and others—my results were finally going to put all of this to the test.

After all, as a 73-year-old female APOE4/4 carrier, these results were going to be the proverbial “proof in the pudding.”

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Last week, on August 19th, I went back to Boca Raton for the “verdict.” To say I embarked on that trip with mixed feelings would be an understatement. What if I was told my p-tau was elevated? What if other markers were worrisome as well?

The Wait Is Over

I’m going to keep the details of my follow-up visit very short here because this is an exceptionally busy week for me.

While I’m no longer working full-time, part of my Alzheimer’s prevention strategy is to remain mentally active. My business, in the industrial sector, is celebrating its 40th anniversary this year, and this week we are exhibiting at our industry’s largest trade show.

While the day-to-day operations have transitioned to the next generation, I’m at the show all day, on the floor—presenting our products, making new contacts, and truly enjoying seeing customers, vendors, and friends I have known for decades.

Thursday being my “Substack day,” I didn’t want to leave you empty-handed. So, while a more detailed post will be forthcoming, I imagine some of you are wondering where I landed on these tests!

The good news is that my p-tau remains within the normal range, my lipid markers are in a pristine place, and I was sent home with the reassurance that there is no cause for concern at this time.

My instructions?

Remain diligent and stay on top of my brain health.

After eight years of working at this every single day, I couldn’t have asked for much better news. I’ll share more detail and recommendations in a future post!

Phew!!!

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For those of us carrying APOE4, I believe it’s of particular interest.

It’s called Humanin.

Humanin is only 24 amino acids long, yet research suggests that this tiny molecule may influence mitochondrial function, inflammation, insulin sensitivity, cellular stress responses and potentially protection against amyloid toxicity.

Even more intriguing, researchers recently identified a naturally occurring Humanin variant associated with exceptional longevity in APOE4 carriers.

So what exactly is Humanin and could this little mitochondrial signal tell us something important about healthy brain aging?

What Is Humanin?

Humanin is a mitochondrial-derived peptide (MDP).

Unlike most proteins we talk about, which are encoded by DNA in the cell nucleus, Humanin is encoded within mitochondrial DNA.

Mitochondrial-derived peptides such as Humanin and MOTS-c appear to act as signaling molecules, allowing mitochondria to influence metabolism, inflammation, cellular stress responses and survival throughout the body.

Humanin is one of those signals.

Our bodies produce it naturally, and while circulating Humanin can be measured in blood - unfortunately, it’s not something we can get during a routine lab test.

Synthetic Humanin and more potent analogs such as S14G-Humanin (HNG) are also being studied experimentally. Humanin is not FDA-approved as a treatment for any conditions in humans, and much of the intervention research remains preclinical.

But the biology is truly fascinating and exciting.

Humanin and Brain Health

Humanin was originally discovered because of its ability to protect neurons against Alzheimer’s-related cellular stress.

Experimental research suggests Humanin can:

• Protect neurons from cellular stress

• Reduce apoptosis, or programmed cell death

• Protect against amyloid-beta toxicity

• Support mitochondrial function

• Reduce inflammatory signaling

• Influence insulin signaling

• Support cellular resilience during metabolic and oxidative stress

One of Humanin’s mechanisms is particularly interesting.

Humanin can interact with BAX, a protein involved in triggering mitochondrial apoptosis. By interfering with BAX activation and movement into mitochondria, Humanin can interrupt part of the cellular pathway leading to cell death.

In other words, Humanin appears to function partly as a mitochondrial distress-response signal.

Humanin and Alzheimer’s Disease

Humanin has repeatedly demonstrated neuroprotective effects in laboratory and animal models of Alzheimer’s disease.

Research suggests that Humanin and its analogs can:

• Reduce amyloid-beta toxicity

• Increase neuronal survival

• Improve insulin signaling in the brain

• Increase autophagy

• Reduce amyloid accumulation in some animal models

• Influence inflammatory and phagocytic pathways involved in clearing cellular debris

This does not mean Humanin has been demonstrated to prevent or treat Alzheimer’s disease in humans - because it hasn’t. But it does raise an interesting possibility.

Could declining mitochondrial stress defenses be one of the factors that makes the aging brain increasingly vulnerable to Alzheimer’s pathol

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The APOE4 Connection Gets Really Interesting

For APOE4 carriers, a remarkable Humanin finding was published in Aging Cell in 2024.

Researchers identified a naturally occurring Humanin variant called P3S that was enriched among exceptionally long-lived APOE4 carriers.

Even more remarkably, when researchers tested Humanin P3S in an APOE4 mouse model of amyloidosis, it reduced brain amyloid-beta accumulation compared with ordinary Humanin.

The researchers found evidence suggesting that P3S may improve amyloid phagocytosis and clearance.

They also found that the P3S version of Humanin appears to interact particularly strongly with the APOE4 protein.

Think about the implication.

APOE4 is the strongest common genetic risk factor for late-onset Alzheimer’s disease.

Yet some APOE4 carriers reach extreme old age cognitively intact.

A mitochondrial peptide variant may be one piece of the biological resilience that allows some people to withstand APOE4-associated pathology.

Humanin, Astrocytes and GFAP

Another intriguing piece of the story involves astrocytes.

Astrocytes are support cells in the brain that help regulate metabolism, inflammation, neurotransmitters and neuronal health.

When astrocytes become reactive, expression of GFAP (glial fibrillary acidic protein) often increases. Plasma GFAP is now being studied as a blood biomarker of astrocytic activation in Alzheimer’s disease and other neurological conditions.

In a 2013 laboratory experiment, researchers activated astrocytes with LPS, causing inflammatory signaling and GFAP expression to increase.

Humanin treatment suppressed astrocyte activation in a dose-dependent manner and reduced inflammatory signals including IL-6, IL-1β and TNF-α.

More recently, an animal study of traumatic brain injury found increases in GFAP and p-STAT3 following brain injury. Humanin treatment counteracted those increases.

This does not establish that taking Humanin will lower plasma GFAP in humans.

But it raises a fascinating possibility:

Humanin → improved mitochondrial stress response → reduced inflammatory signaling → less astrocyte reactivity → potentially lower GFAP

That pathway deserves considerably more research.

Humanin and Macular Degeneration

Then I came across another intriguing connection: age-related macular degeneration (AMD).

Researchers measured circulating Humanin in people with AMD and healthy controls and found significantly lower Humanin levels in the AMD group.

They then studied retinal pigment epithelial cells containing mitochondrial DNA derived from AMD patients.

When the researchers treated those cells with the potent Humanin analog HNG, inflammatory proteins declined, including:

• TNF-α

• IL-1β

• IFN-γ

• IL-17A

• ICAM-1

• E-selectin

• P-selectin

This experiment is especially interesting because the cells were designed so that their nuclear background was identical while their mitochondrial DNA differed.

That points directly toward mitochondrial dysfunction as a driver of the inflammatory phenotype - and toward Humanin as a potential mitochondrial stress-response signal capable of modifying it.

Again, this was not a clinical trial showing that Humanin treats AMD. Yet, it provides another example of the same pattern:

Mitochondrial dysfunction → inflammation

and

Humanin signaling → reduced cellular stress and inflammation

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Humanin and Insulin Sensitivity

The metabolic side of Humanin may be just as interesting as its neurological effects.

Humanin and its analogs have improved insulin sensitivity and glucose homeostasis in animal experiments.

Experiments using sophisticated glucose-clamp techniques found that Humanin signaling could improve whole-body insulin sensitivity and suppress excessive hepatic glucose production.

Interestingly, some of this effect appears to originate in the hypothalamus, suggesting communication between mitochondrial signaling in the brain and glucose regulation in the liver.

Humanin analogs have also:

• Improved peripheral insulin sensitivity

• Increased glucose-stimulated insulin secretion

• Protected pancreatic beta cells from cellular stress

• Reduced hepatic triglyceride accumulation in animal models

That creates another potential Alzheimer’s connection.

Insulin resistance, impaired cerebral glucose metabolism and mitochondrial dysfunction are all associated with brain aging and Alzheimer’s disease.

Humanin therefore sits at an intriguing intersection:

mitochondria + insulin signaling + inflammation + neuronal survival.

Humanin and Aging

Humanin levels appear to change with aging, and the Humanin pathway has attracted considerable interest from longevity researchers.

Experimental studies have associated Humanin signaling with:

• Improved metabolic health

• Greater insulin sensitivity

• Protection from oxidative stress

• Reduced cellular apoptosis

• Cardiovascular protection

• Neuroprotection

And the discovery of the Humanin P3S variant in exceptionally long-lived APOE4 carriers makes the longevity connection particularly intriguing.

Perhaps Humanin isn’t simply a peptide involved in Alzheimer’s disease.

It may represent part of a broader mitochondrial resilience system that helps determine how successfully cells tolerate the accumulated stresses of aging.

A Different Way to Think About Alzheimer’s

For decades, Alzheimer’s research has focused heavily on amyloid plaques and tau tangles.

Those remain central components of Alzheimer’s biology.

But zoom out and another picture emerges:

Mitochondrial dysfunction
Impaired energy metabolism
Insulin resistance and metabolic stress
Oxidative stress
Inflammation and reactive astrocytes
Reduced ability to withstand or clear cellular damage

Amyloid and tau may exist within this much larger biological environment.

Humanin is interesting because it appears to touch several parts of that environment simultaneously.

For APOE4 carriers - we already appear to have vulnerabilities involving lipid metabolism, mitochondrial function, inflammation and cellular stress - that deserves attention.

Instead of only asking:

“How do we remove the damage once it appears?”

perhaps we should also be asking:

“How do we make our cells more resilient so that they can handle the damage in the first place?”

Can We Increase Humanin Naturally?

This is where the science becomes much less certain.

Exercise and metabolic stress have been investigated in relation to mitochondrial-derived peptide signaling, and interventions that improve mitochondrial health are biologically attractive.

But I would be cautious about claiming that exercise, fasting or particular supplements reliably increase circulating Humanin in humans until we have stronger clinical evidence. Although I did come across one study that supported exercise.

The broader strategies remain worthwhile regardless:

• Exercise

• Maintaining insulin sensitivity

• Maintaining muscle mass

• Avoiding chronic metabolic dysfunction

• Supporting cardiovascular health

• Maintaining mitochondrial fitness

Whether part of their benefit ultimately turns out to involve Humanin remains an intriguing research question.

What About Taking Humanin?

Synthetic Humanin and Humanin analogs are available through some peptide and research-compound sources.

But this is where enthusiasm needs to be separated from evidence.

Humanin is not an FDA-approved anti-aging or Alzheimer’s therapy. And while I’ve personally used some peptides that aren’t FDA approved for human use, it’s a very calculated risk I take in light of my APOE4/4 status and age. I’m NOT suggesting or advocating anyone else do that. I write this post for educational purposes only.

Most of the exciting intervention data come from cells and animals. We do not have robust human clinical trials establishing an appropriate dose, route, long-term safety profile or evidence that administering Humanin prevents cognitive decline.

Something can be biologically fascinating without yet being clinically proven. And since there’s no a big windfall for any pharma company to pursue commercially - any extensive research is unlikely.

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My Takeaway

Humanin is only 24 amino acids long.

Yet this tiny mitochondrial peptide appears experimentally connected to:

mitochondrial resilience
insulin sensitivity
inflammatory signaling
astrocyte activation
neuronal survival
amyloid toxicity and clearance
APOE4 resilience
longevity

That is an extraordinary amount of biology packed into a very small peptide.

But for those of us interested in APOE4 and prevention, Humanin is absolutely a molecule worth knowing about - and watching as the research evolves and develops.

References:

https://pubmed.ncbi.nlm.nih.gov/23277413/

https://pmc.ncbi.nlm.nih.gov/articles/PMC7343442/

Is Alzheimer’s pathology actually developing in my brain and if so, how much time do I have before it affects my cognition - and - more importantly - is there anything else I can do about it (considering my already extensive prevention protocol).

Until very recently, we haven’t had a good way to answer that question.

Now a simple blood biomarker called p-tau217 has changed the conversation.

We’ve already learned that p-tau217 can identify Alzheimer’s pathology with remarkable accuracy.

But research published in JAMA in July 2026 suggests something much more consequential:

p-tau217 may help predict the likelihood that a cognitively healthy person will develop cognitive impairment years into the future.

And that raises an important question: If p-tau217 can predict our future, can we actually still change it?

Increasingly, the answer appears to be yes.

What Exactly Is p-Tau217?

Tau is a protein found primarily inside neurons, where one of its normal jobs is helping stabilize the cellular structures called microtubules.

In Alzheimer’s disease, tau becomes abnormally phosphorylated.

One particular form - tau phosphorylated at amino acid 217, or p-tau217 - levels rise in the blood in association with Alzheimer’s pathology, particularly amyloid accumulation.

Importantly, p-tau217 can begin increasing years before someone develops noticeable cognitive symptoms.

That makes it very different from a cognitive test.

A cognitive test asks:

How well is my brain functioning today?

p-Tau217 potentially asks:

Is the Alzheimer’s disease process already underway?

And now researchers are asking whether it can tell us something about where that process is headed.

Nearly 2,700 Cognitively Healthy People

The new study pooled data from 2,684 cognitively unimpaired older adults enrolled in six longitudinal studies in North America, Australia and Japan.

Their median age was about 70.

Researchers measured baseline plasma p-tau217 and then followed participants for a median of 5.4 years, with some followed for as long as 13.5 years.

During that time, 478 participants progressed to cognitive impairment.

The relationship with p-tau217 was striking.

For every one-standard-deviation increase in p-tau217, the risk of progressing to cognitive impairment increased by approximately 38%.

To explain Standard Deviation:

• Average p-tau217 = 0.20 pg/mL

• Standard deviation = 0.10 pg/mL

• Someone at 0.20 is around the average.

• Someone at 0.30 is 1 SD above the average.

• Someone at 0.40 is 2 SD above the average.

But the absolute numbers are even more interesting.

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What Happened Over Five Years?

Researchers divided participants into four p-tau217 categories.

Their estimated five-year risks of developing cognitive impairment were:

Low p-tau217: 12%

Intermediate: 15%

High: 24%

Very high: 38%

At ten years the modeled estimates became:

Low: 40%

Intermediate: 45%

High: 62%

Very high: 78%

That last number certainly gets your attention.

Someone in the very-high p-tau217 category had an estimated 78% probability of developing cognitive impairment within ten years.

There is an important caveat: only about 5% of participants had more than ten years of follow-up, so the researchers specifically caution that the ten-year estimates are considerably less certain than the five-year numbers.

Still, this represents an extraordinary change in what an Alzheimer’s blood test might eventually be able to tell us.

It Predicted Cognitive Decline Even Beyond Amyloid

One finding I found particularly interesting was that p-tau217 wasn’t simply acting as a cheap substitute for an amyloid PET scan.

The researchers adjusted their analysis for amyloid PET burden.

p-tau217 still independently predicted progression to cognitive impairment.

Higher p-tau217 was also associated with faster decline on longitudinal cognitive testing.

In other words, this blood marker appears to contain information about disease trajectory that isn’t captured simply by knowing how much amyloid someone has.

That makes p-tau217 potentially much more than a diagnostic test.

It could become a prognostic biomarker.

There’s Now an Alzheimer’s “Clock,” Too

Another 2026 study took this concept even further.

Researchers at Washington University followed more than 600 older adults with serial blood measurements and developed a model based on the age at which p-tau217 becomes abnormal.

They found that this could help estimate when Alzheimer’s symptoms were likely to begin.

The predicted onset was generally within approximately three to four years of the actual age of symptom onset.

We’re clearly not at the point where your doctor can look at your blood test and say:

“You will develop Alzheimer’s at age 78.”

But we’re moving remarkably closer to something that would have sounded like science fiction not very long ago.

But Here’s Where This Gets Really Interesting

A biomarker that predicts disease is useful.

A biomarker that predicts disease and can be changed could be transformative.

And we already have evidence that p-tau217 isn’t simply a fixed number marching inevitably upward.

Treatments can move it.

That distinction is enormously important.

Our APOE genotype is fixed. Our age is certainly fixed! But p-tau217 is a dynamic biomarker.

And one of the most surprising demonstrations of that has come from a drug that wasn’t originally developed as an Alzheimer’s drug at all.

Enter Obicetrapib

Obicetrapib is a CETP inhibitor (written about last week) developed primarily to treat cardiovascular disease by dramatically changing lipoprotein metabolism.

But investigators analyzing Alzheimer’s biomarkers in the Phase 3 BROADWAY cardiovascular trial found something unexpected.

The effect appeared particularly pronounced among APOE4 carriers.

In the APOE4/4 subgroup, p-tau217 fell approximately 7.8% over 12 months in participants receiving obicetrapib while increasing approximately 12.7% in the placebo group.

That produced a placebo-adjusted difference of approximately:

20.5%

And p-tau217 wasn’t the only Alzheimer’s-related biomarker moving in a favorable direction.

Changes were also reported in Aβ42/40, the p-tau217/Aβ ratio, GFAP and NfL.

That doesn’t prove Obicetrapib prevents Alzheimer’s.

It doesn’t prove that reducing p-tau217 by 20% reduces dementia risk by 20%.

And the APOE4/4 subgroup was small. But it does prove something extremely important for how we think about this biomarker:

p-tau217 can change.

So Here’s the Billion-Dollar Question

Put these two discoveries together.

The new JAMA study tells us:

Higher p-tau217 → substantially greater future risk of cognitive impairment.

The Obicetrapib data tell us:

An intervention can lower or stabilize p-tau217.

Which leads to the question that Alzheimer’s prevention research now urgently needs to answer:

If we lower p-tau217 early enough, do we lower the person’s future risk of cognitive decline?

We don’t know yet.

But that is an entirely different question from the one Alzheimer’s researchers were asking even a few years ago.

Neurology Is Starting to Look Like Cardiology

Cardiology doesn’t wait until someone has a heart attack before worrying about cardiovascular disease.

We measure LDL.

We measure ApoB.

We measure blood pressure.

We measure coronary calcium.

Then we identify risk and attempt to change the trajectory before the clinical event occurs.

Imagine doing something similar with Alzheimer’s disease!

At some point we may routinely measure:

APOE genotype → underlying genetic risk

Aβ42/40 → amyloid biology

p-tau217 → Alzheimer’s disease activity and trajectory

GFAP → astrocyte activation

NfL → neuronal injury

And instead of waiting for someone’s memory to fail, we may intervene while that person is still completely cognitively normal.

Then we measure again.

Did p-tau217 rise?

Did it stabilize?

Did it fall?

That would represent a fundamental change in Alzheimer’s medicine.

One Test Probably Won’t Be Enough

This also changes how I think about having a p-tau217 test performed.

A single measurement is useful.

But a baseline and capturing this marker over the years offers much more insight.

Suppose someone has p-tau217 measured at age 65, again at 66 and again at 67.

There are three very different possibilities:

0.12 → 0.12 → 0.11

versus

0.12 → 0.18 → 0.27

versus

0.27 → 0.22 → 0.17 following an intervention

The starting number / baseline is important to know. And the direction over time will likely matter just as much.

We don’t yet have validated clinical rules allowing us to interpret those trajectories that simply. Different p-tau217 assays also produce different numerical values, so numbers cannot necessarily be compared across laboratories.

But longitudinal monitoring is where I suspect these biomarkers are ultimately heading.

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What This Means for APOE4 Carriers

For APOE4 carriers, I think this development is particularly significant.

Knowing that we carry APOE4 tells us that our lifetime probability of developing Alzheimer’s is elevated.

It does not tell us whether Alzheimer’s pathology is developing in our brain today.

That’s an enormous distinction.

A 55-year-old APOE4 carrier with normal Alzheimer’s biomarkers is in a fundamentally different biological situation from a 55-year-old APOE4 carrier whose p-tau217 is already rising.

Genetics tells us about risk.

Biomarkers may increasingly tell us about disease activity.

And perhaps, eventually, repeated biomarkers will tell us whether our prevention strategies are actually working.

We’re Not Quite There Yet

I don’t want to get ahead of the science.

The new p-tau217 risk estimates apply to populations, not with certainty to individuals.

The ten-year numbers are based on relatively sparse long-term follow-up.

We don’t yet have universally standardized thresholds across all p-tau217 assays.

And most importantly:

We have not yet proven that lowering plasma p-tau217 in an asymptomatic person prevents Alzheimer’s dementia.

That’s the missing piece.

For most of my life, Alzheimer’s disease has been diagnosed by what it eventually did to someone’s memory.

Now we can increasingly see its biology in a vial of blood years before that happens.

And perhaps the most encouraging development of all is that the number in that vial isn’t necessarily written in stone.

We can measure p-tau217.

It can predict future cognitive risk.

We’ve demonstrated that it can change.

Now we need to find out whether changing it can change our future.

For those of us carrying APOE4, I can’t think of many more important questions for Alzheimer’s prevention research to answer.

In simple terms, most of us think of cholesterol being either good or bad. While we have focused on LDL as the bad guy and HDL as the good guy, less attention has been paid to their dance with each other.

Cholesterol is constantly being transported between tissues, cells, and organs and the efficiency of that movement is likely more important than the lipoprotein on its own.

Think of:

• HDL as the recycling truck

• LDL as the delivery truck

• CETP as the traffic controller deciding where cholesterol moves next

CETP’s job is to exchange:

• cholesterol esters from HDL

• triglycerides from LDL and VLDL

Every second of every day.

Why CETP Exists

This is the fascinating evolutionary question.

Researchers believe CETP probably evolved because:

• humans often faced starvation

• dietary fat availability fluctuated

• rapidly redistributing cholesterol may have improved survival

• it likely supported steroid hormone production and immune responses during infection

So, in effect :

CETP was designed to keep people alive in times of scarcity of food - much like APOE, it isn’t nearly as important in a modern man’s lifelong exposure to food access on demand and abundant calories!

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The Two prominent CETP Variants to know - especially as an APOE4 carrier

rs708272

Genotype: B1/B1 (G/G)

• more CETP

• lower HDL

Genotype B2 carriers (A/A or A/G)

• less CETP

• higher HDL

rs3764261

Probably the most important HDL SNP.

The A (T) allele has:

• lower CETP expression

• higher HDL

• lower CAD risk in many studies

The C (G) allele

• higher CETP

• lower HDL

Why More CETP Usually Looks Bad

Higher CETP generally means:

Lower HDL

Less efficient reverse cholesterol transport

Higher ApoB particles

Higher LDL cholesterol

Higher inflammation

Higher cardiovascular disease risk

What does APOE have to do with CETP?

ApoE transports cholesterol inside the brain.

APOE4 already transports cholesterol less efficiently.

Now imagine adding:

High CETP activity driving less functional HDL, less cholesterol recycling and less neuronal repair - potentially leading to higher dementia risk.

What Human Genetics Tells Us

One of the most compelling pieces of evidence:

People born with CETP variants that reduce CETP activity generally have:

• HDL 10–25% higher

• lower cardiovascular disease risk

• often longer lifespan

• no major syndrome from lifelong partial CETP inhibition

Nature has already shown that lower CETP levels are not detrimental. While I carry the “normal CETP” level gene variants, my mother - who attained the age of almost 96 with no cognitive shortfalls until her early 90s, was heterozygous on both genes referenced above.

CETP Inhibitor Drugs: A Rocky History

Torcetrapib failed - not because CETP inhibition itself was ineffective, but because the drugs had undesirable side effects (including raising blood pressure and aldosterone).

Other proposed drugs stumbled for different reasons:

• dalcetrapib: modest efficacy

• evacetrapib: trial stopped early

• anacetrapib: effective but not pursued because of extremely long tissue retention

The lesson wasn’t that CETP is a bad target. It was that finding the right drug proved difficult.

A Shining Star On The Horizon: Why Obicetrapib Is Different

Here’s where the excitement builds.

Obicetrapib produces approximately:

• LDL reduction of ~45%

• ApoB reduction of +/- 20%

• HDL increase of ~150%

• Lp(a) reduction of up to 45%

It appears more potent than earlier CETP inhibitors and, so far, has shown a favorable safety profile in clinical trials. It is well-tolerated with no side effects that stand out compared to the placebo group.

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Why This Matters For Those Of Us Carrying APOE4

• APOE4 impairs lipid transport in the brain.

• CETP influences HDL remodeling and reverse cholesterol transport.

• Reduced CETP activity may improve the availability of cholesterol needed for neuronal repair.

• Obicetrapib is one of the first therapies capable of dramatically modifying this pathway.

That biological rationale is why it’s attracting a lot of interest as a potential disease-modifying strategy for APOE4 carriers. And, considering it saw a 20% reduction in ptau217 levels in APOE4 carriers, it’s definitely one that gets my attention!

After spending hundreds of hours reviewing the literature on APOE4, CETP, Lipid biology, statins, and now Obicetrapib, I've reached a conclusion that has fundamentally changed how I think about Alzheimer's prevention.

APOE is, first and foremost, a cholesterol transport protein. Increasingly, the genetics, the basic science, and now the emerging drug development all point in the same direction: impaired lipid transport and cholesterol handling are a common denominator.

That doesn’t mean cholesterol is the only mechanism driving Alzheimer’s risk in APOE4 carriers. Inflammation, vascular dysfunction, immune activation, mitochondrial health, and protein clearance all matter. But cholesterol metabolism increasingly looks like the hub from which many of these downstream effects arise.

I cannot say with certainty that lowering LDL-C, ApoB, or improving HDL function will prevent Alzheimer’s. No one can - not yet. But based on everything I’ve read, I would be far less comfortable ignoring elevated LDL as an APOE4 homozygote than I would have been five years ago. The evidence has shifted enough that, for me, the risk of doing nothing now seems too high.

My Thoughts

I’ve followed Alzheimer’s research for years, and few drugs have generated this level of interest for me. Obicetrapib isn’t exciting simply because it lowers LDL or Lp(a). It’s exciting because it targets a pathway that intersects with APOE biology, cholesterol transport, and brain health. We don’t yet know whether it will prevent Alzheimer’s - but it’s one of the most biologically plausible approaches currently being tested - and I’m super excited!

Interesting related links:

The emerging role of CETP inhibition in the prevention of Alzheimer’s disease

Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia

AI Disclosure: I use AI to help explain complex medical and scientific concepts, edit my writing, and reduce the time it takes to produce these free articles. That said, AI is only as good as the prompts and context it's given, so my queries are laser-focused, detail oriented and posed through the lens of APOE4. I cross-check important information across three different AI platforms, and verify it against the published literature to insure accuracy. Used well, it's an extraordinary research tool. Used poorly, it can be superficial, verbose, and a waste of time

During an expedition in the 1960’s to the remote, volcanic island in the Pacific Ocean we call Easter Island (locally named Rapa Nui), this complex, organic molecule produced by a bacterium - Streptomyces hygroscopicus - was collected in soil samples. In the early 1970’s researchers isolated a compound from the sample that could stop immune cells and cancer cells from dividing and appropriately named it after its origin. It took another two decades to discover the exact target this molecule, rapamycin, was binding to - and to identify the responsible genes controlling cell growth, division and metabolism in response to nutrients. More detail on the fascinating discovery of Target of Rapamycin (TOR) can be found here.

This post is a deeper dive on the topic, written for physicians, researchers, and scientifically oriented readers, as well as for APOE4 carriers who are considering a rapamycin protocol and are seeking a clear, mechanistic framework to discuss this option with their physician or primary care provider.

In 2021, I had the opportunity to meet the late Dr. Alan Green of Little Neck, New York, who was widely regarded as the pioneer of off-label rapamycin use for Alzheimer disease prevention in APOE4 carriers.

Dr. Green’s practice included more than 700 APOE4 carriers, a group he often described as one of the most neglected patient populations in medicine. He emphasized that among the APOE4 carriers he followed preventively, with the explicit goal of attenuating gene expression and reducing future cognitive risk, he had not observed progression to cognitive impairment in any of his patients during longitudinal follow-up. His full writings on rapamycin, APOE4 and the prevention of AD can be found here.

APOE4 is a lipid- and vascular stress gene

APOE4 is most often discussed in the context of amyloid, cholesterol, or statistical Alzheimer’s risk. Increasingly, however, a different picture has emerged: APOE4 creates an intrinsic vulnerability of the neurovascular unit, long before plaques or cognitive symptoms appear.

One of the clearest mechanistic explanations for this vulnerability centers on blood–brain barrier (BBB) integrity, and specifically, an APOE4-specific inflammatory signaling cascade that does not occur in APOE2 or APOE3 carriers.

The APOE4-specific pathway: Cyclophilin A, MMP-9, and BBB breakdown

As Dr. Green explained to me, in APOE4 carriers - and only in APOE4 carriers - APOE interacts abnormally with vascular pericytes, triggering activation of Cyclophilin A (CypA), a stress-responsive signaling protein.

CypA activation initiates a downstream inflammatory cascade:

• ApoE4 activates CypA in pericytes

• CypA activates NF-κB and matrix metalloproteinase-9 (MMP-9)

• MMP-9 degrades tight junction proteins and basement membrane

• Blood–brain barrier integrity is compromised

This BBB breakdown occurs early, often decades before clinical Alzheimer’s disease, and is independent of amyloid-β accumulation.

Reference: https://pmc.ncbi.nlm.nih.gov/articles/PMC4047116/

How BBB integrity determines whether APOE4 becomes pathogenic

A crucial implication of the CypA–MMP-9 pathway is that APOE4 pathology appears to be conditional, not inevitable.

When the blood–brain barrier remains intact, APOE4 operates in a relatively protected biochemical environment:

• Peripheral ApoB-containing lipoproteins are excluded from the CNS

• Oxidized lipids and systemic inflammatory mediators are largely kept out

• Astrocytes traffic predominantly endogenous, relatively low-toxicity lipids

• Microglia remain in a homeostatic surveillance state

Under these conditions, APOE4’s intrinsic disadvantages (reduced lipid-binding stability, altered receptor interactions) are buffered rather than amplified. This helps explain why many APOE4 carriers remain cognitively normal for decades, and why enhanced Klotho signaling or early-life interventions can markedly attenuate risk.

BBB failure fundamentally changes this equation.

Once the barrier is compromised, the brain is exposed to a qualitatively different lipid environment:

• Plasma-derived, often oxidized lipoproteins enter the CNS

• Astrocytes shift from lipid export to lipid droplet accumulation

• Microglia adopt lipid-laden, pro-inflammatory phenotypes

• APOE4 is repeatedly forced into inflammatory clearance roles

This transition converts a manageable lipid trafficking vulnerability into a chronic lipid overload and inflammatory amplification state - the condition under which APOE4 consistently performs worst.

Preserving BBB integrity therefore prevents the upstream event that transforms APOE4 from a fragile transport protein into a pathological amplifier.

Where rapamycin enters the picture

Rapamycin’s relevance in APOE4 is often misunderstood as being primarily related to longevity or generic autophagy enhancement. Dr. Green’s clinical rationale is much more specific.

By inhibiting mTORC1 signaling, rapamycin suppresses activation of Cyclophilin A, reduces MMP-9 activity, and preserves BBB integrity. In doing so, it prevents the entry of inflammatory and oxidized lipid species into the CNS, maintains a low-flux lipid environment, and likely spares APOE4 from repeated inflammatory activation.

In this framework, rapamycin is not treating Alzheimer’s pathology directly. It is preventing the upstream vascular event that precipitates lipid trafficking failure, neuroinflammation, and downstream neurodegeneration in genetically vulnerable brains.

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One of the consistent findings in aging brains is that mTOR signaling becomes chronically overactive.

When mTOR stays “on”:

• autophagy declines

• damaged mitochondria accumulate

• abnormal proteins aren’t cleared efficiently

• inflammation increases

• senescent cells persist

• neurons become metabolically stressed

Rapamycin partially reverses many of these changes and why it has become one of the most studied longevity drugs.

Closing perspective

The CypA–MMP-9–BBB pathway provides one of the clearest examples of an APOE4-specific, targetable mechanism that precedes amyloid, tau, and overt neurodegeneration. It also offers a unifying explanation for why lipid trafficking abnormalities, glial lipid accumulation, and inflammatory amplification emerge preferentially in APOE4 carriers.

Whether rapamycin ultimately becomes a mainstream preventive tool remains to be seen. But the biology underlying its use in APOE4 is coherent, mechanistically grounded, and consistent with emerging vascular–lipid models of Alzheimer’s disease risk. On a personal note, I’ve been using rapaymycin (once weekly) since 2021 and will continue do so, indefinitely. I’ve had no side effects and while my neutrophils were often slightly below normal ranges in the first years, they’ve meanwhile normalized completely.

References:
Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: Targeting brain metabolic and vascular restoration

mTOR: Alzheimer’s disease prevention for APOE4 carriers

Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers

mTOR inhibition enhances synaptic and mitochondrial function in Alzheimer’s disease in an APOE genotype-dependent manner

This post is for scientific discussion and educational purposes only and does not constitute medical advice. Rapamycin is an off-label medication with known risks and should only be used under qualified medical supervision.

AI Disclosure: I use AI to help explain complex medical and scientific concepts, edit my writing, and reduce the time it takes to produce these free articles. That said, AI is only as good as the prompts and context it's given, so my queries are laser-focused, detail oriented and posed through the lens of APOE4. I cross-check important information across three different AI platforms, and verify it against the published literature to insure accuracy. Used well, it's an extraordinary research tool. Used poorly, it can be superficial, verbose, and a waste of time

APOE2: cysteine/cysteine APOE3: cysteine/arginine APOE4: arginine/arginine

Changing that one amino acid changes how the protein folds, how it handles stress, and potentially how well the brain cleans house.

This raises an obvious question: if APOE4 carriers are missing cysteine in the protein itself, does taking NAC (a cysteine source) have a potential benefit?

Short answer: yes. Just not for the reason you’d think.

The Folding Problem

The mainstream explanation for APOE4’s Alzheimer’s risk centers on protein folding. Swap in arginine at position 112, and the protein’s internal architecture changes - what researchers call “domain interaction.” The downstream effects are a long list of neurodegeneration risk factors:

• Reduced cholesterol transport

• More inflammatory signaling

• Protein fragmentation

• Impaired synaptic repair

• Mitochondrial stress

• Slower amyloid clearance

• Greater vulnerability to tau

The Chemistry Cysteine Brings - and APOE4 Loses

Cysteine’s superpower is its reactive thiol group. That one feature lets it do things arginine simply can’t: sense redox shifts, buffer oxidative stress, form disulfide bonds, and feed the glutathione system.

So while folding gets most of the attention, the loss of redox flexibility that comes with losing cysteine may matter too.

Oxidized Lipids: The Brain’s Constant Low-Grade Fire

Reactive oxygen species (ROS) damage fats constantly - it’s a normal part of being alive. But the brain takes an outsized hit because it’s oxygen-hungry, mitochondria-dense, loaded with oxidation-prone fats like DHA, and slow to regenerate once damage piles up.

What drives the damage:

• Mitochondrial ROS leakage - normal at baseline, but rises with aging, insulin resistance, inflammation, poor sleep, and over-nutrition

• Polyunsaturated fat oxidation - DHA is essential and fragile; oxidized, it can damage proteins, DNA, mitochondria, and synapses

• Iron-driven Fenton chemistry - the engine behind ferroptosis, an iron-dependent lipid-membrane damage process increasingly tied to Alzheimer’s

• Hyperglycemia and insulin resistance - a likely reason APOE4 carriers seem especially sensitive to metabolic dysfunction

• Chronic inflammation - which generates its own ROS, feeding a loop: oxidized lipids → inflammation → more oxidized lipids

Maybe It’s Not the Damage - It’s the Cleanup

Here’s the reframe: everyone generates oxidized lipids. The real question is what happens after.

APOE4 may not produce more oxidative damage than APOE3. It may just be worse at responding to it - slower recognition, weaker trafficking, less effective membrane repair, and a shorter fuse for inflammatory amplification.

Damage isn’t the problem. Resilience is.

NAC - N-acetylcysteine

Enter NAC - N-acetylcysteine, a supplement form of the amino acid cysteine. The obvious candidate. But if APOE4 carriers are missing cysteine in the protein itself, does taking more of it even do anything?

Yes, but manage expectations. NAC can’t rebuild the missing cysteine inside the APOE4 protein - that sequence is fixed by our genes, full stop. We can’t supplement our way from APOE4 to APOE3.

What NAC can do is supply cysteine for glutathione synthesis - and glutathione is arguably the brain’s best defense against lipid peroxidation, mitochondrial damage, neuroinflammation, and ferroptosis.

Glutathione 101

Glutathione, the body’s master antioxidant, is built from three amino acids: cysteine, glycine, and glutamate. That’s why NAC + glycine (”GlyNAC”) has drawn serious research interest - early studies point to benefits for mitochondrial function, oxidative stress markers, insulin sensitivity, inflammation, and fatigue.

But the more interesting wrinkle is where that glutathione needs to end up.

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The Catch: Mitochondria Can’t Make Their Own Glutathione

Mitochondria don’t synthesize glutathione - they import it from the cytosol. And that import system can degrade with age and disease.

Which means boosting mitochondrial glutathione isn’t just “take more antioxidants.” It depends on synthesis, transport, membrane integrity, and overall mitochondrial fitness - a supply chain, not a single switch. This may be especially relevant for APOE4 carriers

Six Ways to Support Mitochondrial Glutathione

1. NAC + Glycine. Raw materials for glutathione production. Moderate dosing beats megadosing - the goal is resilience, not silencing oxidative signaling entirely.

2. Exercise. Possibly the single most powerful lever here. Counterintuitively, exercise raises ROS in the short term - but that mild stress triggers adaptation: NRF2 activation, more antioxidant enzymes, mitochondrial biogenesis, better glutathione recycling. Classic hormesis.

3. NRF2 activation. The master switch for antioxidant defense. Triggers include exercise, fasting, sulforaphane, sauna, and other mild hormetic stressors.

4. Selenium. Fuel for glutathione peroxidase enzymes - including GPX4, which specifically guards lipid membranes against ferroptosis. No selenium, no optimal glutathione function.

5. Mitochondrial membrane integrity. Damaged membranes impair glutathione transport. Plasmalogens, ketones, good sleep, exercise, and compounds like SS-31 (which targets cardiolipin, a phospholipid critical to mitochondrial membrane function) all play into this.

6. Melatonin. Likely underrated as more than a sleep hormone - it concentrates inside mitochondria and appears to support antioxidant defense and glutathione function directly. Some researchers now think mitochondrial protection may have been its original job. (Melatonin researcher, Doris Loh, shares a great video here about Melatonin’s role in mitochondrial function)

Hormesis: Why “More Antioxidants” Isn’t the Whole Answer

ROS aren’t just villains - they’re signals. Wipe out oxidative signaling entirely, and you may blunt the body’s ability to adapt. Exercise, fasting, sauna, and even HBOT likely work in part because of the mild stress they impose, not despite it.

The target isn’t zero oxidative stress. It’s controlled stress that builds resilience without spiraling into damage - a distinction that may matter more for APOE4 carriers than anyone else.

A Working Theory on APOE4

Here’s my current read: APOE4 looks like biology tuned for survival, immune vigilance, rapid lipid mobilization, infection-heavy environments, and scarcity - not for decades of caloric abundance, sedentary living, chronic metabolic stress, and long lifespans.

Drop that biology into a modern environment, and the cracks show up as oxidative membrane injury, mitochondrial dysfunction, ferroptosis, impaired repair, and inflammatory overdrive.

Which may explain why APOE4 carriers so often see outsized benefits from exercise, sleep, glucose control, fasting, mitochondrial support, and anti-inflammatory strategies.

The Bottom Line

This might not be a cholesterol story at all. It might be a story about how well the brain absorbs oxidative punishment over decades - and mitochondrial glutathione could be one of the biggest levers in that fight.

Alzheimer’s research is shifting away from plaques-only thinking and toward mitochondrial function, membrane biology, lipid oxidation, immune signaling, and metabolic flexibility.

APOE4 doesn’t guarantee disease. It just means the margin for error against modern metabolic stress is thinner. That’s exactly why mitochondrial resilience, redox balance, exercise, sleep, and metabolic flexibility matter so much - and why the real challenge isn’t piling on antioxidants, but supporting adaptation without flattening the very stress signals the body needs to build resilience in the first place.

Researchers tracked over 4,500 older adults for up to 15 years. They measured blood vitamin C levels before any sign of cognitive impairment, then watched what happened to Alzheimer’s-related mortality over the next decade and a half.

The result: people with the highest normal vitamin C levels had roughly 56% lower Alzheimer’s mortality than those at the bottom.

That’s not a rounding error. That’s a number that begs an explanation.

But Wait - More Isn’t Better

Here’s where the story gets genuinely interesting instead of just “take your vitamins.”

The relationship wasn’t a straight line. It was a sweet spot - serum vitamin C between roughly 0.8 and 1.1 mg/dL was tied to the lowest Alzheimer’s mortality.

And the twist nobody saw coming: the tiny sliver of participants (about 1%) with sky-high vitamin C - above 2.3 mg/dL - actually had higher Alzheimer’s mortality risk.

Why Does The Brain Care So Much?

Most of us file vitamin C under “immune support” and move on. The brain disagrees - violently.

The brain actively pumps vitamin C to concentrations many times higher than what’s circulating in our blood. That’s not an accident. That’s evolution spending serious metabolic capital on something it considers non-negotiable.

Inside our skulls, vitamin C is quietly running a full-scale defense operation:

• Neutralizing reactive oxygen species before they torch neurons

• Recycling vitamin E after it’s absorbed free-radical damage

• Powering mitochondrial function

• Synthesizing dopamine and norepinephrine

• Sealing the blood-brain barrier

• Building collagen in cerebral blood vessels

• Fighting the oxidative stress tied to amyloid and tau pathology

That’s not just a vitamin. That’s more like infrastructure.

What Happens When The Infrastructure Fails: Scurvy and the Brain

If you want proof of how deeply the brain depends on vitamin C, look at what happens in its total absence: scurvy.

We tend to picture scurvy as a sailor’s disease of bleeding gums and loose teeth. But long before those hemorrhagic signs show up, scurvy shows up in the brain. Case reports and clinical reviews describe an early, easy-to-miss cluster of neuropsychiatric symptoms — fatigue, malaise, low mood, irritability, and cognitive fog - that clinicians often overlook precisely because they’re so nonspecific. Left untreated, more severe cases have progressed to confusion, delusions, neuropathy, and even seizures, in some cases linked to small brain hemorrhages.

The mechanism tracks with everything above: without vitamin C, neurotransmitter synthesis falters, antioxidant defenses drop, and carnitine production (which the brain leans on for energy metabolism and mood regulation) is impaired. The encouraging part is that these neuropsychiatric symptoms of scurvy tend to resolve quickly - often within days - once vitamin C is restored.

The takeaway isn’t “you might get scurvy.” Scurvy is rare today. It’s that the brain is apparently the canary in the coal mine for vitamin C status - mood and cognition falter early, well before the classic physical signs most people associate with deficiency. That’s consistent with the idea that even mild, sub-scurvy shortfalls could be quietly taxing brain function over years, long before anyone would think to check.

The APOE4 Wrinkle

If you carry APOE4, pay closer attention here.

APOE4 brains run hotter - more oxidative stress, more neuroinflammation, earlier mitochondrial breakdown, more lipid oxidation, and weaker repair mechanisms.

Vitamin C fights on nearly every one of those fronts.

To be clear: vitamin C doesn’t “fix” APOE4. Nothing does. But if you’re already starting from a higher-stress baseline, staying on the wrong side of that vitamin C sweet spot may cost you more than it would someone without the variant.

A Second APOE4 Wrinkle: Lp(a)

There’s another thread worth pulling, and it connects vitamin C, arterial health, and APOE4 in a way that doesn’t get much attention.

APOE4 carriers proportionately tend to carry higher levels of lipoprotein(a), or Lp(a) — a sticky, cholesterol-carrying particle that’s largely genetically determined and, unlike LDL, isn’t lowered by statins. Multiple studies comparing APOE genotypes have found that E4 carriers show higher Lp(a) alongside a more pro-inflammatory lipid profile than E3/E3 carriers, and some case-control research has linked elevated Lp(a) specifically to higher Alzheimer’s risk in APOE4 carriers (though the picture across studies isn’t fully consistent).

Here’s where vitamin C re-enters the picture. Decades ago, Linus Pauling and Dr. Matthias Rath proposed a controversial idea: that Lp(a) acts as an evolutionary stand-in for vitamin C. Species that lost the ability to synthesize their own ascorbate - humans included - tend to be exactly the species that produce Lp(a). Their theory held that when vitamin C runs low, collagen synthesis in artery walls falters, tiny lesions form, and Lp(a) gets dispatched to “patch” the damage - but in doing so, it also seeds plaque buildup. Animal studies in vitamin-C-deficient guinea pigs (bred, like humans, to be unable to make their own vitamin C) showed exactly this pattern: arterial lesions and Lp(a) deposits appeared under deficiency and diminished when vitamin C intake was raised substantially.

It’s important to be honest about where this stands scientifically: this remains a minority, largely unproven hypothesis. It’s never been validated in a large randomized controlled trial in humans, and mainstream cardiology has not adopted Pauling’s high-dose vitamin C/lysine protocol as an Lp(a) treatment. What has held up is more modest - Lp(a) itself is now a well-established, independent cardiovascular risk factor, and a smaller body of human research has explored whether vitamin C supplementation can meaningfully lower Lp(a) or the vascular inflammation associated with it, with mixed but not dismissible results.

Put together, though, the logic is at least plausible enough to take seriously: if APOE4 carriers are already running higher Lp(a), and adequate vitamin C may help limit the arterial micro-damage that Lp(a) responds to, then vitamin C adequacy could be doing double duty for this group - one line of defense for the brain directly, another for the vascular health that brain health depends on so heavily.

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This Isn’t a One-Off Fluke

Skeptical? Good - so was I. But this study doesn’t stand alone:

• A 2022 meta-analysis spanning twelve studies found Alzheimer’s patients consistently run lower circulating vitamin C than healthy controls.

• Another prospective study linked higher serum vitamin C to lower Alzheimer’s mortality in older Americans.

• Animal studies show vitamin C deficiency accelerates amyloid pathology and cognitive decline - while adequate levels appear protective.

Correlation isn’t causation. But when the same signal keeps showing up across different populations, different methods, and different species, it stops being noise.

So Should You Start Megadosing?

Tempting. Probably wrong.

The most protective range in this study wasn’t extreme - it was normal, physiological adequacy. Once your tissues are saturated, your kidneys just flush the excess. There’s no evidence more is better, and this study hints the opposite might be true at the extremes.

The goal isn’t heroic doses. It’s simply not being deficient.

And here’s the uncomfortable truth about longevity science: we love chasing exotic, pharmacologic-dose interventions while walking right past basic nutritional gaps that are quietly sabotaging the very systems we’re trying to optimize.

Getting There Through Food

Ideally, food does the heavy lifting, with supplements filling real gaps. Foods high in Vitamin C include:

• Red bell peppers

• Kiwi

• Strawberries

• Citrus fruit

• Broccoli

• Brussels sprouts

Here’s the catch: many people - especially older adults - eat far less fresh produce than they think they do. And stress, illness, smoking, inflammation, and certain medications all raise your vitamin C requirements, quietly widening the gap.

In Summary

Vitamin C isn’t sexy. It’s not patented, nobody’s launching a startup around it, and it will never headline a biohacking conference.

And yet it keeps showing up, study after study, in the brain-aging literature - and in the arterial-health literature, and in centuries-old accounts of what happens when it disappears from the diet entirely.

While it won’t single-handedly prevent Alzheimer’s, could closing this simple gap be one more small edge that compounds silently over decades?

The real lesson here isn’t that vitamin C is a miracle. It’s that our brains - and, it turns out, our arteries - may care less about the next breakthrough and more about whether we’ve nailed the fundamentals first.

Last week, I traveled to Boca Raton, Florida, for a comprehensive Alzheimer’s prevention evaluation. The program was engineered under the guidance of Dr. Richard Isaacson, one of the pioneers of preventive neurology and founder of one of the first Alzheimer’s Prevention Clinics in the United States while at Weill Cornell Medicine.

Many of you will also be interested to know that Dr. Isaacson has led the NIH-funded Retain Your Brain initiative, a free online brain health assessment designed to help people identify modifiable Alzheimer’s risk factors and receive personalized recommendations. If you’re looking for a place to begin assessing your own risk, I highly recommend taking a look at RetainYourBrain.com. The program is part of an NIH-funded effort to make evidence-based brain health guidance available to far more people than could ever be seen in specialty clinics.

The site is loaded with comprehensive information that is a “must” for anyone serious about AD prevention!

Why I Went

Being an APOE4/4 carrier means I have one of the highest known genetic risks for developing Alzheimer’s disease.

At 73, I’m already beyond the average age at which symptoms begin in many APOE4 homozygote studies. While genetics are certainly not destiny, I wanted to know whether the lifestyle changes I’ve been making over the past several years are reflected in today’s most advanced biomarkers.

I’ve spent years focusing on nutrition, exercise, sleep, metabolic health, hormone optimization, inflammation, and careful tracking of laboratory values.

Eventually, however, the question becomes:

Is what I’m doing actually making a difference?

That was my motivation for making the trip.

What the Evaluation Included

The initial visit included:

● Going over my medical history

● Body composition analysis using an InBody 970

● Grip strength testing

● An extensive blood draw

● A tour of the research laboratory

● A scheduled one-hour follow-up consultation once all laboratory results are available

● One year of blood sample storage in a deep freezer (in case their lab develops new tests in the future, we can go ‘back in time’ to test my samples later and track changes over time)

●some genetic variant testing, including a-Klotho

The Blood Biomarkers

One of the most exciting aspects of the evaluation is that it includes several of the new blood biomarkers that are transforming early detection of Alzheimer’s-related brain changes in the brain.

P-tau

Phosphorylated tau (typically measured as p-tau217 or p-tau181) is currently considered one of the most promising blood biomarkers for Alzheimer’s disease.

Tau is a normal protein found inside nerve cells. In Alzheimer’s disease, abnormal chemical changes cause tau to become phosphorylated, making it more likely to form the tangles that are one of the disease’s defining features.

Elevated p-tau doesn’t diagnose Alzheimer’s by itself, but it may indicate that Alzheimer’s-related changes are occurring in the brain - often years before symptoms develop.

GFAP

GFAP (Glial Fibrillary Acidic Protein) reflects activation of astrocytes, the brain’s support cells.

Researchers have found that GFAP may become elevated very early in the Alzheimer’s process, making it a useful marker for detecting early brain changes.

NfL

Neurofilament Light Chain (NfL) is a marker of neuronal injury.

Unlike p-tau, it isn’t specific to Alzheimer’s disease. It can increase in several neurological conditions. However, when interpreted alongside p-tau, GFAP, cognitive testing, imaging, and clinical history, it helps build a more complete picture of brain health.

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ApoE4 protein Expression Test

One of the surprising new blood tests that I learned about was a new APOE4 protein expression test, and another related APOE blood test, to measure overall APOE function in real-time. Genes are only one part of a person’s risk equation and don’t change over time, but the amount of protein made (or expressed) by a gene can fluctuate. Using a car analogy, the APOE4 genetic variant is like a car engine (that you can’t readily change) but a protein test like this is like an engine light that may go on or off depending on how the car is running. Put in high quality fuel (e.g., nutrition) and perform routine maintenance (e.g., medical care), and the car runs in peak performance. Otherwise, if lifestyle and other medical risk factors are not optimized, it is theorized that more APOE4 protein would be produced, fast-forwarding amyloid accumulation, and the engine warning light may turn “on” - signaling a potential problem in the future.

More Than Just Blood Tests

One aspect I particularly appreciated was that this wasn’t simply a laboratory evaluation.

The team also measured body composition with an InBody scan and tested grip strength.

Those may seem unrelated to Alzheimer’s at first glance, but maintaining muscle mass, preserving strength, and minimizing visceral fat are increasingly recognized as important components of healthy brain aging.

Readers of this newsletter know I’ve become a firm believer in measuring what matters.

A Look Behind the Scenes

After my blood draw, I was given a tour of the laboratory.

It was fascinating to see where much of this work actually happens.

I was especially impressed by the number of Alamar Biosciences ultra-sensitive detection platforms in the laboratory. These research-grade instruments are capable of measuring proteins present in extraordinarily small concentrations - exactly what’s required for today’s advanced Alzheimer’s blood biomarker testing.

I also consented to participate in a research study to one day be able to test my brain biomarkers from home with just a few drops of blood and a fingerprick card that the team is investigating. In fact, I was the 4th participant in this new phase of the study that aims to bring costs down and further expand access to preventive neurology care.

Seeing that level of technology under one roof reinforced my confidence that this is a serious research-driven program.

Now Comes the Waiting

The laboratory results take approximately one month.

Once they’re available, I’ll return for a one-hour consultation where we’ll review every result in detail and discuss what each marker means in the context of my risk profile. My recommendations will be personalized and based on my unique biology, biomarker results, health history, and individual risk profile, not my APOE4 genetics alone!

More importantly, if anything requires attention, we’ll develop a personalized action plan. To me, that’s where the real value lies.

A laboratory result without expert interpretation is simply a number.

Understanding what that number means - and whether it should change anything I’m doing - is what I’m really paying for!

Was It Worth It?

The tests/evaluation and follow-up consultation cost $3,000 (This is special early access pricing).

That certainly isn’t inexpensive.

However, considering the depth of testing, the expertise involved, the advanced biomarkers being measured, and the dedicated one-hour follow-up consultation, I felt it was a reasonable investment for someone with my genetic risk profile.

Interested in Learning More?

If you’re curious about the comprehensive Alzheimer’s prevention assessment I underwent, additional information is available at RetainMed, or reach out to them at info@retainmed.com

And if you’re simply looking for a free place to begin understanding your own brain health risk factors, I encourage you to explore RetainYourBrain.com.

Looking Forward

When my laboratory results are complete and I’ve met with the clinical team, I’ll write a follow-up article sharing what my biomarkers showed, what they mean, and- most importantly- what changes, if any, I’m planning to make.

Most people still associate creatine with muscle and gym performance.

That’s not why I take it.

For me - and especially as an APOE4 (4/4) -t his is about brain energy, stability, and long-term resilience.

We know that APOE4 is linked to:
• impaired glucose utilization in the brain
• early mitochondrial inefficiency
• increased vulnerability to metabolic stress

And importantly - this starts decades before any clinical symptoms.

So the question becomes:

How do we support the brain’s energy system before it struggles?

Creatine is one of the most straightforward answers.

It helps regenerate ATP - the immediate energy currency our cells depend on - and acts as a kind of energy reserve system, especially in high-demand tissues like the brain.

In simple terms:

When energy demand spikes or when energy delivery isn’t optimal, Creatine helps bridge that gap. That’s highly relevant for APOE4.

There’s also evidence suggesting creatine may:
• support mitochondrial function
• reduce oxidative stress
• improve cognitive performance under fatigue or stress
• provide neuroprotective effects in aging populations

A couple of studies worth looking at if you want to go deeper:

• “Creatine Supplementation Improves Brain Performance”
• “Effects of Creatine on Brain Energy Metabolism and Cognitive Function”

(There are many more, but these are a good starting point.)

How I incorporate it

I keep this very simple.

• 5-10 grams daily
• mixed into water or yogurt
• no cycling, no loading phase

It’s tasteless, easy, and requires zero effort to maintain consistency.

Why it’s in my stack

Because this isn’t about chasing performance.

It’s about:
• stabilizing brain energy
• supporting mitochondrial function
• reducing vulnerability over time

Creatine is one of those rare additions that is:
✔ well studied
✔ inexpensive
✔ easy to take
✔ and mechanistically aligned with APOE4 risk

If APOE4 is a lifelong exercise in managing energy and resilience,
then supporting ATP availability is not optional - it’s foundational.

https://pmc.ncbi.nlm.nih.gov/articles/PMC12089086/

https://www.tandfonline.com/doi/full/10.1080/19390211.2026.2616440#d1e1036

While it is not a miracle cure and certainly not a substitute for exercise, sleep, or good nutrition, spermidine may support one of the body’s most important anti-aging mechanisms: cellular housekeeping.

What Is Spermidine?

Spermidine is a naturally occurring polyamine found in all living cells. It is present in foods such as wheat germ, mushrooms, soybeans, aged cheese, and certain fermented foods. Our bodies also produce spermidine, although levels tend to decline with age.

The name may sound unusual, but spermidine has nothing to do with reproductive health in the way many assume. It was originally isolated from semen, where it was found in high concentrations, but it is now recognized as a critical molecule involved in cellular maintenance throughout the body.

Why Are Researchers Interested in Spermidine?

The primary reason is its ability to stimulate autophagy.

Autophagy literally means “self-eating.” It is the process by which cells identify damaged proteins, dysfunctional mitochondria, and cellular debris and recycle them into useful components.

Think of autophagy as the body’s internal housekeeping service.

When autophagy functions well:

• Damaged proteins are removed.

• Dysfunctional mitochondria are cleared.

• Cellular energy production improves.

• Inflammation may decrease.

• Cells remain healthier and more resilient.

As we age, autophagy becomes less efficient. Many researchers believe this decline contributes to aging and the development of age-related diseases.

Spermidine and Longevity

One of the most intriguing findings in longevity research is that spermidine consistently extends lifespan in multiple animal models.

Studies have demonstrated benefits in yeast, worms, flies, and mice. While animal studies do not guarantee similar results in humans, it is notable that spermidine has produced positive findings across several different species.

Researchers believe these effects are largely driven by enhanced autophagy and improved mitochondrial function.

Spermidine and Brain Health

For APOE4 carriers, the brain may be where spermidine becomes especially interesting.

Alzheimer’s disease is increasingly viewed as a disorder involving:

• Impaired cellular cleanup

• Mitochondrial dysfunction

• Chronic neuroinflammation

• Accumulation of toxic proteins

Autophagy plays a role in all of these processes.

Experimental studies suggest that spermidine may:

• Improve neuronal resilience

• Support mitochondrial health

• Reduce inflammatory signaling

• Enhance removal of damaged cellular components

Spermedine’s mechanisms align remarkably well with many of the pathways that appear disrupted in APOE4 carriers.

The cPLA2 Connection

One area of growing interest is the inflammatory enzyme cPLA2 (cytosolic phospholipase A2).

Researchers (Dr. Hussein Yassine and his team at Keck/USC) have identified excessive cPLA2 activation as a potential driver of neuroinflammation, particularly in APOE4 carriers. Activation of this enzyme leads to the release of arachidonic acid and the production of inflammatory compounds that can damage synapses and neurons.

Spermidine appears to reduce some of the upstream conditions that contribute to cPLA2 activation, including:

• Oxidative stress

• Mitochondrial dysfunction

• Impaired autophagy

• Chronic inflammation

In simple terms, spermidine may help reduce the inflammatory environment that allows cPLA2 to become overactive.

How Does Spermidine Compare to Rapamycin?

This is a common question in longevity circles.

Both rapamycin and spermidine promote autophagy, but they do so through different mechanisms.

Rapamycin directly inhibits mTOR, a key nutrient-sensing pathway.

Spermidine appears to stimulate autophagy through alternative pathways and may complement rather than duplicate the effects of rapamycin.

Some longevity researchers view fasting, exercise, rapamycin, and spermidine as multiple tools working toward the same broad goal: improving cellular maintenance and resilience.

Food Sources vs. Supplements

Spermidine occurs naturally in many foods, including:

• Wheat germ

• Mushrooms

• Soy products

• Legumes

• Aged cheeses

• Fermented foods

However, achieving the levels used in some research studies through diet alone may be difficult.

As a result, supplemental spermidine has become increasingly popular among longevity enthusiasts.

Spermidine has been part of my daily stack for the last year.

Is More Better?

Not necessarily.

Unlike some nutrients where deficiency is clearly harmful, there is currently no evidence that extremely high doses of spermidine provide greater benefits.

Most commercial products provide between 1 and 10 mg daily.

At present, the goal should not be to maximize spermidine intake but rather to support healthy cellular function through a combination of diet, exercise, sleep, metabolic health, and other evidence-based interventions.

My Perspective

As an APOE4 homozygote spending a great deal of time interested in mechanisms related to brain aging, spermidine is one of the more interesting additions to a prevention-oriented toolkit.

The idea that we may be able to improve the brain’s ability to clear damaged cellular components, support mitochondrial function, and reduce inflammatory signaling aligns with much of what current Alzheimer’s research is revealing.

Spermidine may be one more piece of a larger strategy aimed at maintaining brain health for as long as possible.

As always, the goal is not merely to live longer. The goal is to remain physically, cognitively, and emotionally vibrant throughout those additional years.

If you're interested in my complete brain health and Alzheimer's risk-reduction protocol, I've consolidated it all at members.apoe44.org.

Spermidine Research Links:

https://pmc.ncbi.nlm.nih.gov/articles/PMC7185103/

https://pmc.ncbi.nlm.nih.gov/articles/PMC12153962/

https://www.sciencedirect.com/science/article/pii/S0014299924005120?via%3Dihub

“Where do I even start?”

And I get it.

When you carry the APOE4 gene, the stakes feel high. The urgency is very real.

When I learned I was APOE4/4, I started reading. Then I started testing and collecting data - lots of data.

Blood tests. Sleep scores. Glucose readings. Blood pressure. Medications. Supplements. Exercise logs. Cognitive assessments. Genetics. Wearable data.

I knew my latest numbers, but often couldn’t remember whether they were improving or worsening - and often, I wasn’t sure what was most urgent to address.

Sound familiar?

That’s where tracking comes in.

One of the most valuable lessons I’ve learned over the years is that health optimization isn’t about finding the newest supplement, peptide, or biohack.

It’s about measuring where we are today so we know what deserves our attention tomorrow.

Understanding the big picture can reveal opportunities for intervention long before disease develops - and not just Alzheimer’s.

What Doctors Measure - and What Actually Matters

An annual physical is a starting point, not a finish line. I know of people whose Homocysteine is 14, A1C is 5.6, or Free T3 is 2.3 who are told everything is "normal" despite ongoing symptoms or risk factors.

Standard bloodwork checks the basics: cholesterol, glucose, a few liver enzymes, and perhaps thyroid function. But for those of us focused on the prevention of cognitive decline and healthy aging, many of the most informative markers are rarely included on a routine lab order.

Markers like:

• ApoB - a far more accurate predictor of cardiovascular risk than LDL cholesterol alone

• hs-CRP and Homocysteine - markers linked to inflammation and cognitive decline

• Fasting Insulin - often one of the earliest signs of metabolic dysfunction

• Omega-3 Status - a modifiable marker with important implications for brain and cardiovascular health

• Free T3 and IGF-1 - hormones that influence energy, metabolism, cognition, and longevity

• Magnesium RBC - a more meaningful measure than standard serum magnesium

And that’s before we get to sleep quality, HRV, blood pressure trends, body composition, cognition, and exercise capacity.

The problem isn’t that this information is unavailable.

The problem is that it’s scattered on lab portals, doctor’s notes, PDFs, sticky notes and wearable apps. When I wanted to see whether my deep sleep was improving over time, I found myself scrolling through weeks of Oura data trying to piece together the trend.

There is rarely a single place where we can see it all together and understand what is actually happening with our health.

Why I’m Giving Away the Tracker

As my own collection of health data grew, I built a spreadsheet to organize it.

Then I improved and expanded it to share with those new to APOE4 and health tracking.

My original intention was to keep it as a members-only resource. But the more I worked on it, the more I realized that understanding our numbers is one of the most powerful things we can do for our future health.

So I’ve decided to make the E4Thrive Health Tracker available to everyone.

Free. No account or membership required.

Over the past eight years, I’ve spent thousands of dollars on testing, made plenty of mistakes, and learned which markers matter most. This is the tracker I wish I’d had from the beginning.

Get the Free Health Tracker

What’s Inside the E4Thrive Health Tracker?

The workbook includes dedicated panels for:

• Cardiovascular Health

• Inflammation & Immune Markers

• Metabolic Health

• Hormones & Thyroid Function

• Nutrients

• Sleep & Recovery

• Standard CBC & CMP Labs

• Brain Health & Cognitive Tracking

• Gut Health & Toxic Burden

• Medications & Supplements

• Personal Notes

At the center is a dashboard that automatically pulls the latest results from across the workbook and compares them to evidence-based optimal targets.

Instead of hunting through dozens of reports to find the last ApoB result, vitamin D level, or latest blood pressure reading, everything is visible in one place.

One screen.

One snapshot.

One organized view of your health.

Whether you’re APOE4-positive or simply interested in healthy aging, start tracking.

We don’t need perfect genetics (nobody has them!), the perfect supplement stack, or the perfect doctor.

We need a plan.

We need a baseline.

And we need a way to see whether the choices we’re making are moving us in the right direction.

We can’t manage what we don’t measure.

Know your numbers.

Start Today!

Get the Free Health Tracker

Rarely does anyone mention riboflavin (vitamin B2).

That may be a mistake.

Riboflavin plays a central role in energy production inside our mitochondria, the tiny power plants that generate energy for every cell in the body. Given that impaired brain energy metabolism is increasingly recognized as an early feature of Alzheimer’s disease, nutrients that support mitochondrial function deserve attention.

But riboflavin’s role doesn’t stop there.

Riboflavin and Homocysteine

Many APOE4 carriers pay close attention to homocysteine levels. Elevated homocysteine has been associated with cognitive decline, brain atrophy, cardiovascular disease, and increased dementia risk.

While folate, vitamin B12, and vitamin B6 receive most of the attention, riboflavin is also required for efficient homocysteine metabolism.

In fact, studies have shown that individuals carrying certain MTHFR variants may be particularly responsive to riboflavin status. Adequate riboflavin appears to help optimize the activity of the MTHFR enzyme, supporting normal methylation and homocysteine processing.

Mitochondria, Oxidative Stress, and Glutathione

Riboflavin is involved in:

• Mitochondrial energy production

• Antioxidant defense

• Glutathione recycling

• Fat metabolism

• Cellular detoxification

These are all systems that become increasingly important as we age.

Are We Getting Enough?

True riboflavin deficiency is uncommon in developed countries, but “not deficient” and “optimal” are usually not the same thing.

Factors that may increase requirements include:

• Aging

• Chronic illness

• Certain medications

• High metabolic demand

• Genetic differences affecting methylation pathways

Many multivitamins contain riboflavin, but amounts vary widely.

My Take

Riboflavin isn’t a magic bullet, and I don’t think anyone should expect dramatic cognitive benefits from a single nutrient.

However, when I look at Alzheimer’s prevention through the lens of supporting brain energy metabolism, methylation, antioxidant defenses, and vascular health, riboflavin appears to get less attention than it deserves.

Sometimes the most important interventions are not the newest or most exciting. They’re the ones that help the machinery run properly in the first place. My riboflavin intake, besides that found in food, is in my daily Multivitamin and a methyl B Complex capsule. Check to see if you’ve got this one covered too!

Sources:

PMC12436091
Riboflavin in neurological diseases: therapeutic advances, metabolic insights, and emerging genetic strategies
PMC10131853
Biomimetic Remodeling of Microglial Riboflavin Metabolism Ameliorates Cognitive Impairment by Modulating Neuroinflammation
nlm.nih.gov/38037028/
Association of vitamin B2 intake with cognitive performance in older adults: a cross-sectional study

A reader sent me a thoughtful note this week. He asked me to write a little about myself - and explain how I came to know so much about APOE4.

It was a fair question.

The internet is full of people who sound credible. Some have impressive credentials. Others don’t. Some are careful with their claims. Others aren’t. We all have to decide whose information is worth our time and trust.

So here’s my honest answer.

I’m not a physician. I‘m not a neuroscientist. I don’t have a PhD.

I’ve never worked in a laboratory or published a scientific paper.

What I do have is a lifelong curiosity, a healthy skepticism, and a stubborn determination to understand things that matter.

Professionally, I spent nearly four decades building a business from the ground up in a highly technical industrial tooling sector. What started small eventually grew into a company serving customers across North America and beyond.

Then Covid arrived - and in an unexpected way, it was something of a gift.

For the first time in decades, I had time. Time to sit with my morning coffee and actually enjoy every sip. Time to take long, unhurried walks with our dogs, Tilly and Molly, alongside my already-retired husband. Time to actually smell the roses - literally and figuratively. The relentless pace I had known for forty years simply... stopped.

It turned out I needed that.

I decided the time had come to step back - and prepare for a proper transition of my company while I’m still here to witness it! Today I stay involved in the parts of the business I enjoy most - strategy, problem-solving, key relationships - while the day-to-day responsibilities have passed to the next generation.

Covid reminded me that there is a life worth protecting beyond the business.

Our grandchildren are a big part of that. And perhaps that's what drove me so deeply into the research once I learned about my APOE4 status.

Those years building a business taught me something I’ve never forgotten: good decisions require more than opinions or intuition. Claims must be evaluated. Assumptions must be challenged. Facts matter. Data matters. Real-world results matter.

When I learned about my APOE4 status, I applied the same mindset.

In early 2018, I decided to do a 23andMe test. I already knew my ancestry, so that wasn't what prompted it. A positive coronary artery calcium (CAC) score had gotten my attention, and I was searching for answers - particularly because my father had died of a massive heart attack at age 73.

I still remember the exact moment I opened the 23andme results. It’s a bit like a snapshot frozen in time.

I was standing in my west-facing sunroom as the sun was beginning to set. I opened the report and read six words that would quietly alter the course of my life:

You have two copies of APOE4. You have an increased risk of Alzheimer’s Disease.

My mother carried one copy of APOE4 and one copy of APOE2. She lived to almost 96 and didn’t begin showing signs of cognitive decline until around 90. She still knew who I was until the end.

So my interest in APOE4 wasn’t driven by a family history of early Alzheimer’s. It was driven by something simpler - curiosity, a desire to understand my own risk, and a determination to do everything reasonably possible to protect my cognitive health until that last breath.

I started reading. Then listening - podcasts, interviews, lectures, on-line conferences and books. I learned enough to realize how much I didn’t know. So I kept going..

Eventually, I realized that science isn't a collection of final answers. It's a process of asking better questions - and being willing to change your mind when the answers change.

Over time, I developed my own approach. I read beyond headlines. I pay attention to study design. I look for consensus where it exists and acknowledge uncertainty where it doesn’t. I cross-reference and cross-examine across three different AI platforms - querying, reframing questions, and digging for detail that a single source might miss.

When I share something, I try to be clear about what it is: established evidence, emerging research, expert opinion, or my own conclusions.

Most importantly, I hold all of this loosely. New evidence changes things, and I'd rather update my thinking than defend a position.

There are things I believed three years ago that I no longer believe. There are things I’m doing today that I may stop doing tomorrow if better evidence emerges. I consider that a strength, not a weakness.

So why should anyone trust what I write?

Honestly - you shouldn’t trust me blindly. You shouldn’t trust anyone blindly. What I’d ask instead is that you trust my process. Trust that I genuinely care about getting it right. Trust that I’ll tell you when something is supported by strong evidence and when it’s merely a promising theory. Trust that I have no clinical practice to fill, and no financial incentive tied to any particular outcome as this is - and will remain - a free Substack!

APOE4 risk is a topic too important to hide behind a paywall. That said, I'm putting the finishing touches on a members-only site where I'll share my personal Alzheimer's prevention blueprint - but this newsletter will always remain free.

And believe this: I have skin in the game.

I want to preserve my cognition, my independence, and my quality of life for as long as possible. I want to stack the odds in my favor. I suspect you do too.

Perhaps the best way to explain my approach to life is through a story from when I was eighteen.

In 1970, my sister and I hitchhiked from Germany through Switzerland, France, and Spain - then crossed the Strait of Gibraltar by ferry to Morocco, where we somehow decided to keep hitchhiking from Tangier to Casablanca.

Looking back, it was equal parts adventurous and reckless. In many ways, it marked the beginning of a fiercely independent streak that would shape much of my life in the decades that followed. The trip gave me confidence, strengthened my sense of self-reliance, and taught me that some of life's greatest rewards lie just beyond the boundaries of what feels comfortable.

It captures something fundamental about who I am. Whether it's a new country, a new challenge, or a complex scientific question, my response has usually been the same: let's see what's on the other side.

Discovering that I carry two copies of APOE4 felt, in many ways, like stepping into unfamiliar territory. The science was complicated. The risks were frightening. The answers were often unclear.

But I’ve never been one to turn back simply because the road ahead looks uncertain.

So I keep reading. I keep learning. I keep asking questions.

And I keep sharing what I find.

After all, I’ve always been more interested in exploring what’s over the next hill than standing still wondering about it.

Thank you for being part of the journey.

Karin Dee

A note: Dee is not my last name. I'm relatively well known in my industry, and I made the deliberate choice to write under a partial name. There is still real stigma attached to this gene - Chris Hemsworth learned that firsthand when headlines declared he had an "Alzheimer's diagnosis" based solely on his APOE4 status. But that's the kind of distortion that follows this topic, and I'd rather keep my professional life separate from it.

When people hear the word “sauna,” many immediately think detoxification, relaxation, or a wellness luxury.

But for those of us carrying APOE4, sauna use may represent something far more important: a powerful hormetic intervention that supports vascular health, mitochondrial resilience, inflammation reduction, sleep quality and potentially dementia risk reduction.

After years of using an infrared sauna, I recently made the decision to replace it with a traditional Finnish-style sauna - the kind capable of reaching true high heat.

My new sauna arrives in July.

And the more deeply I reviewed the research, the more convinced I became that this was the right move.

The APOE4 Brain and Heat Stress

APOE4 brains appear to be uniquely vulnerable to:

• impaired glucose metabolism

• vascular dysfunction

• chronic inflammation

• mitochondrial stress

• reduced synaptic repair

• impaired clearance of metabolic waste

• reduced resilience to aging stressors

Many of the interventions that appear most beneficial for APOE4 carriers share one common feature:

They create a carefully controlled biological stress that forces the body to adapt and become more resilient.

Exercise. Fasting. Cold exposure. Hyperbaric oxygen. Resistance training. Heat.

Sauna belongs squarely in that category.

What the Research Actually Shows

Some of the strongest sauna data comes from Finland, where traditional high-heat sauna bathing is deeply embedded in the culture.

One of the landmark studies followed more than 2,000 middle-aged Finnish men over decades and found something remarkable:

Men who used a sauna 4–7 times per week had dramatically lower rates of dementia and Alzheimer’s disease compared to those using it only once weekly.

The reductions were substantial:

• lower dementia incidence

• lower Alzheimer’s incidence

• lower cardiovascular mortality

• lower all-cause mortality

This matters enormously for APOE4.

Why?

Because vascular dysfunction and impaired cerebral blood flow are increasingly recognized as central drivers of neurodegeneration.

And sauna appears to strongly influence vascular health.

Sauna Is Probably a Vascular Therapy as Much as a Heat Therapy

During a proper sauna session:

• heart rate rises significantly

• blood vessels dilate

• circulation improves

• endothelial function improves

• blood pressure often decreases afterward

• nitric oxide signaling increases

• cardiac output rises

Some researchers have even described traditional sauna bathing as producing cardiovascular effects similar to moderate exercise.

For APOE4 carriers - who often struggle with endothelial dysfunction and impaired cerebral perfusion decades before cognitive symptoms appear - this becomes highly relevant.

Heat Shock Proteins: The Cellular Repair Crew

One of the most fascinating mechanisms behind sauna therapy involves heat shock proteins.

These are highly conserved protective proteins produced when cells encounter stress.

Heat shock proteins help:

• refold damaged proteins

• stabilize mitochondria

• improve cellular resilience

• reduce oxidative stress

• support autophagy

• improve protein quality control

Protein misfolding is one of the hallmarks of neurodegenerative disease.

Anything that enhances cellular housekeeping becomes potentially important.

And high-heat sauna exposure appears to be one of the most potent natural inducers of heat shock proteins.

Why I Moved Away From Infrared

This is where things become controversial.

Infrared saunas are extremely popular in wellness circles.

They are marketed heavily for:

• detoxification

• convenience

• comfort

• easier heat tolerance

And to be fair, infrared saunas absolutely can induce sweating and mild heat stress.

But after digging through the literature, I became increasingly unconvinced that infrared reproduces the physiological intensity seen in the Finnish sauna studies.

The majority of the research showing reductions in dementia and cardiovascular mortality involved:

• traditional Finnish saunas

• very high ambient temperatures

• repeated cardiovascular challenge

• significant core temperature elevation

Many infrared saunas operate in the range of 120–140°F. (mine usually took 30 minutes to get to 130°F).

Traditional Finnish saunas commonly operate between 170–200°F.

That is not a small difference.

The physiological experience is entirely different.

A true Finnish sauna creates:

• far greater cardiovascular demand

• stronger vasodilation

• more profound heat shock protein activation

• higher heart rate elevation

• greater thermoregulatory adaptation

In many infrared saunas, users can comfortably sit for long periods while barely elevating cardiovascular output.

The “Sweet Spot” Appears to Be Repeated High-Heat Exposure

Based on both the Finnish data and mechanistic studies, the apparent sweet spot for brain and cardiovascular benefits seems to involve:

• temperatures roughly 170–190°F

• sessions around 15–25 minutes

• repeated exposure multiple times weekly

• enough heat to meaningfully elevate heart rate and core temperature

Frequency appears to matter.

The strongest protective associations in the Finnish data were seen in people using saunas 4–7 times weekly.

That does not mean everyone needs daily sauna use. But it does suggest that occasional casual use may not generate the same adaptations.

Sauna and Sleep

One of the most immediately noticeable benefits many people experience is improved sleep.

Paradoxically, raising body temperature before bed often improves the body’s later cooling response, which supports deeper sleep onset. I will wait to test that in July - as my infrared sauna usually kept me awake and gave me less restful sleep if I used it at night.

For APOE4 carriers, sleep quality matters enormously.

Deep sleep is when the brain’s glymphatic system becomes most active.

That is the system involved in metabolic waste clearance, including amyloid clearance.

Anything that reliably improves deep sleep may have downstream implications for long-term brain health. If better sleep holds true for me, I’ll report back once I have used my new sauna for a while.

Sauna Is Not a Free Pass

I do think sauna is a powerful tool. But it is not a magic bullet.

No one should imagine they can:

• ignore metabolic health

• remain sedentary

• eat a highly inflammatory diet

• neglect sleep

• ignore insulin resistance

• avoid strength training

…and then “sauna their way out” of APOE4 risk.

Sauna works best as part of a larger prevention-focused lifestyle.

It is one signal among many telling the body:

Adapt. Repair. Become more resilient.

Practical Considerations for APOE4 Carriers

If you are considering sauna use:

• Hydration matters.

• Electrolytes matter.

• Start slowly.

• Heat tolerance improves over time.

• Avoid pushing to dizziness or exhaustion.

• Be cautious with uncontrolled hypertension or cardiovascular instability.

And importantly:

The goal is not maximal suffering. It is repeated, tolerable adaptation.

Consistency likely matters more than heroic sessions.

Why I’m Excited About My New Sauna

On a recent trip to Paris, I used the Finnish sauna daily at our hotel. I noticed the difference in heat and since there was also a pool, I cooled off nicely after the sauna session. I felt wonderfully relaxed, yet invigorated afterwards.

My infrared sauna served a purpose. But ultimately, I now want the real thing:

• higher heat

• stronger cardiovascular conditioning

• more robust heat shock response

• a more authentic Finnish-style experience

Given everything we currently know about APOE4, vascular health, mitochondrial resilience, and hormesis, I suspect it may become one of the most valuable tools in my prevention toolbox.

Final Thoughts

If I had to summarize the sauna literature for APOE4 carriers, it would be this:

Heat - when applied intelligently and consistently - appears to train resilience across nearly every system APOE4 tends to stress.

The brain. The vasculature. The mitochondria. The inflammatory system. Sleep. That does not mean sauna is a cure, but it may very well be one of the most evolutionarily ancient and biologically coherent interventions we have.

And unlike many expensive therapies in longevity medicine, this one has thousands of years of human history behind it.

Interesting Research Links:

https://pubmed.ncbi.nlm.nih.gov/41848374/

https://www.mayoclinicproceedings.org/article/

https://pmc.ncbi.nlm.nih.gov/articles/PMC6965159/

https://pubmed.ncbi.nlm.nih.gov/27932366/

We spend a lot of time discussing what to eat, which supplements to take, which labs to track. And that conversation matters. But underneath all of it is an assumption that rarely gets examined - that we’re all working with roughly the same biological machinery, just with an APOE4 variant layered on top.

We’re not.

And for some of us, that difference is significant enough to fundamentally change what an effective protocol actually looks like.

I know this because I’ve spent years building mine - and the more I’ve learned about my own genetics, the more I’ve understood why certain interventions matter more for me than standard recommendations would suggest, and why some things that work for others may not work the same way for me.

Here’s what I mean.

The Compounding Genetic Stack

Most people in this community know their APOE status. Fewer know their MTHFR status. And almost nobody is talking about PEMT.

I carry all three:

• APOE4/4 - homozygous, two copies

• MTHFR C677T - homozygous, two copies

• PEMT rs7946 T/T - homozygous, two copies

Each one individually warrants a specialized approach. Together, they create a compounding vulnerability that sits at the intersection of lipid transport, methylation, and phosphatidylcholine synthesis - three systems that are deeply interconnected and all critically relevant to brain health.

Let me walk through what each one actually means, and why the interaction between them matters more than any single variant in isolation.

APOE4/4 - You Already Know This One

If you’re reading this, you’re likely familiar with what APOE4 does. It impairs cholesterol recycling and lipid transport, particularly in the brain. It reduces amyloid clearance efficiency. It increases neuroinflammatory vulnerability.

What’s less often discussed is that APOE4’s impact on lipid transport means your brain has a harder time getting the phospholipids it needs to maintain neuronal membranes, support synaptic function, and clear metabolic waste.

This isn’t just a cardiovascular story. It’s a membrane integrity story. And that matters for everything that follows.

MTHFR C677T Homozygous - The Methylation Bottleneck

The MTHFR enzyme converts folate into its active form (5-methyltetrahydrofolate) which feeds the methylation cycle and ultimately supports the production of SAMe, your body’s primary methyl donor.

C677T homozygous reduces this enzyme’s activity by approximately 70-80%.

The practical consequences:

• Synthetic folic acid - found in fortified foods and many supplements - doesn’t just fail to help. It actively competes with and blocks what little conversion capacity you have. It works against you.

• SAMe production is compromised, affecting dozens of methylation-dependent processes throughout the body

• Homocysteine tends to accumulate - and elevated homocysteine is directly neurotoxic, independently associated with cognitive decline, and particularly concerning in APOE4 carriers

For anyone with this variant, the form of B vitamins in your supplement stack isn’t a minor detail. It’s foundational. Methylfolate - not folic acid. Methylcobalamin - not cyanocobalamin. This distinction matters enormously and most generic B complexes and most multi-vitamin blends get it wrong.

PEMT rs7946 T/T - The Liver Connection Most People Miss

PEMT stands for Phosphatidylethanolamine N-Methyltransferase. It’s an enzyme responsible for one of the body’s pathways for synthesizing phosphatidylcholine - primarily in the liver.

The rs7946 T/T variant (also called G523A, ‘A’ allele) reduces PEMT activity by approximately 30% in laboratory assays. The primary documented consequence in research is increased risk of non-alcoholic fatty liver disease - specifically because reduced PC synthesis in the liver impairs the liver’s ability to shuttle fats out of hepatic cells efficiently, leading to fat accumulation.

A few important caveats:

• The 30% reduction has been measured outside the human body - in vivo human experiments haven’t yet confirmed the precise mechanism

• The negative effect appears diet-dependent - observed primarily in individuals consuming high calorie Western dietary patterns

• It has not been consistently observed across all populations studied

Why it’s still relevant to this conversation:

The liver is the primary site of PC production for systemic distribution. If hepatic PC synthesis is impaired - even partially - it plausibly affects phospholipid availability more broadly. This is mechanistically interesting in the context of APOE4’s already impaired lipid transport, but I want to be clear: this is a plausible connection, not a confirmed one.

What I can say with more confidence is that my dietary pattern - low sugar, Mediterranean-leaning, lean body composition - is essentially the opposite of the high calorie Western diet that appears to trigger the negative PEMT expression. My liver enzymes are normal and triglycerides are low, suggesting this variant isn’t expressing negatively in my current context.

The practical implication I draw from carrying this variant - alongside the APOE4 and C677T combination - is that supporting PC availability through direct supplementation and dietary sources makes mechanistic sense as a precautionary measure. BodyBio PC, egg yolks, and choline-rich foods aren’t just generally good APOE4 choices. For someone with my genetic profile, they feel specifically warranted.

But I share this with appropriate humility - the science here is preliminary, and I’d encourage you to evaluate it accordingly rather than treating it as established fact.

What This Means Practically

Here’s what it means for my protocol specifically - shared not as prescription but as illustration of the principle:

BodyBio PC has become non-negotiable for me. Not just helpful - essential. Given impaired PEMT function, my endogenous phosphatidylcholine synthesis capacity may be less efficient. Delivering it directly via phospholipid complex bypasses the reduced efficiency pathway entirely. My Prodrome scan data shows this working - Total Phosphatidylcholines jumped from the 13th to 43rd percentile between annual scans following consistent PC supplementation.

Egg yolks matter more than standard recommendations suggest. Dietary phosphatidylcholine from egg yolks partially bypasses PEMT by delivering preformed PC directly. This isn’t about cholesterol anxiety - it’s about membrane substrate delivery. For me, three to four yolks daily feels biologically justified by this specific genetic context.

Methylated B vitamins are non-negotiable. Thorne Basic B or equivalent using 5-MTHF methylfolate and methylcobalamin. I personally avoid folic acid. Auditing every supplement in your stack for synthetic folic acid matters.

TMG (Trimethylglycine) supports both impaired pathways simultaneously. It provides an alternative methylation route that bypasses the impaired MTHFR enzyme, supporting homocysteine clearance and partially restoring methyl donor availability for whatever residual PEMT activity remains.

Homocysteine tracking becomes a primary biomarker. Not an afterthought. The C677T and PEMT combination creates compounding pressure on homocysteine elevation. Getting it below 7 and ideally toward 6 µmol/L is a meaningful target with direct neuroprotective implications.

Importantly, PEMT is not the body’s only phosphatidylcholine synthesis pathway. The CDP-choline (Kennedy) pathway also contributes significantly, but reduced PEMT efficiency may still increase reliance on dietary choline and preformed phosphatidylcholine.

Explore The Members Site

The Bigger Point

Generic APOE4 protocols are built for the average APOE4 carrier. They’re useful starting points. But the APOE4 community is not genetically homogeneous, and the assumption that one protocol fits all is the same oversimplification we rightly criticize in mainstream medicine’s one-size-fits-all approach.

Knowing your APOE status is the beginning of personalization, not the end of it.

If you haven’t looked at MTHFR status, PEMT rs7946 or your phytosterol absorption genetics - and you’re finding that standard APOE4 protocols aren’t moving your biomarkers the way you’d expect - these variants are worth investigating.

Not to induce more anxiety. But because knowledge of the actual biological terrain you’re working with allows you to build something precise rather than generic.

The goal isn’t to follow someone else’s protocol. The goal is to understand your own biology deeply enough - it goes well beyond the APOE gene - to build one that actually fits.

That’s what I’m working on. And these three variants - APOE4/4, C677T, PEMT T/T — are a significant part of why my protocol looks the way it does.

As always - this is what I do and why. Not medical advice. Take it to your clinician, your functional medicine practitioner, or your own research process. The point is to give you better questions, not ready-made answers.

If you’ve tested for PEMT or MTHFR and found similar results, I’d love to hear about it in the comments. This is exactly the kind of community knowledge that helps all of us build more precise protocols.

Related resources worth exploring:

• Goodenowe’s plasmalogen research and ProdromeScan for phospholipid biomarker tracking

• Bredesen PreCODE framework for comprehensive APOE4 protocol building

• Husseine Yassine’s DHA transport research in APOE4 carriers

• MTHFR specific resources from Ben Lynch’s Dirty Genes framework

And then the obvious question hit me: if beneficial compounds get in that easily... what else does?

The Back Door to the Brain

Most people have heard of the blood-brain barrier (BBB) - that remarkable biological security system that keeps harmful substances out of your brain. We take comfort in it. We assume it’s doing its job.

What we’re rarely told is that there’s an unsecured back door.

The olfactory nerve runs directly from the nasal epithelium straight into brain tissue. It doesn’t cross the BBB. It bypasses it completely. This pathway - called the olfactory-trigeminal route - allows substances to travel via:

• Transcellular transport - through nerve cells themselves

• Axonal transport - riding along nerve fibers directly into the brain

• Paracellular transport - slipping between cells along the nerve

This is why intranasal drug delivery is so promising for neurological conditions. Researchers are using this pathway to deliver Alzheimer’s treatments, peptides, and hormones directly to brain tissue without the usual barriers.

But here’s what is largely ignored: the brain doesn’t distinguish between a therapeutic peptide and a toxic fume. The door doesn’t check credentials. It just opens.

The Workers Nobody Is Warning

When I sat with this idea, my mind immediately went to the people who spend eight hours a day, five days a week, breathing in chemicals that most of us encounter only occasionally - if ever.

Hairdressers and salon workers live inside a chemical cocktail. Hairspray, keratin treatments, hair relaxers, permanent wave solutions, and bleaching agents fill the air of salons daily. Formaldehyde - a known carcinogen and neurotoxin - is a primary ingredient in many keratin smoothing treatments. The women who perform these services often work in poorly ventilated spaces, breathing it in for hours on end, for entire careers. Most are never told what that means for their brain.

Nail technicians face a particularly insidious mix. Acrylic monomers, acetone, UV gel chemicals, and adhesive solvents create a persistent chemical haze in nail salons. Studies have found significantly elevated levels of volatile organic compounds (VOCs) in nail salon air - many of which are known neurotoxins. Ventilation is often inadequate. Many nail technicians are immigrant women who may face additional barriers to accessing health information or advocating for safer working conditions.

Welders and machinists have one of the most well-documented occupational neurotoxin exposures of any profession. Manganese fumes — produced during welding - are so consistently linked to Parkinson’s-like neurological damage that the condition has its own name: manganism. The olfactory-nasal pathway is believed to be a primary route by which manganese reaches the brain. Yet welding remains one of the most common trades in the world, often performed with minimal respiratory protection.

Painters and auto body workers breathe solvents - toluene, xylene, isocyanates - that are fat-soluble, meaning they readily cross into neural tissue. Long-term solvent exposure is associated with cognitive decline, memory impairment, and mood disorders, a constellation sometimes called painters’ syndrome in occupational health literature.

Dry cleaning workers spend their days with perchloroethylene (PERC), a chlorinated solvent classified as a probable human carcinogen. PERC is also a neurotoxin with documented links to cognitive decline and Parkinson’s disease risk with long-term exposure.

Farmers and agricultural workers face pesticide drift - chemicals that were designed to affect the nervous systems of insects don’t stop at species boundaries. Organophosphate pesticides in particular have been linked to neurological damage in farmworkers, and chronic low-level inhalation via the olfactory pathway is an area of growing research concern.

Embalmers and funeral workers work with formaldehyde daily, for entire careers. This is one of the highest-exposure occupational groups for a compound with both carcinogenic and neurotoxic properties, yet it receives almost no public health attention.

Firefighters deserve a category of their own. Structure fires produce a toxic soup of combustion byproducts - benzene, hydrogen cyanide, acrolein, heavy metals from burning electronics - that firefighters inhale repeatedly throughout their careers. The neurological consequences are increasingly being studied, and the findings are not reassuring.

It’s Not Just What You Breathe

The story gets broader when you realize the nasal pathway isn’t the only backdoor.

Cashiers handle receipt paper dozens to hundreds of times per shift, every working day. What most people don’t know is that about 80% of thermal receipt paper is coated in free BPS (Bisphenol-S, a chemical cousin of BPA) not bound into plastic like in water bottles, but sitting on the surface, ready to absorb through skin on contact. Studies have found that cashiers carry significantly higher Bisphenol levels in their urine than the general population. Bisphenols are endocrine disruptors that mimic estrogen, disrupting hormonal systems, thyroid function, and metabolic health. The health implications are well known and conscientious corporations are moving to phasing out use of receipt paper containing Bisphenol. Receipts from Best Buy, Costco, CVS, H&M, Starbucks, and Target were among those that didn't contain Bisphenols in recent testing.

Here’s the detail that makes it worse: using hand sanitizer before handling receipts dramatically increases Bisphenol absorption. The alcohol in sanitizer increases skin permeability, essentially opening the door wider. Well-meaning hygiene habits, making things worse.

Bank tellers handle currency all day - currency that itself picks up Bisphenol from contact with receipts throughout its circulation. Bartenders and servers handle printed tickets all shift while also working with alcohol-based cleaning products that increase their skin’s absorptive capacity. These are not exotic industrial workers. These are people working in every town, every city, in jobs that nobody associates with toxic exposure.

The Alzheimer’s and Parkinson’s Connection

This is where the research gets both fascinating and deeply troubling.

The olfactory bulb - the first brain structure substances reach via the nasal pathway - is also one of the first brain regions to show damage in both Alzheimer’s and Parkinson’s disease. The loss of smell is now recognized as an early warning sign of both conditions, often appearing years before other symptoms.

This is probably not a coincidence.

Some researchers now believe that chronic low-level nasal exposure to environmental toxins may be a significant and under-appreciated driver of neurodegenerative disease. The nose offers a relatively unguarded route of entry, repeated exposures accumulate over decades, and the first casualties - the olfactory neurons - are the very cells whose death we’re now recognizing as an early marker of neurodegeneration.

Ultrafine air pollution particles - produced by vehicle exhaust and combustion — have been physically found in human brain tissue. Urban residents who live near high-traffic areas show higher rates of cognitive decline. Children in heavily polluted cities show measurable differences in brain development.

The picture that emerges is one where the brain is far less protected from its environment than we have assumed - and where the people carrying the greatest burden of that exposure are often the least able to do anything about it.

What This Means Practically

For most people, complete avoidance isn’t realistic. But awareness changes behavior, and behavior changes outcomes.

Ventilation is neurological protection. This isn’t just about lungs. Opening windows, running exhaust fans, and working in well-ventilated spaces reduces the concentration of airborne compounds reaching the olfactory nerve. For salon and workshop owners, this is a moral obligation as much as a practical one.

N95 masks filter particles more effectively than surgical masks. For anyone in high-exposure occupational settings, the difference matters - not just for lungs but for what reaches the brain.

Nitrile gloves when handling receipts significantly reduce BPA skin absorption. This is a cheap, easy intervention that virtually no cashier has been told about.

Nasal saline rinses are being studied as a way to clear particulates before absorption occurs. The evidence is still emerging, but the mechanism is plausible and the risk is essentially zero.

The hand sanitizer and receipt combination is worth specifically knowing about - the interaction isn’t intuitive, but it’s documented. Wash hands after handling receipts rather than sanitizing before.

A Quiet Injustice

There is something worth sitting with here beyond the science.

The people with the highest occupational exposures to neurotoxic compounds are, disproportionately, people in lower-wage service jobs - nail technicians, cashiers, hairdressers, agricultural workers, cleaners. They are making other people look beautiful, keeping stores running, growing food. They are often working in conditions they didn’t choose, with information they are never given.

The research on occupational neurotoxin exposure exists. The mechanisms are increasingly understood. But the distance between what researchers know and what a nail technician in a strip mall salon knows is vast - and that distance has consequences that play out over decades, quietly, in the form of cognitive changes and neurological disease that nobody connects back to the air she breathed for thirty years.

Understanding how the body’s defenses actually work - and where they don’t - is a first step toward changing that.

The earliest stages are also the most treatable.

Decline is not inevitable. The trajectory can be bent - sometimes dramatically - when the right systems are targeted early and consistently.

One of the most inspiring examples of this is Judy Benjamin, diagnosed with Alzheimer’s 13 years ago, who recently completed a 3,000-mile walk across the United States at age 81 to raise awareness for prevention. Judy is often described as Dale Bredesen’s “Patient Zero,” having implemented his RECODE protocol as outlined in Dr. Bredesen’s book, “The End of Alzheimer’s”.

Judy’s story isn’t a miracle. It’s a roadmap.

Early, aggressive, multi-system intervention can preserve function for years -sometimes more than a decade. And that’s especially true for APOE4 carriers.

Why Early Intervention Matters

Alzheimer’s doesn’t begin with memory loss. It begins silently, years earlier, with:

• Glucose hypometabolism

• Mitochondrial dysfunction

• Synapse loss

• Chronic neuroinflammation

• Sleep disruption

• Lipid and membrane breakdown

The earlier you interrupt these cascades, the more brain you preserve.

My 15 Most Important Staples for Early Alzheimer’s Prevention

I’m not waiting for a diagnosis. I’ve been implementing extensive prevention strategies in my daily life since finding out my APOE4/4 status years ago.

These are the interventions with the strongest human data, the most compelling biology, and the best real-world results, particularly for APOE4 carriers.

1. Fix Metabolism, Insulin Resistance, and Gut Health (the #1 lever)

Brain energy failure appears years before symptoms.

Targets:

• Fasting glucose: 75–85 mg/dL

• A1C: ≤ 5.2

• Fasting insulin: < 4

• Microbiome testing and correction

Metabolic repair stabilizes cognition better than almost any drug.

2. High-Dose DHA (2–3 g/day, APOE4-aware) and PC

APOE4 brains struggle to transport DHA across the blood–brain barrier.

High-DHA intake (especially DHA-PC) supports:

• Synapse repair

• Reduced neuroinflammation

• Slower hippocampal atrophy

PC supports:

• Synaptic membranes

• DHA delivery

• Neurotransmission

• Lipid balance

PC + DHA is one of the most effective synaptic repair combinations. I eat SMASH fish (Sardines, Mackerel, Anchovies, Salmon, Herring) at least 4 times a week, which is a more effective delivery of phospholipid DHA to the brain than taking a supplement! (I skip the anchovies because I don’t like their salty taste).

3. Plasmalogens (Neuro + Glia)

Plasmalogens drop early in Alzheimer’s. Supplementation has been shown to:

• Improve memory

• Increase cognitive scores

• Support synaptic integrity

I’ve used plasmalogens for years. They aren’t cheap - but neither is cognitive decline. Studies show that those with the highest brain plasmalogens have the lowest incidence of dementia.

4. Lower Homocysteine (< 7 µmol/L)

High homocysteine predicts brain atrophy and faster decline - yet is rarely tested.

Lowering it slows progression in randomized trials.

Key tools:

• Methyl or hydroxy-B12 (injections early on)

• Methylated folate

• TMG (trimethylglycine)

Nearly half the population carries an MTHFR gene variant and doesn’t know it. It can negatively impact methylation - a vital process for DNA, neurotransmitters and detoxification.

5. Repair Sleep Architecture (Critical for APOE4)

Sleep is when the brain clears amyloid and tau.

Foundational supports:

• Melatonin (≥ 2–3 mg; I personally use higher doses)

• Glycine, magnesium, L-theanine

• Evening red light

• Consistent bedtime

• Eliminate alcohol - it obliterates deep sleep!

6. Reduce Neuroinflammation (Microglial Control)

Chronic inflammation accelerates decline.

Helpful tools include:

• DHA

• Curcumin

• Optimized vitamin D

• Polyphenols

• Melatonin

• Low-dose aspirin (if appropriate)

• Low-dose naltrexone (LDN) to reduce hs-CRP … this addition to my stack made a marked improvement in my hs-CRP - now usually below 0.5!

7. Mild Ketosis (APOE4-Friendly)

Ketones bypass glucose failure and fuel neurons directly.

My Goal: mild, not extreme ketosis

• Low-glycemic diet

• 12–14 hour overnight fast

• C8 MCT powder (better lipid profile for APOE4). While I am not on a ketogenic diet due to my slender build and having no weight to lose, I add C8 MCT Powder to my morning coffee and I am generally in mild ketosis in the hours before noon. (0.5 – 2 mmol/L)

8. Lithium (Low-Dose, Neuroprotective)

Lithium is one of the most underappreciated neuroprotective tools available.

Low-dose lithium:

• Inhibits GSK-3β (tau phosphorylation)

• Enhances autophagy

• Supports mitochondrial resilience

• Is associated with lower dementia rates in epidemiologic studies

This is not psychiatric-dose lithium and generally has no noticeable side effects.

9. NAD⁺ Support (Cellular Energy & Repair)

NAD⁺ declines with age and is critical for:

• Mitochondrial function

• DNA repair

• Sirtuin activation

• Neuronal survival

Support options include:

• NMN or NR

• NAD⁺ injections or infusions (advanced)

• Exercise and fasting (foundational)

Energy failure is an early Alzheimer’s event - NAD directly addresses it.

10. Daily Exercise — Non-Negotiable

Exercise raises BDNF and slows progression.

AD-optimized formula:

• Zone 2: 45 min, 5–6×/week

• Strength training: 3×/week

• Steps: 10,000–12,000/day

I do 20 minutes of weight training every other day. Usually two sets (12 repetitions) of 5-6 exercises. Minimum 3 times a week I add a 45 minute Nordic Walking hike through a peaceful woodland preserve in my neighborhood. In addition, I use my rebounder daily, usually enjoying two 15 minute sessions of jumping to my favorite music!

11. Thyroid Optimization (Especially T3)

Low thyroid function - especially low T3 - accelerates decline.

Targets:

• Free T3: upper third of range

• Reverse T3: low. (I’ve fine-tuned mine to <11)

Cellular hypothyroidism = cognitive vulnerability. If you’re on Levothyroxine replacement therapy, please check out my previous post on the topic!

12. Red / Near-Infrared Light (Photobiomodulation)

Supports:

• Mitochondrial ATP

• Cerebral blood flow

• Neuronal repair

• Sleep quality

• Reduced inflammation

Often used alongside metabolic and exercise therapy in long-term success cases. I use redlight therapy daily and believe it’s a non-negotiable addition to brain protection.

13. Melatonin (Neuroprotective Doses)

Melatonin:

• Reduces oxidative stress

• Stabilizes mitochondria

• Modulates protein phase separation

• Reduces tau and amyloid toxicity

For APOE4 carriers, melatonin is profoundly protective.

14. HBOT (Hyperbaric Oxygen Therapy)

HBOT is one of the most promising non-pharmacologic interventions for early cognitive decline.

Emerging human data show improvements in:

• Cerebral blood flow

• Mitochondrial function

• Processing speed and memory

• Neuroinflammation

• Sleep and overall energy

By increasing dissolved oxygen in plasma, HBOT enhances mitochondrial ATP production, supports angiogenesis, and improves tissue repair - all critical in a brain suffering from hypometabolism.

If accessible, HBOT is a high-leverage investment early in the disease process.
I personally invested in my own chamber in 2025 and noticed meaningful improvements in energy, drive, and overall well-being within the first few weeks.

15. Rapamycin (Intermittent, Carefully Dosed)

Rapamycin targets one of the core drivers of neurodegeneration: chronic mTOR overactivation.

When used intermittently and at low doses, rapamycin may:

• Enhance autophagy (clear damaged proteins and organelles)

• Reduce neuroinflammation

• Improve mitochondrial efficiency

• Support vascular and immune health

Importantly, this is not daily immunosuppression. In longevity and neuroprotection contexts, rapamycin is pulsed, with careful attention to dose, timing, and individual response.

I’ve been taking once weekly rapamycin since 2021. With occasional breaks to wash out any residual buildup, I believe it’s an easy strategy for anyone past reproductive years carrying the APOE4 gene to protect the blood-brain barrier integrity.

The Takeaway

You cannot “cure” Alzheimer’s - but you can implement a thoughtful prevention strategy and, especially when addressed early, potentially change its trajectory. Dale Bredesen’s books The End of Alzheimer's and The End of Alzheimer's Program offer an invaluable roadmap for anyone concerned about Alzheimer’s disease - whether for themselves or a loved one.

Judy Benjamin’s 3,000-mile walk sends a clear message to everyone:

You are not powerless.
Your brain is not doomed.
Your choices matter.

Disclaimer

This article reflects my personal research, experience, and health practices and is shared for educational and informational purposes only. It is not medical advice and should not be used to diagnose, treat, or replace guidance from a qualified healthcare professional.

Many of the interventions discussed - including supplements, peptides, off-label medications, hyperbaric oxygen therapy, and lifestyle strategies - may not be appropriate for everyone and can carry risks depending on individual health status, genetics, and medications. Decisions about medical treatment should always be made in consultation with a knowledgeable physician.

Alzheimer’s disease and cognitive decline are complex, multifactorial conditions. While early, multi-system intervention may improve outcomes or slow progression, no intervention discussed here is presented as a cure.

If you are new here: APOE status is determined primarily by two SNPs (genetic markers): rs429358 and rs7412. In most direct-to-consumer genetic reports, APOE4/4 corresponds to rs429358 C/C and rs7412 C/C.

But upstream, there’s a potential failure in the making - one that doesn’t get nearly enough attention.

It starts in the mitochondria.

More specifically, it starts with something called cardiolipin.

Cardiolipin is a specialized fat found almost exclusively in the inner membrane of our mitochondria. It’s not just structural - it’s essential. It holds the entire energy-producing system together. Without it, the machinery that generates ATP begins to falter.

And here’s where it could be relevant - and especially for APOE4 carriers.

As we age, cardiolipin becomes damaged and oxidized. In Alzheimer’s brains, this process is significantly accelerated. The result is a gradual breakdown in mitochondrial efficiency: less energy, more oxidative stress, and increasingly vulnerable neurons.

In other words, before there are plaques… there is an energy problem.

APOE4 appears to amplify this vulnerability. Increased oxidative stress and altered lipid handling make it harder to maintain membrane integrity - including cardiolipin. Over time, this may potentially contribute to the metabolic fragility we see in the APOE4 brain.

So the question becomes:

Can we stabilize the system before damage becomes irreversible?

That’s what led me to SS-31 (Elamipretide).

SS-31 is a small peptide that targets the mitochondria directly. It binds to cardiolipin and helps stabilize the inner membrane, improving efficiency of the electron transport chain and reducing oxidative stress.

It doesn’t address amyloid.
It doesn’t target tau.

It supports something more fundamental: the cell’s ability to produce energy cleanly and efficiently.

In animal models, SS-31 has been shown to:
• Improve mitochondrial function
• Reduce oxidative damage
• Support synaptic health
• Improve cognitive performance

Human data - honestly - is very limited, and this is definitely not a mainstream intervention. But mechanistically, I find it compelling - especially when I’m thinking of ways to maintain my brain until the proverbial “fat lady” sings.

For that reason - and in consideration of my risk that compounds continuously with age (and particularly in the 8th decade of life!) - I decided to incorporate SS-31 into my protocol. Not continuously - but in cycles.

My goal is not constant stimulation, but periodic support - giving mitochondria a chance to repair and reset.

This fits into my broader strategy:
• Maintaining metabolic flexibility
• Supporting mitochondrial biogenesis (exercise)
• Providing membrane building blocks (DHA, phospholipids)
• Reducing oxidative stress

SS-31 is simply one piece of that puzzle.

As always, this is not medical advice - just a reflection of how I’m thinking about prevention, based on current science and personal exploration.

But if there’s one takeaway, it’s this:

We shouldn’t wait for visible pathology to start supporting the systems that keep our neurons alive. And at 73, I certainly don’t have the luxury of time on my side - to wait for science to catch up.

Sometimes the most important interventions are the ones that protect what we can’t see and I’m absolutely willing to take calculated risks when it comes to protecting and preserving the most important part of my body - my brain.

For those interested in diving a little deeper, here is more on the mechanistic picture of SS-31:

1. It stabilizes cardiolipin structure (prevents distortion)

Cardiolipin is uniquely shaped (4 fatty acid tails), which makes it fragile, especially under oxidative stress.

SS-31:

• Inserts itself along cardiolipin-rich regions of the inner mitochondrial membrane

• Prevents cardiolipin from becoming disorganized or “floppy”

2. It protects cardiolipin from peroxidation

Cardiolipin is extremely vulnerable to oxidation (especially its DHA-rich forms).

SS-31:

• Reduces reactive oxygen species (ROS)–induced peroxidation

• Interrupts the cycle where damaged mitochondria → more ROS → more cardiolipin damage

Key effect:

• Preserves functional (non-oxidized) cardiolipin pools

3. It restores electron transport chain supercomplexes

This is one of the most important (and underappreciated) effects.

Cardiolipin is required to assemble:

• Complex I, III, IV into supercomplexes (“respirasomes”)

SS-31:

• Helps cardiolipin maintain the proper curvature and charge environment

• Re-forms and stabilizes these supercomplexes

Result:

• More efficient electron flow

• Less electron “leak” → less ROS

4. It improves cytochrome c function (without triggering apoptosis)

Normally:

• Cardiolipin anchors cytochrome c to the inner membrane

When cardiolipin gets oxidized:

• Cytochrome c detaches → triggers apoptosis cascade

SS-31:

• Maintains cardiolipin in a reduced (healthy) state

• Keeps cytochrome c functionally engaged in energy production, not cell death signaling

Subtle but powerful:

• Supports ATP production

• Reduces inappropriate apoptosis signaling

5. It improves mitochondrial membrane curvature & cristae integrity

Cardiolipin shapes:

• The folds (cristae) inside mitochondria

SS-31:

• Preserves proper membrane curvature

• Prevents cristae collapse or fragmentation

6. It decouples ROS production from ATP generation

In damaged mitochondria:

• ATP production ↓

• ROS ↑

SS-31 helps:

• Restore efficient coupling

• So mitochondria can produce ATP without excessive oxidative spillover

7. It may facilitate cardiolipin remodeling indirectly

Cardiolipin undergoes constant remodeling (via enzymes like tafazzin).

While SS-31 doesn’t directly remodel:

• By protecting cardiolipin from oxidation

• It preserves substrates needed for proper remodeling cycles

Bottom line (what it’s really doing)

SS-31 doesn’t just “bind cardiolipin”, it:

• Preserves its structure

• Prevents its oxidation

• Keeps cytochrome c in energy mode (not death mode)

• Stabilizes mitochondrial ultrastructure

• Restores efficient ATP production

Pain. Fatigue. Brain fog. A racing heart.

But blood pressure?
It’s silent - while exerting a constant mechanical force on one of the most delicate systems in the body: our brain.

From My Own Experience

I’ve seen this play out personally.

There was a time when I was taking T4-only thyroid medication, and my thyroid labs looked acceptable.

But my blood pressure told a different story - it was consistently registering a bit elevated and gradually increasing, without any obvious reason.

Diet hadn’t changed. Lifestyle hadn’t changed. It wasn’t until I threw out the T4 meds in 1999/2000 - and addressed my continuing sub-clinical hypothyroid state - that my blood pressure gradually returned to a solid baseline under 120/80.

That connection stayed with me.

Why Blood Pressure Matters

Our brain is not just an organ - it’s a dense network of microscopic vessels delivering oxygen, glucose, and nutrients with extraordinary precision.

Now imagine those vessels under constant pressure.

Not enough to trigger symptoms.
Not enough to send us to the doctor.
But just enough - over years - to cause subtle damage.

The resulting damage is:

• Micro-tears in vessel walls

• Reduced elasticity

• Impaired blood flow

• Breakdown of the blood-brain barrier

Over time, this can translate into:

• Reduced cognitive resilience

• Increased risk of vascular dementia

• Greater vulnerability to Alzheimer’s pathology

“I feel fine” doesn’t mean much here

One of the most misleading assumptions is that if blood pressure were a problem… you’d know it.

You wouldn’t.

Elevated blood pressure is often completely asymptomatic - even when it’s doing real damage.

And there is nuance:

• A “normal” reading at the doctor’s office doesn’t tell the full story

• Spikes during stress, poor sleep, or exertion often go unnoticed

• Nighttime blood pressure (when our brain is repairing itself) may be the most important - and the least measured

We can feel great… and still be quietly accumulating risk.

What This Means for APOE4 Carriers (and Anyone Who Cares About Their Brain)

To protect our cognitive future - blood pressure becomes important and a marker we want to understand clearly!

Why?

Because it amplifies everything else.

• Inflammation becomes more damaging

• Lipid transport issues become more consequential

• Microvascular dysfunction accelerates

It’s not just a number. It’s a damage multiplier.

Subtle Signs Something May Be Off

We may not “feel” high blood pressure - but our bodies sometimes give us subtle cues.

• Poor sleep quality or frequent nighttime waking

• Feeling wired but tired

• Head pressure (not pain - just pressure)

• Reduced exercise tolerance

• Increased heart rate variability instability

While these symptoms aren’t diagnostic - they’re clues worth paying attention to.

What to do (Without Overcomplicating It)

1. Measure - Don’t Assume

• Take your blood pressure at home

• Measure at different times (morning, evening, post-exercise)

• Pay attention to patterns - not just isolated readings

2. Hydration Matters

Even mild dehydration can elevate blood pressure.

• Start your day hydrated

• Maintain steady fluid intake - not just when thirsty

3. Vascular System Training

Our blood vessels respond to how we use them.

• Regular walking

• Resistance training

• Short bursts of higher intensity (as tolerated)

This is more than just fitness - it’s vascular conditioning.

4. Sleep Is a Blood Pressure Event

If your sleep is fragmented, your blood pressure likely is too.

• Prioritize consistent sleep timing

• Reduce late-night stimulation

• Pay attention to nighttime awakenings

5. Manage the “Invisible Load”

Stress doesn’t just affect your mind - it affects your pressure.

• Breathing practices

• Time outdoors

• Deliberate downshifting during the day

The Takeaway

Since we are building a plan for long-term brain health, we can’t overlook the quiet forces.

They’re often the ones that matter most. I used to assume my blood pressure was great. Now, I verify! Periodically I track pressure for several weeks at a time - several times a day - consistently at the same time.

That naturally raises the next question:

If this biology is real, how do we know whether it’s being pushed, or kept relatively quiet, in our own bodies?

We don’t yet have clinical tests that show lipid droplets in astrocytes or APOE lipidation in the brain. But we do have something useful: advanced lipoprotein panels that offer indirect signals about how hard the lipid system is being asked to work.

These markers are good context, and for APOE4 carriers, context matters.

A quick framing (important)

This post is not about chasing perfect numbers or defining universal targets.

What follows are the markers I personally watch, and the directional ranges that give me confidence that my APOE4 biology is operating in a relatively calm environment.

This is not a prescription.
It is how I translate mechanism into monitoring with available information I can get.

The markers I pay closest attention to

1. VLDL & VLDL-P

VLDL reflects triglyceride-rich particle flux and inflammatory lipid signaling, a burden APOE4 is less equipped to manage.

What I look for

• Low and stable VLDL

• No upward drift over time

• No post-meal or fasting spikes

For me, lower VLDL suggests a quieter peripheral lipid environment and less downstream stress on fragile lipid-handling pathways.

2. Remnant lipoproteins (one of the most important signals for me)

Remnant lipoproteins are highly inflammatory and APOE-dependent for clearance. When elevated, they are associated with endothelial dysfunction and increased inflammatory signaling.

What I aim for

• Remnant lipoproteins firmly in the low range

• Consistency over time, not one-off lows

Low remnants suggest that APOE4 is not being repeatedly activated to clear lipid debris in a hostile metabolic environment - a situation where it behaves worst.

3. Triglycerides

Why they matter

Triglycerides themselves are not inherently toxic. Chronically elevated levels, however, reflect impaired lipid utilization and increased remnant production - both of which amplify APOE4 stress.

What I look for

• Low fasting triglycerides

• Minimal variability

4. LDL-P and LDL-C (with perspective)

LDL often dominates lipid discussions, but I view it as context, not the primary signal.

• Particle number matters

• But metabolic environment matters more

• LDL is rarely the first system to fail in APOE4 biology

5. ApoB (with context)

ApoB reflects the total number of atherogenic particles circulating in the blood. Each LDL, VLDL remnant, and IDL particle carries one ApoB molecule.

For APOE4 carriers, ApoB provides a useful summary of particle burden, but it does not tell the whole story.

How I interpret it

• ApoB tells me how many particles are present

• It does not tell me how inflammatory, triglyceride-rich, or metabolically stressful those particles are

• It does not reflect lipid trafficking efficiency inside the brain
  
  When ApoB is low and remnants, VLDL, and triglycerides are low, that combination is reassuring.
  When ApoB is low but remnants are high, I care far more about the remnants.

6. ApoA1 (supporting capacity, not a shield)

ApoA1 is the main structural protein of HDL and reflects the body’s capacity for reverse cholesterol transport and lipid recycling.

• ApoA1 provides information about transport capacity

• Higher is not always better

• Function matters more than quantity

I monitor ApoA1 as a supporting signal, not as a guarantee of protection. Favorable ApoA1 does not override inflammatory lipid flux, poor metabolic control, or impaired lipid utilization.

7. Omega-3 Index (membrane resilience, not a nutrient checkbox)

The Omega-3 Index reflects the percentage of EPA and DHA incorporated into red blood cell membranes, serving as a proxy for long-term membrane composition and stability.

For APOE4 carriers, this marker is particularly relevant because APOE4 biology places chronic stress on lipid membranes, mitochondrial function, and glial support systems - all areas where DHA plays a foundational structural role.

Omega-3 Index is not simply a dietary or cardiovascular marker. It is a membrane quality signal.

It reflects how resilient cell membranes are in the face of oxidative stress, inflammatory signaling, and metabolic strain - conditions under which APOE4 tends to perform worst.

Low Omega-3 Index suggests membranes that are more rigid, more vulnerable to peroxidation, and less able to buffer lipid-related stress. For APOE4 carriers, that fragility matters.

What I look for

• Omega-3 Index in a robust, stable range (9%+)

• Consistency over time rather than episodic highs

• Alignment with low triglycerides, low remnant lipoproteins, and low inflammatory markers

A favorable Omega-3 Index does not override poor metabolic control or inflammatory lipid flux. But when it is adequate and stable - alongside quiet lipid signaling - it supports a more resilient, less reactive membrane environment.

8. HDL markers (with restraint)

HDL quantity does not equal HDL function.

Very low HDL-P can suggest reduced lipid recycling capacity, but HDL metrics are blunt tools. I view them as supporting indicators, not decision drivers.

9. Lp(a): context, not control

Lp(a) is genetically determined and largely non-modifiable. I track it for vascular awareness, but I don’t confuse it with lipid trafficking failure or neurodegenerative risk. I am one of the +/- 25% of the population who carries elevated lp(a). If you haven’t been tested for this highly atherogenic lipoprotein, don’t delay. It should be checked at least once. Levels usually remain fairly stable throughout life since elevated levels are genetic.

My personal “directional targets”

Again, these are not universal goals. They are the ranges that, I believe in my case, suggest a quieter lipid environment for APOE4 biology.

• Triglycerides: low and stable

• VLDL / VLDL-P: low

• Remnant lipoproteins: low

• LDL-P: interpreted in context, not isolation

• hs-CRP: low

• Fasting insulin: low

• Glycemic variability: minimal

• Sleep: deep, continuous, and protected

What these markers cannot tell me (and I’m clear about this)

Advanced lipid panels:

• Do not measure brain APOE directly

• Do not show glial lipid droplets

• Do not guarantee protection

  What they do tell me is whether the background metabolic environment is likely to amplify or dampen APOE4-related stress.

Quieting the system vs chasing numbers

My goal is:

• Reduced inflammatory lipid flux

• Less clearance burden

• Stable metabolic signaling

• Fewer repeated stress cycles

In other words: a quieter system that allows fragile lipid-handling pathways to keep up over time.

The bigger picture

Advanced lipoprotein panels don’t replace imaging or future molecular tools. But today, they are among the best accessible ways to infer whether APOE4 biology is being chronically challenged - or given room to function.

Combined with upstream strategies like membrane support, lipid replacement, metabolic stability, and sleep protection, these markers help me course-correct and give me a sense of control.

The takeaway

For me, learning how to read lipoprotein signals through an APOE4 lens has shifted prevention from fear-based interpretation to informed, systems-level monitoring.

Not certainty, but clarity.

And clarity is what facilitates calculated, common sense strategy that will hopefully retain my cognition and memory until that last breath.