This was my first brain biomarker test in the eight years I’ve known of my increased AD risk as an APOE4/4 carrier. While I’ve been tracking all the usual suspects - lipids, glucose, inflammation, sleep, exercise and other metabolic markers - I felt I’d postponed the brain biomarker tests long enough. When the opportunity to visit RetainMed presented itself, I seized the chance to be tested and have a licensed clinician with subject matter expertise present when the verdict was delivered who could explain the results and any potential actions or interventions I might need. RetainMed’s program was very appealing since it incorporates newer blood-based AD biomarkers along with genetics, metabolic, cardiovascular, inflammatory, and hormonal risk, lifestyle and nutrition factors and individualized follow-up recommendations!

In the following deep dive, I will share what was tested, where my results fell directionally and what I’ve learned from the process.

First, I’ll cut to the chase

The overall outcome was reassuring, with a few barely-above-range markers to follow and keep an eye on! Despite being in my 70s and carrying two copies of APOE4, my amyloid blood markers were favorable for my age and genetic status.

One of the biomarkers I found pretty reassuring was my amyloid-beta 42/40 ratio.

Amyloid-beta exists in several forms, including Aβ40 and Aβ42. Aβ42, being the stickier form of amyloid, has a greater tendency to aggregate in the brain. Rather than looking simply at how much Aβ42 is circulating, researchers have found that the ratio of Aβ42 to Aβ40 provides considerably more useful information.

A lower Aβ42/40 ratio in the blood is associated with greater cerebral amyloid deposition, while a higher ratio is more favorable. Perhaps counterintuitively, a higher Aβ42/40 ratio in the blood is considered more favorable. As RetainMed explained it to me, one way to think about this is that my brain and body are working together to efficiently dispose of these proteins. Lifestyle behaviors such as exercise may help support this process, while adequate sleep and other factors support the brain's “trash disposal” and clearance systems.

My ratio fell comfortably within RetainMed’s normal age-adjusted range and, interestingly, at 0.07348 fell within the desirable range for those 25 years younger (which is >0.0713)! That was quite reassuring. One of the more helpful components of the lab reports is that the normal (or expected values) for blood testing results was broken down into ranges based on a person’s age and biological sex, allowing for more of a customized comparison.

It does not prove that I have zero toxic amyloid build-up in my brain. A blood biomarker isn’t the same thing as an amyloid PET scan. It’s also important to note that beta amyloid does occur naturally in the brain as a product of regular brain cell metabolism and is present in healthy brains throughout life. But the risk of cognitive decline related to Alzheimer’s disease pathology occurs when that beta amyloid aggregates improperly and clearance is impaired.

But, now being a few days away from my 74^th birthday, I will definitely put a favorable amyloid ratio in the GOOD NEWS column.

Tau was more nuanced

RetainMed also measured two phosphorylated tau markers: p-tau181 and p-tau217.

These proteins have become increasingly important Alzheimer’s biomarkers.

Tau normally helps stabilize the internal structure of neurons. In Alzheimer’s disease, abnormal phosphorylation and aggregation of tau become part of the disease process.

Both of my individual p-tau measurements remained within the laboratory’s normal ranges.

My p-tau181 was normal and reassuring.

My p-tau217 was also normal, which is very reassuring, but through a careful precision-prevention lens, it’s still a number they want me to keep an eye on over time. For me, it’s another reminder to stay proactive about the things I can control—supporting my brain health, addressing my individual risk factors, and doing what I can to help keep tau from trending in the wrong direction as I age. That’s where I’m personally hedging my bets on access to Obicetrapib as soon as it’s available in Europe (although the RetainMed team isn’t quite sure I even need that just yet). While normal, even a modest reduction in p-tau217 would move me more comfortably into the optimal range.

It’s important, however, not to directly compare the cutoff on my report with Mayo Clinic’s p-tau217 cutoff as though they are interchangeable-because they are not. Different assays use different reference ranges and thresholds. Mayo’s current plasma p-tau217 interpretation considers ≤0.185 pg/mL negative, 0.186–0.324 pg/mL intermediate, and ≥0.325 pg/mL positive. A positive result is consistent with the presence of Alzheimer-associated neuropathological changes. As an APOE4 carrier, I don’t want to get close to that territory!

A marker can still fall within a population reference range while its trajectory over time may eventually tell us something equally (or even more) important.

For me, p-tau217 has therefore become a marker I want to watch — not a marker I am panicking about.

Turn the Research Into an Action Plan

The ratios added another layer

RetainMed also calculated ratios comparing phosphorylated tau with Aβ42.

My p-tau181/Aβ42 ratio was considered optimal.

My p-tau217/Aβ42 ratio was mildly elevated according to their reference system.

Importantly, this did not appear to be driven by a poor Aβ42/40 ratio. My amyloid ratio itself was favorable.

GFAP was the result that initially got my attention

Another marker they measured was GFAP - glial fibrillary acidic protein.

GFAP is produced primarily by astrocytes, the incredibly important support cells that surround and interact with neurons.

When astrocytes become activated or stressed, GFAP in the blood can increase. Researchers are studying it as a marker of neuroinflammation and neurodegenerative processes.

Mine was considered mildly elevated according to RetainMed’s reference ranges.

I subsequently did some digging of my own and discovered that GFAP interpretation is not nearly as simple as a single universal cutoff. Levels rise substantially with age, different assays produce different values, and age-adjusted reference intervals matter.

So I am much less alarmed by this result than I initially was.

RetainMed also emphasized that GFAP is not specific for Alzheimer’s disease. It can be influenced by numerous biological and medical factors (including metabolic health, inflammatory conditions, infections, amongst quite a few others.).

Something worth watching to more globally understand how brains age, but not clear evidence of one specific neurodegenerative disease.

And that brings me to another biomarker that I found particularly reassuring.

My NfL was normal

Neurofilament light chain, or NfL, is a structural protein found in neuronal axons.

When neurons or their axons are injured, NfL can escape into cerebrospinal fluid and eventually into blood.

Elevated NfL can occur in numerous neurological conditions, so it isn’t an Alzheimer’s-specific marker. But it is useful as a marker of neuroaxonal injury.

Mine was comfortably within the normal range - and fell within the expected range for ages 40-49.

In other words, the panel showed no elevated NfL signal suggesting active neuroaxonal injury.

My genetics offered another encouraging finding

In addition to confirming gene variants I was already aware of — APOE4/4 and MTHFR C677T homozygosity — the testing also confirmed my protective KLOTHO genotype. While I believed to have the Klotho variant based on my 23andme results, I wasn’t 100% certain.

I carry one copy of a KLOTHO variant that has been associated in some research with healthy aging, cognitive resilience and longevity.

The science around KLOTHO is still evolving, and it absolutely does not erase APOE4 risk.

But I found it encouraging for another reason:

APOE is not the entire genome.

We tend to talk about APOE4 as though one gene determines our neurological destiny. In fact, thousands of genetic variants, environmental exposures, metabolic factors and lifestyle choices interact over decades.

That is why two people with exactly the same APOE genotype can age very differently.

Along these lines, I also learned about my results on their new APOE4 protein expression test, and a related APOE blood test that measures overall APOE gene function in real-time. As I’ve written about previously, 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. Yet 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. While research in this area is still in its early stages, measuring a baseline that we can monitor over time may be an important emerging tool to help people with one or more copies of the APOE4 genetic variant.

Turn the Research Into an Action Plan

Cardiovascular health looked very good

The cardiovascular portion of my evaluation was also reassuring.

My atherogenic cholesterol markers were extremely well controlled, including LDL-related measures and ApoB. RetainMed’s ApoB target for APOE4 carriers similar to me is <55 mg/dL.

Their emphasis on lipid markers is obvious, and from what I’ve heard Dr. Isaacson say more than once, those carrying APOE4 had better have their lipids in a good place. With so much misinformation online — such as people taking fellow APOE4/4 carrier Nick Norwitz’s self-experimentation with high cholesterol in LMHR phenotypes and extrapolating from it that it’s perfectly OK for APOE4 carriers to ignore high LDL/ApoB as long as their inflammation is low and their CAC score is ZERO — it’s eyebrow-raising, to say the least. I’ve personally heard Nick Norwitz say more than once that the long-term effects of high cholesterol in LMHR phenotypes are not known.

I firmly believe Alzheimer’s prevention and cardiovascular prevention should not be viewed as separate projects. And while the internet continues to perpetuate claims about statin evils and cholesterol benefits, the nuance of individual risk factors and biology is often entirely missed.

For APOE4 carriers in particular, I continue to believe that maintaining excellent vascular health is one of the most important modifiable pieces of the prevention puzzle. And the science appears to be pretty clear that reducing atherogenic lipid burden is beneficial for cardiovascular risk, which is itself relevant to brain health. Obicetrapib’s BROADWAY trial and the resulting exploratory p-tau217 findings in APOE4/4 carriers add an intriguing piece to that discussion.

My fatty acids were another bright spot

The Boston Heart testing included a fairly sophisticated fatty-acid panel.

My omega-3 status and DHA were considered very well optimized.

That was gratifying because DHA is a major structural fatty acid in neuronal membranes, and maintaining good omega-3 status has been a deliberate part of my nutritional strategy for years.

So what happens next?

This was probably the most important part of my follow-up visit.

RetainMed was very clear that these blood biomarkers are not intended to diagnose Alzheimer’s disease. And that the preventive brain health journey is a marathon - not a sprint.

Their recommendation was to establish care with a neurologist — particularly in light of my advancing age — and create a proper neurological baseline.

That may include:

● comprehensive neuropsychological testing

● a baseline structural brain MRI, preferably with volumetric analysis

● additional testing the neurologist considers appropriate

Once that baseline is established, the plan is to repeat selected blood biomarkers periodically and look at trajectory.

This is where prevention medicine is headed

What excites me most about this experience isn’t my individual result – although I was very pleased with it. It is the possibility that we are moving toward a very different model of Alzheimer’s prevention.

In the past, waiting for memory loss, poor cognitive test results or — God forbid — an AD diagnosis was the norm.

Today, we have far better tools for identifying risk and biological changes earlier, along with interventions that may modify risk factors and, in some cases, disease biomarkers. Whether those changes translate into prevention or reversal of Alzheimer’s disease depends on the intervention and the individual, so I don’t think we can yet say broadly that interventions can “halt decline” or “reverse damage.”

But we are indeed living in exciting times!

In Conclusion

Following my test-results review, I received a detailed copy of everything, along with explanations and numerous educational materials and reference links to learn more. It also included recommendations for additional optional testing, medication adjustments, supplements I should continue, those that are optional, and those that aren’t really needed — all of which I can use for guidance in my ongoing effort to maintain my cognitive function and enjoy my life until that last breath! I am very grateful to the RetainMed team, and to Dr. Isaacson for his guidance and for training the team in his precision-prevention approach. Most of all, I’m grateful for the reassurance this experience has given me.

I plan on returning to RetainMed in the future to track my markers and stay on top of my brain health. Having a competent partner to do that with has been life-changing.

Turn the Research Into an Action Plan

In a previous post, I explained what CETP inhibition is and how it protects the brain and cardiovascular system. The biology is very intriguing - and while the cardiovascular benefits of CETP inhibition have been known for about 30 years - a successful drug development has remained elusive - until now!

In addition to astonishing improvements in cardiovascular risk biomarkers, the recent PREVAIL trial discovered something else - the possibility that manipulating cholesterol transport might have implications extending beyond cardiovascular disease and into Alzheimer’s disease, especially for those of us carrying APOE4.

Just 3 days ago, the European Commission approved Obicetrapib as Ubeslo®, as well as a fixed-dose combination of Obicetrapib plus Ezetimibe called Evlarco®. This is the first regulatory approval of Obicetrapib anywhere in the world.

The approval follows several Phase 3 trials showing substantial LDL cholesterol lowering on top of existing lipid-lowering therapy. But perhaps even more interesting for this community, we now also have peer-reviewed data suggesting an effect on Alzheimer’s biomarkers - and the strongest signal appeared in people carrying APOE4.

So rather than repeating what I’ve previously written regarding CETP, I want to look at where the evidence stands now.

And there is a lot to unpack.

First: What Exactly Is Obicetrapib?

Obicetrapib is a once-daily, oral CETP inhibitor.

CETP stands for cholesteryl ester transfer protein. It participates in the transfer of cholesterol esters and triglycerides between lipoproteins.

Blocking CETP produces a somewhat unusual lipid profile:

LDL-C falls. HDL-C rises—dramatically. ApoB falls. Lp(a) also falls.

That combination is part of what originally made CETP inhibition so attractive.

But there is a long and rather disastrous history behind this drug class - until now!

The Obicetrapib Trials

ROSE: An Early Hint That This Drug Was Different

The Phase 2 ROSE trial studied 120 people whose LDL-C remained at least 70 mg/dL despite high-intensity statin therapy.

Participants received either a placebo or 5 mg or 10 mg of Obicetrapib for eight weeks.

Those participants on a higher Obicetrapib dose, compared with placebo, saw reductions of approximately:

• LDL-C: 51%

• ApoB: 30%

• non-HDL-C: 44%

• Lp(a): 57%

HDL-C increased by as much as 165%.

Those numbers got people’s attention.

Although just a Phase 2 trial - the results certainly looked impressive!

BROADWAY: The Big Test

As a next step, the BROADWAY trial enrolled 2,530 patients at high cardiovascular risk who had established atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia.

Importantly, these weren’t untreated people.

They were already receiving maximally tolerated lipid-lowering therapy but still had LDL-C of at least 70 mg/dL.

Participants were randomized 2:1 to:

Obicetrapib 10 mg daily

or

a placebo

for one year.

Their average LDL-C at baseline was about 98 mg/dL.

At 84 days, LDL-C had fallen 29.9% from baseline in the Obicetrapib group, versus a 2.7% increase with placebo, a placebo-adjusted difference of 32.6 percentage points.

Adverse-event incidence was similar between groups. The results of the Broadway trial laid the foundation for the European approval this week!

But there was another trial that may be even more interesting!

TANDEM: Obicetrapib + Ezetimibe

Many readers here will already be familiar with Ezetimibe, which reduces intestinal cholesterol absorption through a completely different mechanism.

The TANDEM trial asked an obvious question:

What happens if we combine Obicetrapib and Ezetimibe?

The trial randomized 407 participants to:

• Obicetrapib 10 mg + Ezetimibe 10 mg

• Obicetrapib alone

• Ezetimibe alone

• Placebo

At 84 days, the combination produced approximately 49% greater LDL-C reduction than placebo.

It lowered LDL-C about 28% more than Ezetimibe alone and about 17% more than Obicetrapib alone.

And it does this in one oral tablet.

That combination has now been approved in Europe as Evlarco®.

For people who cannot achieve their LDL goals with statins—or cannot tolerate sufficient statin doses, this potentially creates another potent oral option before moving to injectable therapies.

BROOKLYN: Familial Hypercholesterolemia

The BROOKLYN trial tested Obicetrapib in 354 people with heterozygous familial hypercholesterolemia whose LDL remained elevated despite existing treatment.

The mean starting LDL-C was 122 mg/dL.

At day 84, compared with placebo, Obicetrapib produced:

LDL-C: −36.3%

ApoB: −24.4%

non-HDL-C: −34.5%

Lp(a): −45.9%

and an extraordinary:

HDL-C: +138.7%

Again, the drug was generally well tolerated.

But LDL-C Isn’t the Entire Story

LDL-C, LDL particle number and ApoB don’t necessarily change by identical percentages with CETP inhibition.

ApoB represents the number of circulating atherogenic particles. Every LDL, VLDL remnant, IDL and Lp(a) particle carries one ApoB molecule.

So when LDL-C falls 35–40% but ApoB falls perhaps 20–30%, we should not simply assume cardiovascular risk has fallen by the LDL-C percentage.

CETP inhibition changes the composition of the particles themselves.

For those of us who follow ApoB rather than relying exclusively on LDL-C, this is an important distinction.

It is also one reason the next trial matters so much.

Build Your APOE4 Prevention Strategy

PREVAIL: Does Obicetrapib Actually Prevent Heart Attacks and Strokes?

Lower LDL is encouraging.

Lower ApoB is encouraging.

But ultimately we want to know whether people experience fewer cardiovascular events.

That is what the PREVAIL study is designed to answer.

More than 9,500 patients with established ASCVD and inadequately controlled LDL-C have been enrolled.

The primary question is whether adding Obicetrapib reduces major adverse cardiovascular events.

Until those results are available, we should distinguish between two statements:

Obicetrapib has convincingly demonstrated substantial lipid lowering.

and

Obicetrapib has independently demonstrated that it reduces cardiovascular events.

We have evidence for the first.

PREVAIL is intended to answer the second.

And now we get to the part that I suspect most readers of this newsletter are waiting for.

What Does Any of This Have to Do With Alzheimer’s?

Potentially quite a lot.

APOE isn’t just an Alzheimer’s gene.

APOE is fundamentally a lipid-transport gene.

And the brain is an extraordinarily lipid-rich organ.

Because circulating cholesterol does not simply cross the intact blood-brain barrier in meaningful quantities, the brain largely manages its own cholesterol economy.

Astrocytes manufacture cholesterol and package lipids into APOE-containing particles that distribute them to neurons and other cells.

APOE4 appears to perform some of these jobs differently from APOE3.

Research increasingly implicates APOE4 in altered lipid handling, cholesterol accumulation, oxidative stress, inflammation, impaired amyloid clearance and blood-brain-barrier dysfunction.

Which raises an intriguing possibility:

Could modifying CETP activity improve the lipid environment of the APOE4 brain?

There have been clues for years that it might.

Certain genetic variants associated with reduced CETP activity have been associated with longevity and slower cognitive decline, and some studies suggest that CETP genetics can modify APOE4-associated memory decline.

But genetics and biological plausibility alone are insufficient - now we have some data to back it up.

The Surprise Inside the BROADWAY study

The BROADWAY trial was a cardiovascular trial.

But forward-thinking investigators had prespecified an Alzheimer’s biomarker substudy.

Of the 2,530 BROADWAY participants, 1,535 had known APOE status and plasma p-tau217 measurements at both baseline and 12 months.

And this is where things become exciting!

Across the entire substudy population, plasma p-tau217 increased 4.94% with placebo but only 2.09% with Obicetrapib.

That difference was statistically significant.

Not an enormous effect - until researchers separated participants by APOE genotype!

APOE4 Changed the Picture

Among APOE4 carriers:

Placebo: p-tau217 +6.91%

Obicetrapib: +1.92%

Again, a significant difference.

But among the small group of APOE4 homozygotes, the signal became considerably larger.

The placebo group experienced a:

+12.67% increase in p-tau217

while the Obicetrapib group experienced a:

−7.81% decrease.

The treatment difference was:

20.48%

with P=0.010.

As an APOE4/4 carrier myself, that number is the most exciting thing I’ve read about APOE4 in the last decade.

But there is an important caveat.

There were only 29 APOE4 homozygotes in this analysis.

Twenty-nine.

So however exciting that result looks, and I do think it is very exciting - it needs replication in a much larger APOE4/4 population study.

And It Wasn’t Only p-tau217

This is perhaps the part of the study that makes the result harder simply to dismiss as noise.

Researchers also examined:

• p-tau181

• GFAP

• neurofilament light (NfL)

• Aβ42:40

• p-tau217/Aβ42:40

Across the full population, Obicetrapib significantly limited the increase in the p-tau217/Aβ42:40 ratio.

And among APOE4/4 participants, researchers reported significant favorable effects on several additional biomarkers.

For example:

GFAP

Obicetrapib: −6.39%

Placebo: +8.85%

and:

NfL

Obicetrapib: −10.49%

Placebo: +6.82%

The biomarker directions therefore weren’t confined to one isolated measurement.

That is encouraging.

But I want to put a large caveat next to the word encouraging.

Build Your APOE4 Prevention Strategy

Biomarkers Are Not Alzheimer’s Disease

This distinction is essential.

Obicetrapib has not been shown to prevent Alzheimer’s disease.

It has not been shown to prevent cognitive decline.

And this substudy was conducted in cardiovascular patients - not in cognitively normal APOE4 carriers selected specifically for Alzheimer’s prevention.

What it showed was that over one year, several blood biomarkers associated with Alzheimer’s pathology progressed differently in people taking Obicetrapib.

Even the investigators conclude that dedicated prevention trials are needed to determine whether these biomarker changes translate into clinical benefit.

Why Might APOE4/4 Respond More Strongly?

This may be the most fascinating question of all.

If the result holds up, the increasing treatment effect with increasing APOE4 burden could be telling us something about mechanism.

APOE4 is associated with dysfunctional lipid transport in the brain.

Astrocytes carrying APOE4 can accumulate cholesterol esters and lipid droplets. Lipid trafficking and cholesterol efflux may become impaired. Oxidative stress and inflammatory signaling can increase.

HDL-like particles within the central nervous system participate in moving cholesterol between cells.

CETP may influence that system.

So one hypothesis is that CETP inhibition improves cholesterol transport and HDL-particle function in a brain whose lipid-handling machinery is particularly impaired by APOE4.

The more impaired the starting system - in theory - the greater the opportunity for improvement.

That would offer one possible explanation for why the biomarker signal appeared progressively stronger from the overall population from APOE4 carriers to APOE4 homozygotes.

Again, this is hypothesis only!

We don’t yet know that this is the mechanism responsible for the BROADWAY findings.

Does Obicetrapib Have to Cross the Blood-Brain Barrier?

This is another fascinating wrinkle.

The simplistic model would be:

Drug enters brain → inhibits brain CETP → improves Alzheimer’s pathology.

But biology may be more complicated.

Peripheral lipoprotein metabolism can influence vascular function, inflammation and blood-brain-barrier integrity without requiring large concentrations of a drug to enter the brain.

At the same time, an earlier proof-of-concept study specifically investigated Obicetrapib in APOE4 carriers with early Alzheimer’s disease and examined cerebrospinal-fluid lipoproteins and cholesterol-efflux capacity.

So researchers are actively investigating both peripheral and CNS mechanisms.

This is an area where I expect we will learn considerably more.

The Cardiovascular/Alzheimer’s Intersection

This is also why I think Obicetrapib is especially interesting for APOE4 carriers.

We tend to talk about cardiovascular disease and Alzheimer’s disease as separate problems.

Biologically, they overlap far more than that separation suggests.

APOE4 increases Alzheimer’s risk.

It also adversely affects lipid metabolism and cardiovascular risk.

Vascular dysfunction can affect cerebral perfusion.

Blood-brain-barrier dysfunction may facilitate neuroinflammation.

Lipid dysregulation influences both atherosclerosis and brain biology.

And many of the things we do to protect our cardiovascular system - exercise, blood-pressure control, metabolic health, avoiding smoking and managing atherogenic lipoproteins - also appear relevant to maintaining brain health.

Obicetrapib is unusual because the same molecular target may potentially influence both sides of this equation.

A Particularly Interesting Attia Interview

If you want to understand the history and reasoning behind all of this, I highly recommend Peter Attia’s recent conversation with Dr. Michael Davidson, founding CEO of New Amsterdam Pharma, the company that developed Obicetrapib. Bookmark it and do listen - it’s absolutely worth the time!

Davidson is both a cardiologist/lipidologist and developed this medication as a result of his own familial experience with cardiovascular disease.

When I first wrote about CETP inhibition, I regarded it as one of the more intriguing emerging targets for APOE4 - and I still do.

But we have moved beyond pure speculation. We now have large randomized Phase 3 cardiovascular trials showing substantial LDL-C lowering, reductions in ApoB and Lp(a).

We have European regulatory approval.

We have a large cardiovascular outcomes trial underway.

And, perhaps most intriguing for this community, we now have a prespecified, peer-reviewed Alzheimer’s biomarker analysis involving more than 1,500 people, showing a modest effect in the overall population but a progressively larger signal in APOE4 carriers - and a striking result in the small APOE4/4 subgroup.

For those of us carrying APOE4, the idea that an oral drug could simultaneously improve cardiovascular risk factors while potentially influencing pathways involved in Alzheimer’s pathology is difficult to ignore.

And Next Comes SPINOZA

Perhaps the most important next chapter will be SPINOZA, NewAmsterdam’s planned Phase 2b trial designed specifically around Alzheimer’s prevention.

More information on this clinical trial can be found here: https://clinicaltrials.gov/study/NCT07794670

Unlike BROADWAY, which enrolled people for cardiovascular disease risk and discovered the Alzheimer biomarker signal in a prespecified substudy, SPINOZA is being designed to test that signal prospectively in people with preclinical Alzheimer’s disease. The randomized, double-blind, placebo-controlled study is expected to enroll up to 400 participants, including at least 100 APOE4/4 carriers, along with approximately 125–150 APOE3/4 and 125–150 APOE3/3 participants. The primary endpoint will be the change in plasma p-tau217 at 52 weeks, with additional Alzheimer biomarkers and cognition, using the PACC5 cognitive composite, also being followed.

That deliberate enrollment of a much larger APOE4/4 group is particularly important. The remarkable BROADWAY result in APOE4 homozygotes came from only 29 people. SPINOZA should give us a much better opportunity to determine whether that striking APOE4 gene-dose signal was real—and whether CETP inhibition can actually alter the trajectory of Alzheimer’s pathology before cognitive symptoms appear.

For me, this is where the Obicetrapib story becomes particularly exciting. We are no longer talking only about lowering LDL-C, ApoB and Lp(a), nor are we simply speculating from genetics about what CETP inhibition might do in the APOE4 brain. We now have a signal in humans and a trial being designed specifically to test it.

If SPINOZA confirms what BROADWAY unexpectedly uncovered - particularly in APOE4/4 carriers - we may be looking at something much bigger than a new cholesterol medication. We may be looking at an entirely new approach to Alzheimer’s prevention: targeting lipid biology years before the disease becomes symptomatic.

We aren’t there yet. But this is one trial we should all be watching very closely.

Build Your APOE4 Prevention Strategy

Today, September 21, 2026, the European Commission granted marketing authorization for obicetrapib, marking its first regulatory approval anywhere in the world.

Two versions have been approved:

Ubeslo® — obicetrapib 10 mg as a once-daily tablet.

Evlarco® — a single tablet combining obicetrapib 10 mg with ezetimibe 10 mg.

This is particularly interesting because obicetrapib has produced substantial LDL-C reductions in Phase 3 trials. NewAmsterdam reports reductions of up to approximately 40% with obicetrapib alone and approximately 50% when combined with ezetimibe, compared with placebo. Tolerability in these trials was reported as comparable to placebo.

Obicetrapib is a CETP inhibitor, but unlike earlier drugs in this class, it is a low-dose oral therapy being developed primarily for its ability to substantially lower LDL-C and other atherogenic lipoproteins.

For those of us interested in APOE4 and cardiovascular risk reduction, this is a development worth watching closely. Cardiovascular health and brain health are intimately connected, although it is important to emphasize that obicetrapib is not approved as an Alzheimer’s treatment or prevention therapy.

What happens next?

European approval does not necessarily mean you can walk into a pharmacy tomorrow and get it. Menarini holds the European commercialization rights, and we are now waiting for details regarding country-by-country launch dates, pricing and actual pharmacy availability.

But the big regulatory hurdle has now been crossed.

Obicetrapib is officially an approved drug.

Read the NewAmsterdam Pharma announcement

In the years I’ve been researching the APOE4 and AD Prevention topic, I’ve often seen reference to the integrity of our blood-brain barrier (BBB). The BBB is a highly specialized vascular system that controls what passes from our circulation into the brain - both the good and the bad.

We have known for some time that APOE4 is associated with greater blood-brain barrier dysfunction. Exactly what the role of APOE4 is, and how it behaves at the blood brain barrier, remains elusive.

A fascinating new study published September 11, 2026 in Nature Aging may have identified another important piece of that puzzle: Fibronectin.

Although fibronectin isn’t exactly a household word, this study may have important implications for how we think about protecting the APOE4 brain long before cognitive symptoms appear.

What Is Fibronectin?

Fibronectin is a normal and essential protein in the extracellular matrix—essentially part of the structural environment surrounding our cells. It plays important roles in wound healing, cell adhesion, tissue repair and communication between cells.

The problem appears to be too much fibronectin in the wrong place.

Turn the Research Into an Action Plan

APOE4 Astrocytes Produce More Fibronectin

The researchers used genetically matched human astrocytes carrying either APOE3/3 or APOE4/4.

The difference was striking.

APOE4/4 astrocytes showed increased fibronectin expression and abnormal fibronectin deposits. In human brain data, astrocytes also showed the strongest APOE4-associated increase in FN1, the gene encoding fibronectin.

The researchers then looked at aged APOE3 and APOE4 knock-in mice.

The APOE4 mice had approximately 99% higher brain fibronectin levels than APOE3 mice.

Importantly, this occurred in an APOE4 model without requiring overt Alzheimer’s pathology.

That suggests that APOE4 itself may help create a vascular environment favorable to fibronectin accumulation.

Amyloid and Inflammation Make It Worse

APOE4 wasn’t acting alone.

The researchers found that amyloid-beta 42 and inflammatory signaling also increased fibronectin production.

TNF, an inflammatory cytokine, activated NF-κB signaling in astrocytes and increased fibronectin.

This results in an interesting convergence:

APOE4 + amyloid + inflammation → increased fibronectin

And the location matters.

The fibronectin accumulated around the blood vessels at astrocytic endfeet—the very interface where communication between brain cells and the vascular system helps maintain the BBB.

Fibronectin Wasn’t Just a Marker

This is perhaps the most important part of the study. It would be easy to assume that fibronectin simply accumulates because the brain or blood vessels are already damaged.

The researchers tested that possibility.

When they experimentally increased fibronectin in astroglia, fibronectin itself was sufficient to cause blood-brain barrier leakage.

Conversely, reducing fibronectin improved BBB function in experimental models.

That moves fibronectin from being merely an interesting biomarker toward being a possible mediator of the damage.

How Does Fibronectin Damage the BBB?

The mechanism is fascinating.

Excess fibronectin appears to disrupt the normal communication between astrocytes and the blood vessels they help protect. It interferes with important signaling pathways that help maintain healthy blood vessels and an intact blood-brain barrier.

Put simply:

APOE4 + amyloid + inflammation
↓
Too much fibronectin around brain blood vessels
↓
Normal communication between astrocytes and blood vessels is disrupted
↓
The blood-brain barrier becomes more vulnerable and leaky

Importantly, this pathway offers researchers several possible targets for preventing or reversing the damage.

There May Be More Than One APOE4 Pathway to BBB Damage

This is where the new discovery becomes even more interesting.

Fibronectin isn’t the first mechanism researchers have identified linking APOE4 to BBB breakdown.

More than a decade ago, researchers identified another way APOE4 may damage the blood-brain barrier. APOE4 can trigger inflammatory activity in cells surrounding brain blood vessels, leading to the breakdown of proteins that help keep the barrier strong.

Put simply:

APOE4
↓
Increased inflammation around brain blood vessels
↓
Breakdown of the blood-brain barrier
↓
Increased leakage

That pathway is particularly interesting because vascular abnormalities appeared before neuronal dysfunction in experimental APOE4 models.

We may therefore be looking at at least two interacting mechanisms:

Pericytes:
APOE4 → CypA → NF-κB → MMP-9 → BBB degradation

Astrocytes:
APOE4 / amyloid / inflammation → fibronectin → integrin/FAK → disrupted growth-factor signaling → BBB dysfunction

Different cells. Different pathways.

Same vulnerable blood-brain barrier.

And inflammation—particularly NF-κB signaling—may connect portions of the two.

Turn the Research Into an Action Plan

An Unexpected Connection to mTOR

This is where another piece of research caught my attention.

The new fibronectin study did not test rapamycin, so what follows is a mechanistic possibility—not evidence that rapamycin prevents this newly identified APOE4 pathway.

However, there is older research showing that mTOR signaling regulates extracellular-matrix production, including fibronectin.

In fibroblast experiments, activation of the Akt/mTOR pathway increased production of extracellular-matrix proteins, while inhibiting mTOR with rapamycin reduced fibronectin production and secretion.

Other experimental studies have similarly found that rapamycin can suppress TGF-β-induced fibronectin production.

Why is that particularly interesting in APOE4?

Because rapamycin has already been tested in APOE4 mice.

In a published APOE4 mouse study, rapamycin restored blood-brain barrier integrity and cerebral blood flow and normalized vascular cyclophilin A levels. The treated animals also showed improvements in brain glucose metabolism and early learning deficits.

So we already have evidence in an APOE4 animal model connecting rapamycin with:

↓ abnormal CypA signaling

and

↑ BBB integrity

Separately, we have experimental evidence from other tissues showing:

mTOR inhibition → ↓ fibronectin production

Now we have a new APOE4 study showing:

↑ fibronectin → BBB dysfunction

The missing experiment is obvious—and important:

Does mTOR inhibition reduce the abnormal astrocytic/perivascular fibronectin produced in an APOE4 brain?

As far as I can determine, we don’t yet know.

That is very different from saying rapamycin has been proven to prevent this pathway. It hasn’t.

But mechanistically, it’s a question worth asking.

Can We Lower Brain Fibronectin Today?

This is where I think caution is warranted.

There is currently no established treatment shown to selectively lower pathological perivascular fibronectin in the human APOE4 brain.

What the research does reinforce, however, is the potential importance of controlling the biological environment that appears to promote abnormal fibronectin deposition.

In the new study, inflammation increased fibronectin.

Amyloid increased it.

APOE4 increased it.

That gives me another reason to pay attention to metabolic and vascular health, chronic inflammatory burden, exercise, sleep and the other modifiable factors that influence the environment in which the aging brain operates—even though we cannot yet say that any particular lifestyle intervention lowers brain fibronectin.

My Bigger Takeaway

For me, this paper reinforces something I’ve increasingly come to believe about APOE4 and Alzheimer’s prevention:

Researchers are identifying the downstream consequences of APOE4—and those may be much more modifiable than the gene itself.

Research discussed

Bhattarai P, Yilmaz E, Cakir EÖ, et al. Fibronectin mediates APOE4-driven blood–brain barrier dysfunction in Alzheimer’s disease. Nature Aging. Published September 11, 2026.

Bell RD, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012.

Lin AL, et al. Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease. Journal of Cerebral Blood Flow & Metabolism. 2017.

Some fascinating new research out of Stockholm University is looking at something we don’t normally associate with Alzheimer’s disease: the liver.

The researchers are investigating whether APOE4 produced in the liver may contribute to Alzheimer’s risk through its effects on metabolism, inflammation and the vascular system - even though liver-produced APOE itself does not cross the blood-brain barrier (BBB).

Why did this immediately catch my attention?

Because it brought me right back to one of the reasons Dr. Alan Green prescribed rapamycin to me in 2018.

As I explained in a previous post, Dr. Green was very interested in the APOE4 → Cyclophilin A (CypA) → blood-brain barrier pathway.

Research has shown that APOE4 can activate an inflammatory pathway in the cells surrounding our tiny brain blood vessels:

APOE4 → ↑ Cyclophilin A → NF-κB → MMP-9 → weakening of the blood-brain barrier.

And this isn’t just theoretical. Researchers have found evidence of BBB breakdown in cognitively normal APOE4 carriers, particularly in brain regions important for memory. Importantly, that vascular damage can occur independently of amyloid and tau.

So where does rapamycin come in?

In APOE4 mice, rapamycin has been shown to normalize vascular Cyclophilin A signaling, restore blood-brain barrier integrity, improve cerebral blood flow and improve brain glucose metabolism.

That research was one of the things that fascinated Dr. Green and why he insisted that every APOE4 carrier at mid-life (women after menopause) should be proactively protecting the blood brain barrier with once weekly rapamycin.

Now Sweden’s researchers are asking whether some of the signals driving APOE4-related brain vulnerability may actually originate outside the brain - in the liver and systemic circulation.

They are even planning to study approximately 1,500 liver-transplant recipients, creating a remarkable natural experiment: the recipient keeps his or her own APOE genotype in the brain while receiving a liver that may have a different APOE genotype.

Turn the Research Into an Action Plan

Just imagine what we could learn from that!

The Swedish research doesn’t yet show that the liver acts through Cyclophilin A, nor does it prove that rapamycin prevents Alzheimer’s disease in humans.

But the pieces certainly make for an intriguing hypothesis:

APOE4 systemic effects → vascular inflammation → CypA activation → BBB damage → increased brain vulnerability

And potentially:

Rapamycin → mTOR inhibition / reduced vascular inflammatory signaling → better BBB integrity

Nearly eight years after Dr. Green first explained his theory to me, I’m fascinated to see Alzheimer’s research increasingly looking beyond the brain itself. Next month marks 2 years since Dr. Green left this realm…and it would be so exciting to see his theory validated.

We are living in very exciting times. Research is finally closing in on the contributing factors driving cognitive decline. I truly believe we are on the cusp of knowing how to mitigate APOE4 - and I won’t be surprised if APOE4’s deleterious mechanism is uncovered in this decade yet!

Turn the Research Into an Action Plan

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.”

See What I'm Tracking & Trying

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!!!

See What I'm Tracking & Trying

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.

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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