Alzheimer’s doesn’t have a single cause. It’s a multifactorial disease, which means there are many underlying contributors, and they aren’t the same for everyone. Some of them are simple to address, and some aren’t. I wrote about 4 simple ones in Low-Hanging Fruit for Alzheimer’s Prevention.
The goal of Alzheimer’s prevention is to find and improve as many of them as possible, ideally long before symptoms show up. That’s still the goal after symptoms start or after an MCI diagnosis, but the longer you wait after a diagnosis, the lower your chances of cognitive improvement.
One of the not-so-simple contributors is how cholesterol behaves in the brain.
Just FYI: this post gets a little technical. I’ve kept it as plain as I can for anyone who wants to understand the process, but if you want the bottom line: Lowering brain cholesterol really isn’t “a thing” and would miss the real problem if it were, although we hear that high cholesterol in the brain is a dementia risk factor. It’s actually poor cholesterol transport in the brain, especially for APOE4 carriers, and we can do something about that.
Several things affect how well the brain handles its cholesterol:
Your APOE genotype
How well brain cells move extra cholesterol out
How efficiently the brain gets rid of what it doesn’t need
Insulin resistance
Oxidative stress
Inflammation
Aging
Plasmalogen levels
That last one, a group of fats called plasmalogens, is missing from most of the conversations I’ve heard, and it’s tied to most of the others on the list.
It matters for anyone working on prevention or helping someone with MCI or early dementia, and it matters most for people who carry a gene called APOE4.
What does APOE4 have to do with cholesterol?
If APOE4 is new to you, it’s the strongest known genetic risk factor for late-onset Alzheimer’s. About one in four people carry at least one copy. One copy raises the risk, and two copies raise it more.
The APOE gene makes a protein, also called APOE, that helps move cholesterol around the body. Because of the way the APOE4 version handles cholesterol, APOE4 carriers tend to have more of it in their blood.
That may or may not be a problem, depending on other factors, but it makes them more likely to be prescribed medication to lower it. Some are even told it will protect their brain.
Is lower cholesterol always better?
Cholesterol itself isn’t dangerous. Your cells depends on it.
Every cell in your body uses it to build and maintain its outer layer.
Your body uses it to make hormones like estrogen, progesterone, testosterone, and cortisol, along with vitamin D.
Your brain needs it. Your brain is about 2% of your body weight, but holds about 25% of your body’s cholesterol.
Your brain uses cholesterol to build the connections between brain cells where memories get made.
It uses cholesterol to make myelin, the protective coating that wraps the brain’s wiring so signals travel fast.
It uses cholesterol to make its own hormones, including pregnenolone and its own estrogen and progesterone, which support memory, mood, and myelin repair.
Cholesterol becomes a problem when it gets damaged by oxidation, which is most often driven by high triglycerides, insulin resistance, and a few other things I’ll cover in a future post.
Low cholesterol carries its own risks. In older adults, higher total cholesterol has been linked with a lower risk of dementia, and low cholesterol has been linked with shrinkage in the brain’s memory centers.
In long-term studies, lower cholesterol showed up years before people were diagnosed. In the ReCODE protocol, we view total cholesterol under 150 as a serious risk factor.
Where does your brain get its cholesterol?
The cholesterol system in your brain is separate from the one in the rest of your body. Your brain makes its own cholesterol. A protective lining around the brain’s blood vessels, called the blood-brain barrier, keeps the cholesterol in your bloodstream out, along with other things that could harm the brain.
Keeping the two systems separate is how your brain stays in control of its own cholesterol supply.
A high cholesterol number on your blood test is telling you about your blood, not your brain. Cholesterol in the brain can become a dementia risk factor, but not because there’s too much of it.
The problem comes when it can’t be transported as well as it was when you were younger, and that’s especially true for people who carry the APOE4 gene.
What happens when cholesterol builds up in the brain?
When cholesterol isn’t transported well, it builds up in brain cells. Through a complicated process related to that buildup, the brain makes more amyloid-beta, the sticky protein that forms clumps and is used to help diagnose Alzheimer’s.
Your brain relies on a few key players to move extra cholesterol out of its cells.
A pump in the outer layer of brain cells pushes extra cholesterol out.
The APOE protein picks it up and carries it to where it’s needed. A building block in APOE called cysteine helps it do this job well, and the APOE4 version is missing it.
Plasmalogens help cholesterol leave the cell so it can be carried away.
Plasmalogens are a special kind of fat built into the outer layer of your cells. Besides helping clear cholesterol, they make up a large share of myelin, which breaks down in Alzheimer’s.
Brain plasmalogens can’t be measured directly, but blood levels can, and low blood levels have been linked with Alzheimer’s and with how severe the dementia is.
Plasmalogen levels peak somewhere between 30 and 40, then decline, dropping significantly by around 70. Blood levels start falling years before memory problems appear, and the lower they go, the more severe the dementia tends to be.
Why are APOE4 carriers hit hardest?
Those of us who carry the APOE4 gene make a version of the APOE protein that’s missing the cysteine building block, so it doesn’t transport cholesterol as well. That doesn’t matter much when we’re young, because our bodies are making plenty of plasmalogens, which make up for it and keep cholesterol moving.
As we get into our 50s and beyond, our plasmalogen levels drop. APOE4 carriers tend to have even lower levels on top of that decline. In a study of about 6,300 people, blood plasmalogens were highest in APOE2 carriers, lower in APOE3, and lowest in APOE4.
Without enough plasmalogens to make up for the missing cysteine building block, cholesterol builds up, more amyloid-beta gets made, and the risk climbs.
Low plasmalogens can lead to cholesterol buildup with any APOE type, but APOE4 carriers are more vulnerable.
Low plasmalogen levels are treatable. It’s clear from the before/after test results that the right supplementation increases them. Eating plasmalogen-rich foods like scallops or taking a standard supplement doesn’t raise them enough.
It takes plasmalogen precursor supplements, like Prodrome’s N3 and N9, which make it through digestion and give your body what it needs to build plasmalogens, skipping the early steps of production that slow down with age.
Does a statin help your brain?
Some statins, including atorvastatin (Lipitor), simvastatin (Zocor), and lovastatin, are fat-soluble and cross into the brain, where they slow how much cholesterol it makes.
Over time, that can lower the amount in the brain somewhat. Some researchers suspect that’s part of why some people report memory problems on those statins, though the FDA’s review didn’t tie the reports to any particular type.
The brain’s problem isn’t that it’s making too much cholesterol. It’s that it isn’t clearing the extra. Making less doesn’t help clear what’s already built up, and it leaves the brain with less of the cholesterol it needs. Two large trials gave simvastatin or atorvastatin to people with mild to moderate Alzheimer’s, and neither slowed their decline.
Why haven’t you heard about plasmalogens?
Plasmalogens aren’t a trace lipid. They make up about 20% of the fats in the outer layer of the brain’s gray matter and more than 30% in white matter, and your heart, lungs, kidneys, and muscles depend on them too.
Researchers have been reporting low plasmalogens in Alzheimer’s brains since the 1990s, while most Alzheimer’s research spent the next 30 years focused on amyloid itself.
That may be starting to change. In 2026, John Hardy, one of the two scientists who first proposed the amyloid hypothesis, the idea that amyloid plaques cause Alzheimer’s, which has driven most drug research for 30 years, co-authored a study finding that APOE4 carries less plasmalogen than APOE3, even in people with no sign of Alzheimer’s.
His team concluded that low plasmalogens likely help cause Alzheimer’s and called for research on raising them as a treatment.
What does the research show for APOE4 carriers?
In 2019, researchers measured plasmalogen levels and APOE type in 1,205 older adults.
Overall, APOE4 carriers were about twice as likely to have dementia as people with the common APOE3/3 type.
APOE4 carriers with high plasmalogen levels had a dementia rate of 14.3%.
People with APOE3/3 had a dementia rate of 14.0%.
Those last two numbers are basically the same, which is significant. It suggests that high plasmalogen levels put APOE4 carriers at about the same risk as people with APOE3/3. Suggesting that APOE4 carriers with high plasmalogens have about the same dementia risk as the APOE 3/3 carriers
This study didn’t prove that raising plasmalogens will prevent dementia. What it does tell APOE4 carriers is that the gene doesn’t decide everything on its own.
Plasmalogens can be measured, and if they’re low, they can be raised. And in this study, higher plasmalogens went along with less dementia for everyone, whatever their APOE type:
The results of these analyses indicate that the net effect of APOE genotype on cognition and the prevalence of dementia is dependent upon the plasmalogen status of the person.
The 2019 study came from Prodrome Sciences, the company behind the plasmalogen blood test, and I’m certified in their testing. The independent research I’ve shared in this post points in the same direction.
Plasmalogens aren’t a silver bullet because there isn’t one for Alzheimer’s. They’re part of the silver buckshot. The biology linking low plasmalogens, cholesterol buildup, and amyloid is strong enough that I consider plasmalogen levels as one of the targets worth testing and addressing, alongside everything else that person needs.
Next week, I’ll move from the brain to the body: what turns the cholesterol in your blood from something your cells need into something that damages your blood vessels, and why the same things that damage it also raise your risk for Alzheimer’s.
Knowing your plasmalogen level, or your loved one’s, is a good move toward reducing Alzheimer’s risk related to brain cholesterol.
I covered how to test, which supplements I use, and how to get started in the upgrade/paid section of Plasmalogens: The Brain’s Essential Fat. Paid subscribers have access to the full archive and my brain resources list as well as supplement discounts, including plasmalogen precursors.
As always, joining my Direct Access membership is where I see people successfully make sustainable lifestyle changes that support Alzheimer’s prevention. They have access to all the implementation info for the ReCODE protocol, but even more important is the connection with others on the same path. Direct Access for Q/A with me, what’s working, troubleshooting, and a monthly Zoom call to make it all so much more personal and create lasting relationships.
Email info@angelachapman.net chat for more info and/or a 3-day free pass!
Great stuff! Thank you!