Prodrome Science™ — Webinar Series
Three lipids — plasmalogens, phosphatidylcholine, and cholesterol — regulate each other in ways that are usually missed when they are read one at a time. This is the lecture that sits underneath every other webinar on this site: what the cell membrane actually is, why these three are rate-limiting, and what the research says about restoring them.
Excerpt — full video on Dr. Goodenowe’s website.
Dr. Goodenowe presents the complete lecture on lipid deficiencies — the epidemiology on cholesterol and mortality, the cell-biology mechanism linking plasmalogens to cholesterol efflux, the choline and methylation story, and an extended Q&A.
Watch on DrGoodenowe.com ↗1 hour 32 minutes · Free to watch · Opens in a new tab
Dr. Goodenowe opens by saying this presentation contains material he hasn’t shown before, and that the context is what matters: these fats are usually looked at one at a time when they should be read together. He is explicit about his own standing — he is a PhD research scientist, not a physician, and he asks viewers repeatedly to work with a medical doctor.
The argument runs in three parts. First, that the cell membrane — the thin skin that wraps every cell — is the physical basis of nearly everything a cell does. Second, that three fats — plasmalogens, phosphatidylcholine, and cholesterol — are the ingredients that limit how well that skin can be built, and that each one affects the other two. Third, that all three can be measured, that running short of any of them is linked in published research to disease and earlier death, and that they can be replaced.
The reason a human being is not, in Dr. Goodenowe’s phrase, a bowl of soup is that everything is kept in its own compartment. Roughly thirty-seven trillion cells are held apart from one another by a thin biological wall called a membrane, and inside each cell that same kind of wall separates the working parts: the mitochondria (the cell’s power plants), the peroxisomes (its recycling and clean-up units), the Golgi (its packaging and shipping department), and the nucleus (where the DNA is kept). His analogy is a house: walls are what let you run an oven next to a refrigerator without either one defeating the other.
That wall is built not from wood and plaster but from phospholipids — fat molecules with a water-loving head and a water-repelling tail, which line themselves up side by side into a sheet. And it is not a dead barrier. Everything that enters a cell, leaves a cell, or signals to a cell has to transact through it. His summary: membranes are the core physical structure of every cell and every part inside it; almost every cellular activity depends, directly or indirectly, on what the membrane is made of; the membrane is the storeroom a cell draws from when it has to respond to something; and changes in membrane make-up are among the most consistently reproduced warning signs of ageing and disease.
What the membrane is made of varies depending on where it sits, and the numbers matter for what follows. In the outer wall of the cell there is roughly one cholesterol molecule for every phospholipid — meaning about half of that outer wall is free cholesterol. That is cholesterol built into the wall itself, which is not the same thing as the cholesterol measured in a blood test. Inside the cell it is very different: the membranes around the mitochondria are only around ten percent cholesterol. The outer wall needs to be stiff; the inner ones need to stay fluid.
Dr. Goodenowe calls this one of his biggest pet peeves, on the grounds that the data is unusually solid and has been reproduced again and again. He begins with a Korean study of 12.8 million adults asking which total cholesterol level goes with the lowest death rate from all causes combined. His reading: the best range falls somewhere around 220–240 mg/dL (the unit used on a US lab report), and deaths climb as cholesterol drops below that.
He then widens to an analysis covering 164 countries that shows the same shape, with the lowest death rate at a total cholesterol of 210–230. Buried in that same chart, he notes, are even steeper lines for deaths from infections and parasites — low blood cholesterol is linked to more death from infection specifically, not just more death overall.
A third study, of more than three thousand people, looks only at deaths from heart and blood-vessel disease. Below 200 mg/dL total cholesterol, the death rate is roughly double what it is in the 200–240 band. Above 240, he reports, there is still a survival advantage. His pointed observation about everyday medical practice: a patient over 200 gets flagged in red on a lab report at exactly the level where, in this data, overall survival is best.
LDL and HDL are not two different kinds of cholesterol. They are the particles that carry it around: LDL delivers cholesterol out to the body’s cells, and HDL picks up the surplus and hauls it back to the liver. Working within that framing, Dr. Goodenowe presents an all-causes-of-death analysis of roughly seven thousand men and nine thousand women. Starting from an LDL under about 97 and working upward, each higher band shows fewer deaths; LDL above 155 carries an odds ratio of about 0.52 — in plain terms, about half the risk of dying compared with the lowest band.
He then sets the LDL and the HDL results side by side, and points out something odd about how such papers get written: the HDL finding is discussed at length, while the LDL finding is printed and then passed over. In men, on his reading, high LDL is more protective than high HDL. Very low HDL, he is clear, is still bad news.
Some people are born with a fault in the LDL receptor — the docking port on the outside of a cell that grabs LDL and pulls it in. Because their cells cannot take LDL out of the bloodstream, it piles up there: total cholesterol averaging around 437, LDL around 352, HDL around 50. On the conventional model, Dr. Goodenowe observes, these people should not be alive.
What was actually recorded, set against what would have been predicted for a group that size, is more mixed than that. Deaths from heart and blood-vessel disease were up — 52 observed against 33 expected, roughly fifty percent more. But cancer deaths were lower than expected, 35 against 46–47. Deaths from all causes combined showed no increase at all and, if anything, a reduction: 113 observed against 130 predicted. Deaths from other causes were 26 against 50.
His conclusion from this: even with LDL at extreme levels, the overall survival picture does not fall apart — which he takes as evidence that LDL itself is not the villain it is treated as.
The cancer signal keeps reappearing. In a separate analysis, people whose non-HDL cholesterol (total cholesterol minus the HDL portion) was below roughly 135 and whose HDL was below about 35 were around 2.7 to 2.8 times more likely to die of cancer. He also presents a comparison of people taking cholesterol-lowering medication against those not taking it, in which the group with the highest LDL had the least cancer — and bringing LDL down with drugs did not break the link between low cholesterol and cancer.
Dr. Goodenowe next takes apart the idea that the cholesterol you eat sets the cholesterol in your blood, working through a stack of large studies: 177,000 adults on egg eating and blood fats; 8,000 people with high blood pressure; 8,000 Chinese adults; three UK studies finding that an extra egg a day carried no added heart risk; and thirty-nine long-running studies across North America, Europe, and Asia in which six eggs a week were associated with fewer heart problems, not more.
His conclusion has two halves, and the second is the interesting one. Cholesterol in food has very little effect on cholesterol in blood — and yet eggs themselves show a positive effect on heart disease and on survival. So something in an egg is doing real work, and it isn’t the cholesterol. That sets up the rest of the lecture.
This is the mechanical heart of the talk, and it reframes every number above. A cell can get cholesterol for its membrane in two ways: it can pull in LDL through the docking port described earlier, or it can build cholesterol itself from scratch. Almost all the cholesterol in the brain is made in the brain — none of it crosses over from the blood — and building-from-scratch is the main source throughout the body, which is why what you eat moves the number so little.
Here is the part that matters: the cholesterol already in the membrane controls the docking port. When the wall is full, the port shuts, the cell stops importing, and LDL backs up in the blood. So, in Dr. Goodenowe’s chain of reasoning, a cell that is bad at building its own cholesterol ends up with a low-cholesterol membrane, which leaves the docking port wide open, which pulls LDL out of the blood, which shows up on a lab report as a low LDL. On this model a low LDL is a symptom of cells that cannot feed themselves, not a sign of good health.
He applies the same logic to statins. These drugs work by blocking the cell’s own cholesterol production, which forces it to take cholesterol from the blood instead — and that is what mathematically pulls the blood LDL number down. He describes the mechanism as working very well indeed. His disagreement is with what people take the resulting number to mean.
HDL is the other half of the thermostat. Before cholesterol can leave a cell, a chemical tag is attached to it (chemists call this esterification), and only then can it be pushed out and carried away on an HDL particle — a process known as reverse cholesterol transport. If HDL isn’t working properly, the cell cannot shed what it doesn’t need and cholesterol builds up in the membrane. Hence his summary: low HDL and low LDL are both bad, but for opposite reasons. Low HDL means you can’t take cholesterol out. Low LDL means your cells can’t make it in the first place.
This is the connection Dr. Goodenowe describes as the most interesting part of the lecture, and it is the hinge that joins the three fats together. The evidence comes from cells taken from children with a rare inherited condition (RCDP) that leaves them unable to make plasmalogens. Those cells move much less cholesterol out onto HDL — they end up with high total cholesterol and high untagged cholesterol, and very little of the tagged form that is ready for export.
Treating those cells with the building blocks plasmalogens are made from reverses the pattern: total and untagged cholesterol fall, and tagging goes up. And the effect isn’t limited to cells that were deficient to begin with — adding plasmalogens to normal human cells produces the same shift, and the more you add, the larger the shift. The proposed explanation is that changing what the membrane is made of changes how the enzymes sitting inside it behave. (An enzyme is simply a protein that speeds up one specific chemical step.) In this case, the enzyme that attaches the tag and drives cholesterol out of the cell starts working harder.
Phosphatidylcholine completes the pathway. Cholesterol cannot board an HDL particle until that tag is attached, and the tag is attached by an enzyme called LCAT — which uses phosphatidylcholine as its raw material. In the data he shows, the more phosphatidylcholine is present, the more actively LCAT works. Which brings us back to the egg question: an egg delivers cholesterol together with the phosphatidylcholine your body needs in order to process it.
“Plasmalogens and phosphatidylcholines are essential for optimal cholesterol maintenance and regulation. These things work together.”
Dr. Goodenowe reads out a passage about how much choline the diet needs to supply that, by his own account, unsettled him. Phosphatidylcholine is required to package fat for shipping out of the liver, and one of the first clinical signs of running short of choline is a fatty liver. In rodents, a long-running shortage leads to liver cancer arising on its own, with no cancer-causing chemical involved — and choline shortage is, he notes, the only nutrient shortage ever shown to bring on cancer by itself.
The explanation he offers runs through a process called methylation. Methylation just means attaching a small chemical tag (a methyl group) onto something. The body does this constantly, including on genes, where the tags act as switches that decide which genes get read and which stay quiet. Choline either comes in through the diet, or the body builds it by taking a related membrane fat, phosphatidylethanolamine, and adding three of those tags one after another. Every tag added leaves behind two waste products: homocysteine and S-adenosyl homocysteine, usually shortened to SAH. SAH is a powerful brake on every tag-attaching enzyme in the body — he calls it the engine-hot light of the whole methylation system. Since gene tagging is part of what stops cells turning cancerous, not getting enough choline in food puts strain on the very system that provides that protection.
The same mechanism has a brain arm. Thinking and memory run on acetylcholine, a signalling chemical the brain makes out of choline. When there isn’t enough choline available outside the cell, the nerve cells that depend on acetylcholine start dismantling their own membranes to get more — and the nerve endings and mitochondria are precisely where that tag-attaching activity is highest in the brain. The chain he draws from there is this: SAH is elevated in the brains of people who died with Alzheimer’s; extracts from Alzheimer’s brains put a brake on tag-attaching activity in lab dishes; and as SAH rises, so does phosphorylated tau — the tangled protein deposits found in Alzheimer’s brains — with more SAH producing more tangling. Consistent with all this, people with more homocysteine in their blood develop dementia more often.
The final link is a detail Dr. Goodenowe describes as having surprised the field. The transporter that recycles used choline back into the nerve cell — the protein that acts as its doorway — is not spread out across the cell surface at all. It sits on the vesicles: the tiny bubbles inside the cell that hold signalling chemicals until they are needed. The doorway becomes usable only in the instant a bubble merges with the outer membrane and releases its contents.
And what determines whether that merging happens properly is the plasmalogen content of the membrane. Above roughly seventy-five percent plasmalogen, merging is complete; as plasmalogens fall, the bubbles fail to merge. The chain he draws: low brain plasmalogens mean choline cannot be recycled, which forces the nerve cell to build choline from scratch, which raises SAH, which jams the tagging system, which produces tangles.
What makes a plasmalogen different from an ordinary membrane fat is one unusual chemical link, called a vinyl ether bond. It keeps the membrane fluid, and it acts as a sacrificial target — it takes the damage from reactive molecules so that something more important doesn’t. These are not a trace ingredient: plasmalogens make up around half of the phospholipid in the heart, and up to eighty percent of one major fat class in the myelin sheath, the fatty insulation wrapped around nerve fibres. Levels peak in the forties and fifties — the same period when myelin is at its fullest — and then decline. The DHA type (DHA is an omega-3 fatty acid) declines the fastest, falling to roughly half by the nineties.
His own work here goes back to a 2007 paper covering several populations in Japan and North America, which matched DHA plasmalogen levels against how advanced a person’s dementia was. That was followed by much larger studies with Rush University in Chicago, running to some nine thousand blood samples from people whose thinking was still normal.
That finding wasn’t only a snapshot. People whose thinking tested normal at the start but whose plasmalogens were low were considerably more likely to have dementia when they were tested again 3.7 years later.
One hundred brains from the Rush group, average age 88, with each person’s mental status established before death — 38 thinking normally, 24 with mild memory and thinking problems, and 38 with confirmed Alzheimer’s dementia. Mental ability was scored by combining the results of nineteen separate tests.
In the temporal cortex — the region running along the side of the brain, heavily involved in memory — the lower the plasmalogen level, the lower the test scores. At the bottom end, a score of three standard deviations below average puts those participants in the lowest 0.1 percent for mental ability. At the top end — the part Dr. Goodenowe finds more interesting — participants with high brain plasmalogens scored more than one standard deviation above the group as a whole, putting them in the top seven percent, while still being 88 years old.
In a further 553 post-mortem analyses, he reports that people with high brain plasmalogens had less dementia than people whose brains showed no Alzheimer’s damage at all — meaning plasmalogen level predicted dementia better than the visible brain damage did.
The survival data is the graph he calls the scariest of the set: 1,262 people measured at two separate visits, with deaths over the following five years sorted by plasmalogen level at the start. On his reading, a sixty-five-year-old with low plasmalogens has roughly a thirty-five percent chance of being dead by seventy — the same five-year odds as a ninety-five-year-old. Separately, brain-scan work with the ADNI research consortium found that people with low plasmalogens had a thinner outer layer of brain tissue, in the same temporal region the Rush post-mortem work had already flagged.
Every plasmalogen in the body is built from a single starting molecule, a fat called an alkylacylglycerol, which is essentially absent from an adult diet — though it is present in human breast milk during early development. Dr. Goodenowe describes making these molecules synthetically from 2006 onward and patenting them for use in Alzheimer’s. Earlier attempts in the 1970s to treat plasmalogen-deficient children with two related natural compounds, chimyl and batyl alcohol, had not produced results.
The human data he presents is early. A study in Santa Monica with Dr. Jordan started participants on a low dose and stepped it up, and was designed mainly to track what the body does with the compound rather than to test whether it helps. It enrolled around twenty-two people. Blood plasmalogen levels rose with dose, as predicted. Unexpectedly, within four months about seventy-five percent of the participants with moderate dementia improved by a full point on the standard dementia rating scale, and also improved at standing up from a seated position. He notes the result was strong enough to be unlikely to be chance, despite how few people took part.
He closes on his own brain scans: maps of his cortical thickness from January 2022 through August 2024, thirty-one months into the protocol, which he presents as evidence that brain structure can be rebuilt rather than merely held steady.
Asked to tell the three fats apart, Dr. Goodenowe describes cholesterol as a flat, nearly indestructible molecule that the body recycles over and over; it slides in between the fatty tails of the membrane and stiffens it. Phosphatidylcholine is both a building material and an active ingredient — a stored supply the body draws on to make acetylcholine and betaine. Plasmalogens he calls the yin to cholesterol’s yang: the DHA type keeps membranes fluid, the omega-9 type forms the sealed barrier that myelin needs, and that unusual chemical link acts, in his image, like a fire blanket thrown over damage.
On why these shortages went unmeasured for so long, he gives two reasons: positions on cholesterol are entrenched, and lab tests tend to be developed alongside the drugs they support — he cites the PSA test for prostate problems as an example — so a test for something with no matching drug simply never enters routine practice. He notes it took roughly fifty years from the recognition that too little choline was harmful to an official recommended daily intake being set, and frames the gap between what is known and what actually gets used as the problem he is working on.
On eggs, his answer is relaxed: phosphatidylcholine holds up well to heat, so how you cook them doesn’t much matter. On why plasmalogens fall off faster after fifty, he ties it to losing muscle mass and losing peroxisomes — the cell’s recycling units, which are where plasmalogen production actually happens. Plasmalogens, phosphatidylcholine, and cholesterol all have to be manufactured, and a cell with less capacity to manufacture makes choices that favour bare survival over thriving. Resistance training, in his framing, is a way of building up those recycling units.
As with the other lectures on this site, the evidence here comes in several different grades, and it is worth keeping them apart. The cholesterol-and-survival material is observational — researchers measured large numbers of people and watched what happened, rather than assigning anyone to a treatment. Those studies are large and have been reproduced many times, but what they mean is genuinely disputed. The membrane chemistry and the plasmalogen work on cholesterol export were done on cells in dishes, not in people. The plasmalogen findings from Chicago and Japan are observational too, though part of that work followed people forward in time. And the human restoration data is small, early, and had no comparison group taking a placebo — as Dr. Goodenowe himself says.
That spread is normal for research still in progress. It is also why this page points you to the full lecture rather than standing in for it — so you can look at the studies and the Q&A yourself, and take whatever matters to you to your own physician.
“If you can’t measure human biochemistry with sufficient detail, you have no idea if whatever you’re doing is working.”
His closing frame is what he calls the three M’s of a life worth living — mood, mobility, and mental acuity — and the instruction he leaves the audience with is deliberately plain: measure them, restore them, and get on with living.
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