What is Your APOE4 Gene and How Does it Work?
You need to know your APOE4 status! About 25% of folks have one APOE4 gene and 2% of us have two. When you have two, your risk of developing Alzheimer's is about 80%. Even one doubles your risk from 17-20% to 40%. Just what is it?
Here is the explanation. Your brain is in its own little cocoon. It does not share many chemicals with the rest of the body and is protected by the blood-brain barrier that keeps all sorts of compounds out of the brain. Now, every cell in your body must have cholesterol to function. Cholesterol gives rigidity, firmness, and structure to cell membranes. That rigidity has to be balanced with fluidity, function, and chemical activity. Yin and yang. Every cell has to balance its cholesterol rafts, rigid, firm regions with very few embedded proteins, with phospholipid regions (composed mostly of DHA-plasmalogens) in which there are the critical enzymes and proteins that give the cell its character and function. You need both, balanced.
In the brain, there are no LDLs to deliver cholesterol. LDLs exist in the rest of the body to deliver cholesterol from the liver, where it is made, to the periphery, where it is used for structure. HDLs pick up extra cholesterol when a cell doesn't need it, and takes it back to the liver to be excreted. The APOE system is the LDL/HDL cholesterol transport system in the brain. Astrocytes, cells sitting next to every neuron, are the makers of brain cholesterol and other neuron nutrients. There are 3 versions of the APOE protein, 2,3,4. You get one from each parent so you can be an APOE 2/2, an APOE 2/3, 2/4, 3/3, 3/4, or 4/4. APOE 3/3 is the most common with about 50% (varies in populations) having 3/3. The APOE 2 is not common. Too bad because it is the best exporter of excess cholesterol.
That's what the APOE system is in the brain. It is the exporter of excess cholesterol. APOE2 does it very well, APOE3, less well. APOE4 is really bad. With dysregulated cholesterol export, your lipid rafts get larger and your brain cells function poorly. How that poor function works isn't completely understood, but some fascinating workarounds and confounding variables exist.
First of all, what does amyloid have to do with all this? Traditional medicine considers amyloid to be the sine qua non of Alzheimer's. Not so in this construct. Here's why. You have an enzyme in your brain called secretase A that comes from the DHA-plasmalogen-rich regions of the brain. It chops up amyloid precursor protein (APP) into innocuous pieces. No amyloid was made. Secretase-B, however, is the Darth Vader of APP disposal and it makes a fragment called APP1-42 which turns into amyloid.
You need amyloid precursor protein for a whole raft of functions, probably, most notably the excretion of excess iron, copper, and other toxins. It's a necessary protein but needs its own means of disposal in our isolated, insulated brains. Secretase A disposes of it nicely. Secretase B makes amyloid.
In conclusion, amyloid accumulation is a sideshow. It is the result of Secretase A switching off to B switching on. That switch happens when the DHA-plasmalogen-rich region of the cell membrane is constricted by too much cholesterol and larger "cholesterol rafts". Did you get the implications of that? Yes-siree! If you have sufficient DHA-plasmalogens in your brain, you never make secretase B because the lipid raft region is limited. And that's exactly what we see in the APOE epidemiology data. If you follow large populations of people with Alzheimer's, there are a few precious ones with the dreaded 4/4 genotype who don't get Alzheimer's. What do they have in common? High levels of plasmalogens. High DHA-plasmalogens trumps APOE4. High DHA-plasmalogens trump APOE4. High DHA-plasmalogens trump APOE4. Repeat. Let it soak it. The whole show is plasmalogen content.
Finally, like every biological system, there is almost always a workaround. Ditto in the brain. A protein called SOAT1 turns out to be a backup cholesterol exporter. What turns it on? Sufficient levels of DHA-plasmalogens activate it. Without DHA-plasmalogens, it fades and free cholesterol levels drop as much as 10-fold.
There you have it. Cholesterol export out of brain cells is part of making the balanced presence of DHA-plasmalogens with cholesterol-rich lipid rafts. In balance, with sufficient DHA-plasmalogens, secretase A and SOAT1 take care of cholesterol export. (Just like high HDLs in your systemic cholesterol). No amyloid is made. Aging, and exposure to oxidizing events (anesthesia, COVID, head trauma, pesticides, sugar.....) deplete plasmalogens and a death spiral begins. Secretase B is activated, SOAT1 is turned off, cholesterol accumulates in lipid rafts and amyoid accumulates. Remember, amyloid was at the house fire, but it wasn't the match that started it. It's a sideshow. Its presence is a warning, your DHA-plasmalogen level is too low. But, you wouldn't remember that.
And the end result is? No one should ever get Alzheimer's. We can identify sufficient plasmalogen content in the brain by blood test. And we can replace it. This is a new dawn.
www.What will Work for me? The loss of cognitive function isn't a diagnosis at age 82 and a 5-year term in a memory unit. It is a 25-year process for all of us with the only difference between us is the slope of that decline. The first symptoms are the inability to remember words you use in everyday language. Heck, I do that. Don't you? About 10% of us have sufficient plasmalogens. If you have word blocking and can't remember something that you know is there, that is an early sign of impending trouble. That can be repaired. It's far cheaper to fix than it is to spend 5 years in memory care, bankrupting everyone caring for you. My heart is singing with the good fortune in living in this time. We can all take a collective sigh of relief. But don't wait, it's easier to fix when the defect is modest. Start your repair when you still have 95% of the neurons and synapses to make a memory and only pause for 3 seconds to remember that word.
References: NIH Matters, NIH Alzheimer's Fact Sheet, Dayan Goodenowe-Breaking Alzheimer's, PNAS, Nature Communications,
Pop Quiz
1. What APOE gene combination is the worst? Answer: APOE4/APOE4
2. How many of us have at least 1 APOE4 gene? Answer: Around 25%
3. What does the APOE system do in our brains? Answer: Exports excess cholesterol.
4. Why is exporting excess cholesterol so important? Answer: We aren't completely sure of that detail, but we do know there is an intricate balance between the rigid, inert cholesterol lipid raft and the delicate, fragile, biochemically active, anti-oxidant protective DHA-plasmalogen membrane.
5. What is APP protein? Answer: Amyloid precursor protein is tasked with getting rid of extra iron, copper, and all sorts of other toxins.
6. What happens to amyloid when you have enough DHA-plasmalogen in your brain? Answer: You make secretase A and chop up amyloid precursor protein in a fashion such that it disappears. No amyloid accumulates.
7. Amyloid precursor protein does not excrete cholesterol. What protein does, if activated by sufficient DHA-plasmalogens? Answer: SOAT1. 10-fold increase in cholesterol excretion. But only if sufficient DHA-plasmalogens.
Low Plasmalogens in Midlife Predict Later Heart Disease
We have known for some time that folks on dialysis have much more heart disease and die of heart attacks at about 4 times the rate of the rest of the population. They make pretty good "canaries" to monitor why their heart disease is so much worse than in the general population. We have also learned recently that their level of DHA-plasmalogens correlates precisely, and inversely, with their risk of heart attack and their ability to export HDL particles. When they export HDLs from the cell, the blood level goes up, and it is generally recognized that high levels of HDLs are protective from heart disease.
We also know in a landmark study from Korea following 16 million people for 10 years that the optimal level of total cholesterol was 210-240. Our guidelines for cholesterol in America are to treat anyone with statins for cholesterol over 200. Very simple and very off-the-mark. It's not the main show.
What is going on in a cell over cholesterol? How do plasmalogens fit in? Here is the explanation. Every cell must, must have cholesterol. It is a very rigid molecule and makes good building blocks for a cellular membrane. Much of the outer membrane of any given cell is composed of cholesterol. Now, 75% of a body's cholesterol is made in the liver with the final 25% coming from the food we eat. In the process of absorbing it in our gut, the cholesterol is attached to another lipid molecule and tucked into LDL particles to carry it around in the blood to give it to cells that need it. Every cell in the body has LDL receptors to take up cholesterol. If blood levels of cholesterol are low, that means somewhere in the body there are cells taking it up avidly. That is not a good situation. When cholesterol levels are high, the cell is happy and has enough. It's HDLs that tell the real story. The content of plasmalogen lipids in mitochondrial membranes affects the fluidity of the mitochondrial membrane and is closely monitored to keep the function of the mitochondria in good shape. When the fluidity is just right, HDL gets exported because there is just enough cholesterol to make the membrane at perfect fluidity. HDL going up means happy, functioning mitochondria. But not too high. Just 60-90. How to get there? Intermittent fasting, avoiding sugar, and resistance exercise all help.
The question arises, how do we predict who will have a heart attack down the road? The cholesterol model shows unequivocally that people live longer with total cholesterol of 230 rather than 180. The cholesterol model is broken. What gives? This week's featured paper is on just that. Mid-life plasmalogens predict future heart attacks better than cholesterol. 1,852 participants, mean age 59 were followed for 16 years for possible cardiac events. What was unique was the use of metabolomics, meaning, measuring a wide range of blood compounds, not just one or two. That is the exact same process Goodenowe did with Alzheimer's patients in the Rush Catholic Clergy study. He examined 25,000 metabolites. In this study, a total of 1228 metabolites were followed by mass spectroscopy. Not as big a screen but still huge. Three different plasmalogen species were found to be associated with future heart attacks in an inverse fashion. The lower the level, the more likely the heart attack. They also found two amino acid metabolites, and a bilirubin degradation product, all of which have anti-inflammatory properties to be inversely associated with heart disease. Cholesterol didn't make the list.
We also know that heart disease is ongoing for decades before it becomes clinically dangerous. It all starts, way back with "sheer stress" on the wall of the artery. Guess what plays a central role in signaling and responding to sheer stress? Well, nitric oxide is possibly the main actor, but plasmalogens are playing a role in mediating that response.
Once you have lack of nitric oxide and lower plasmalogens, then you get LDLs accumulating and foam cells,,,and, and, and finally a heart attack. Cholesterol then shows up as the plugging event. Reducing cholesterol with a statin begs the issue. It's not at the starting point. It is a passive participant, but not the director. The slight anti-inflammatory effect of statins gives them their measured benefit in heart disease, but there are other better alternatives.
www.What will Work for me. You want to predict your risk of future heart attacks? Get a Prodrome Scan. It is the only company on the market right now giving us insight into plasmalogen content. I got one and I was half a standard deviation below average, meaning I was headed for trouble. I'm now taking plasmalogen supplements every day, in part because my mother had dementia. But my father had a heart attack. And Nitric Oxide every day too. No statin for me. They are bad for your brain, bad for your diabetes risk, bad for your muscles. You just don't need to lower your cholesterol. You need to fast, exercise, eat less sugar, don't smoke, eat 5 servings of vegetables every day (Nitric oxide galore), and make sure you are on B vitamins, K2, D, NAC and creatine/choline.....and make sure your plasmalogens are robust.
References: MedRxiv, Atherosclerosis, Neph Dial Trans, Atherosclerosis, Eur Jr Prev Cardiol, FASEB,
Pop Quiz
1. What are plasmalogens? Answer: part of membranes all over the body that give the membrane fluidity, and the ability to shape-shift allowing membrane fusion, and they have a vinyl ether bond n the surface of the membrane, giving them the role of anti-oxidant of first resort.
2. What is the problem with being the antioxidant of first resort? Answer: In oxidizing environments, you become depleted. COVID is one example. It is particularly oxidiizing, leaving membranes badly depleted and struggling to catch back up. Hence, long COVID. Yes, you can fix long COVID with Plasmalogens therapy.
3. How do plasmalogens intersect with cholesterol? Answer: They modulate how much cholesterol to keep inside the cell, and how much to send back out. The yin and yang of membranes are that cholesterol brings strength and rigidity and structure, and plasmalogens bring fluidity, function, and protection. Balance.
4. What predicts future heart attack better, cholesterol or plasmalogens? Answer: If you don't know this answer, go back and read the whole article again.
5. If you want to prevent a future heart attack what will help you more, statins or plasmalogens? Answer: Plasmalogens have been found, by metabolomics, to be the best, underline best, most accurate chemical in your body to predict longevity. Taking a statin, as proven by Oxford's review of the 5 largest statin studies, will add 1 day to your life. What is still missing is a 25-year study of plasmalogen replacement to prove it. The discovery is still too recent and too fresh.
Your Oral Microbiome and Exercise Capacity
Did you know you have a distinct biome of bacteria, viruses, and fungi in your mouth? More specifically, on your tongue? There are some 10 billion bacteria in your mouth, gums, and tongue, that represent some 700 distinct species.
These bacteria do important work. Your oral bacteria are key to making nitric oxide. When you eat green, leafy vegetables you will concentrate the natural nitrates from those vegetables in your salivary glands within about 90 minutes. Your saliva has about a 10-fold concentration of nitrates over your serum. The bacteria on your tongue take those nitrates and reduce them into nitrite. When swallowed, those nitrites are converted to Nitric Oxide if the pH of the stomach is below 3. Guess what happens if you take any PPI for GERD or ulcer disease? You are correct. NO production goes to zero. And your risk of cardiovascular disease rises by some 30% over the next three years. Yes, PPIs are dangerous for your long-term health and are not approved by the FDA for long-term use.
If you take 20, young dental students and give them mouthwash twice a day for two weeks, you can completely wipe out their oral biome. With that, you also will successfully raise their blood pressure by 12 points. And if you measure the complexity of oral biomes in people, you can predict who has high blood pressure and who doesn't by the range of their oral biome. Folks with high blood pressure will universally have very simple oral biomes with just a few dominant bacteria. Folks with low blood pressure will have a wide variety of bacteria and four specific strains that are responsible for nitrate-to-nitrite conversion. Humans do not have the genes to do that.
Humans do have a pathway to convert arginine to NO. It's complicated and slow, degrading with aging. Taking arginine as a supplement has been disappointing and with two seminal studies has been shown to cause more harm than good. Don't take arginine. But what's an older person to do? We lose 12% of NO production per decade and find ourselves with little effective NO above age 50-60.
The stimulus to make NO naturally is sheer stress on the walls of our arteries. That is otherwise called exercise. Exercise has been shown to have all sorts of beneficial effects on overall health. NO is the mediator of those benefits. In fact, we can now measure the effect of sufficient NO on exercise. Peak exercise and capacity is based on NO production. This has big implications for all sports. As a general rule, younger people play competitive sports because they are more capable. That capability rests, in part, on their ability to make NO. It is NO that allows oxygen to penetrate further into tissue. It is NO that facilitates the biogenesis of new mitochondria, extending exercise capacity.
All of those effects flow from having a healthy oral biome. Those 10 billion cells on your tongue drive a huge amount of downstream benefit. And it can all be undone with chlorhexidine mouthwash, fluoride toothpaste and PPI antiacid drugs.
www.What will Work for me? Well, I've had a bottle of mouthwash I've used with relative infrequency. I threw 3/4s of it out. I'm flossing much more and water-piking more. I ordered the spinach salad for dinner last night at the restaurant. I refrained from boring the guests with NO information. And I now take NO lozenges twice a day. Those lozenges might just become as vital for your health as Vitamin D, K2, and B12. Stay tuned to NO information. The link to exercise capacity startled me. We all need to know this.
References: Nitric Oxide, Jr Bacteriology, Meth Debak, Nature, Med Sci Sports Med.,
Pop Quiz
1. How long does it take for orally ingested nitrates to get into our saliva? Answer: 90 minutes
2. How much does our saliva concentrate nitrates over blood? Answer; 10 fold
3. How much does chlorhexidine mouthwash reduce NO production? Answer: Just about 100%
4. What else reduces NO production inadvertently? Answer: Any PPI or other systemic acid reducer.
5. What is the correlation between NO blood level and exercise capacity? Answer: Strikingly positive. The more NO, the better the capacity.
Controlling Chronic Pain with Turmeric
Curcumin is an interesting spice. It is foundational to curry and the yellow in mustard. The spice has 3 components but it is only the bis-demethoxy-curcumin, missing two methyl groups, and comprising only 3% of the spice that is the active ingredient for inducing super-long chain GTAs, or gastrointestinal acids that protect against cancers. All three components have effects on inflammation.
The inflammation of chronic pain is tied up with many complex interplaying effects. Once the initial immune response happens, a flood of inflammation-inducing compounds has to be cleared. That occurs through lymphatic drainage and disorders of lymphatic drainage are beginning to be recognized. Curcumin works by affecting the initial controllers of inflammation. Much inflammation is set off of "pro-inflammatory cytokines that travel through the lymph system to the liver. In the liver, they induce the production of C-reactive protein which proceeds to activate Nf-kappaB all over the body. Curcumin blocks that conversion cold. Add that to 4-5 other participating effector steps and curcumin is quite a useful anti-inflammatory compound.
But stopping inflammation is only half the battle. Pain is a curious phenomenon. It is a warning that there is unaddressed inflammation, for one thing. It also is signaling tissue damage, abnormal friction, inadequate lubrication, pressure...on and on. To address chronic pain, you have to get to the pathways that are causing it, and those that are sustaining it and not letting it go.
That's where SPM's come in. SPM stands for Specialized Proresolving Mediators. As a general rule, they are made from EPA and DHA, the two main Omega-3 fatty acids derived from fish/krill oil. (Names like (18-HEPE), (17-HDHA), (14-HDHA) are enough to confuse the most patient reader). What's interesting about these "Resolvins" or SPMs, is that when combined together, they assist in the resolution of pain. These mediators are the first identified in human chronic pain, but every review article lists dozens more. This sort of interdependent complexity is where AI (artificial intelligence) may play a role as the interplay is way above our ability to understand or predict.
But one study of 29 individuals with mild to moderate pain, who were on no other meds, given turmeric and the above 3 mentioned SPMs had pretty reasonable resolution of their pain over the course of a month of supplementation. Were there any controls? No. Can any conclusion be made? No. Is this cause for rejoicing and celebration.....? Maybe, if replicated in a controlled study. Can we use this to sell supplements? YES! And that is how the supplement industry works. They are right some of the time, but not always. Frequently a tiny shred of accuracy exists, and the chronic pain sufferer will eagerly try it.
Another approach to chronic pain would also be to consider the endocannabinoid pathway. It is essentially the backbone of most of the controlling hormones coming out of our hypothalamus, the gearbox of your brain's endocrine response. Our discovery of the endocannabinoid system came through a very alternative route, the use of cannabis, first illegally and now, finally, with some legal review and serious scientific inquiry. It's no coincidence that there were 5 presentations at the annual meeting of Functional Medicine doctors on the current advances in endocannabinoid research. It remains a blunt instrument, but it helps resolve the pain pathways.
www.What will Work for me? I don't like THC. I've "tried it" and found I really don't like the spacey feeling. (1970, Baltimore, Johns Hopkins Sophomore year). But I have now heard from enough users of legal THC gummies like Delta 9 that they get pain control. And I think all of us should be on turmeric for a variety of reasons. As a general rule, South Asians, who eat turmeric breakfast, lunch and dinner have 50-70% reductions in all cancers, Alzheimer's, and heart disease. All attributed to their turmeric consumption. They take it for the flavor. I have low back pain. I'm taking turmeric. I'm sitting in straighter chairs, doing situps and crunches and lunges. I may give the Life Extension Turmeric Elite product a whirl. I am amused by the irresistible urge to buy Life Extension products after reading their articles. They are very well crafted to nudge you to purchase.
References: Int Jr Mol Sci, Drug Des Dev Ther, Carcinogenesis, Trends in NeuroSci, Prost Oth Lip Med, Translational Med Communications, Handb Exp Biol, Life Extension,
Pop Quiz
1. Turmeric is a spice? T or F. Answer: True, eaten by billions.
2. Turmeric works on pain through what mechanism? Answer: It turns down NF-kappa B and multiple other inflammation mediators.
3. Your body has to clean up the inflammatory response, once it has been kicked into gear. How does it do that? Answer: Complex web of lymph system activities and many mediators based on Omega-3 derived compounds.
4. What are the chemical mediators of that clearing system? Answer: We are just learning their names. There appear to be dozens with complementary, overlapping and synergistic mechanisms. They are called resolving and SPMs.
5. Pain carries a nervous system component. What line of research is bearing fruit with that? Answer: The endocannabinoid system affects our mediators of pain. Stay tuned. More research to follow.
How to Cure Migraine: Forever!
"Dad, I've got the worst headache I've ever had. It came on suddenly." My own son, calling me from the mid-Atlantic on a plane from Switzerland, coming to a family reunion. This is the worst possible thing you can tell a parent. He must have an aneurysm that's leaking. He needs a CT scan and probably surgery.
"When do you land? We'll be there."
He was coming with his family from Switzerland, to land in Boston in 90 minutes. We had minutes to get on the road, but it was Memorial Day weekend. We were at the resort on Cape Cod getting prepared for our reunion. Two of us rushed for the car and got on the road....to meet 100,000 people leaving the Cape at the end of the weekend. Traffic was backed up for miles. There is only one major bridge off the cape and everyone was going home. That's why there are signs all over the cape saying, "Plan your departure, expect delays 4-7 pm." His life depended on speed, and we were stuck...
They landed. We were 5 miles closer, but still 40 miles away. They made it to baggage control. We were 3 miles closer. Almost to the bridge. They were at the rental car. We were still 35 miles away.
"Don't pick up any suitcases....Let Laura drive......We'll meet you at MacDonald's at .....exit". I watched the car on Google Live inch closer. There was the car...they had made it to our car. He looked awful. We switched drivers and in my own head I decided he would get faster service at Cape Cod Hospital than a huge city hospital, even if Mass General is the best in America if not the world.
Forty precious minutes later with him lying back and making no exertion, we pull into the ER arrival bay. I was about to witness the best of American ER medicine. Triage in 1 minute, CT scan ordered from the triage desk. The ED doctor examined him while rolling. Into the CT scanner to see if his brain was filled with blood from an aneurysm.....results in 5 minutes. Negative. No blood. No aneurysm.
Just a horrible, first migraine. "Worst pain I ever had in my life." IV cocktail of Reglan, Benadryl, and Decadron.....and the pain gradually eased away. What a relief! What a scare. Post-Covid migraine? Are they linked? He had C0vid a year ago and had long Covid for 6 months. Is that linked? Yes, they are linked.
Does migraine have the same defects in white matter showing demyelination that we see in long Covid, autism, ADHD, manic depressive disease, MS....? Yes! Yes! Yes!It's all the same pathway of excessive inflammation overwhelming the mitochondria, making too much peroxide, overwhelming glutathione and eventually making the dreaded OH- hydroxyl ion that damages myelin. Microglia, the garbage trucks of the brain then try to clear up the mess and start demyelinating white water. So-called white matter are the axons covered in myelin that link all the neurons to each other. With damage to myelin and decreased myelination, speed of nerve conduction slows down. Victims experience brain fog. And that damage shows up on MRI diffusion studies. You can see it with the newer, MRI 2 Tesla machines. Wait till we get 4 Tesla machines! Imagine the detail.
If you look at 44 patients with chronic migraine and measure their malondialdehyde, the chemical you make when the OH- hydroxyl ion damages the cis-bonds of plasmalogens (proving that you have the inflammatory pathway common to autism, ADHD, long COVID, MS, etc), it is statistically much higher than it should be. The brain is on fire. And MRI scans confirm it. Migraine sufferers have detectable white matter defects in their brain. You can see the excessive white matter water that is linked to uncontrolled inflammation and the chemical changes that confirm the process.
That gives us a pathway to repair the damage and turn off the chronic activation of OH-. Address all of the pathway mechanics and chemical imbalances. Give NAC, Acetyl-carnitine, lecithin, B12, B1, B6, B9 and most importantly, Prodrome Glia so that you can repair the white matter and stop the microglial activation that is wreaking the havoc.
www.What will Work for me. So that's what I did. I first asked David if I could use his story. He said sure! Because he got better so quickly. This is an important story. It expands the reach of Goodenowe's autism study. I gave him 50 mg per kg of Prodrome Glia and his headache disappeared in 12 hours. He was still a 4 on return from the hospital. It dropped to a "1" with the Glia and then after 24 hours was zero. It was a first migraine after long COVID, but headache is clearly linked to COVID and can last for months with debilitating pain. We can interrupt this whole vicious cycle. We now have a tool for understanding the pathophysiology of migraine (MRI diffusion studies), and address the root cause....some sort of inflammation that overwhelms mitochondria, allowing electrons to escape at such a rate that they overwhelm the control mechanisms. The hydroxyl ion escapes and we end up with damaged white matter, elevated malondialdehyde. Support each and every control mechanism, and provide plasmalogen support, and we may have the demon migraine in a corner and controlled. How fortunate we are to live in a time with the expansion of scientific discovery. We plan to "fill up his tank" for the next 6 months with the Glia and all the support chemicals that address all the antioxidant control pathways. Exhale. He is ok. "Just" a migraine.
References: BMC Neurology, Frontiers, Jr Headache and Pain,
Pop Quiz
1. A description of one patient is sufficient to make conclusions with? T or F. Answer: Absolutely not. But it does confirm data and needs to be further tested.
2. The pathophysiology of migraine being similar to long COVID, MS, ADHD and autism comes as a surprise. T or F. Answer: False. That's how medicine works. It should follow established, testable pathways. So far we have 44 patients being reported with exactly this pathway. Just not with the treatment arm attached to that study.
3. What was missing from the 44 patient series? Answer: An action plan for cure. The ability to manufacture the plasmalogen molecule chassis called Prodrome Glia is new in the last 6 months, so still not widely tested.
4. What is the key ingredient in the action plan? Answer: Addessing each of the four critical support systems and finally, supplying the building blocks of myelin replenishment, Prodrome GLIA.
5. Why is migraine so persistent and keep relapsing? Answer: Like ADHD, autism, manic depression, long COVID, all share the same conundrum. Our brains have expanded to such a degree that our capacity to add extra plasmalogens to the mix is limited. It's as if we have a vulnerability/bottleneck in that the human body can only supply so much new plasmalogen. When we get a huge insult of inflammation, we can never recover back to "sufficiency" much less resilience and redundancy. We need outside help. Prodrome Glia gives that help. Without that help, we continue to tip-toe along the edge of recurrent symptoms with ongoing, low grade damage. The symptoms come and go with mysterious exacerbations from the tiniest of insults. We can never escape it...... until now. Now, we can.
Crohn's Disease is caused by Atypical Tuberculosis from Your Milk
Fifteen years ago, as I started my journey into functional medicine, I was intrigued by Vitamin D and its effects. I read an article in the Journal, Science that indicated you did not put out the peptide cathelicidin, (your natural internal antibiotic that kills viruses and bacteria by puncturing a hole in their cell walls) until your level of Vitamin D was 30. Below 30, no cathelicidin, and TB flourishes. Above thirty, you kill TB. There it was! That's why the age-old method of sending TB patients off to the mountains for "fresh mountain air" was actually to get more UVB radiation and make more D.
At that time, Aurora Health Care's "normal D level" was considered 5-50 ng because that was what we saw in the population.
I called up the Aurora pathologist to request a reconsideration of that level. I argued that "normal" should be considered medically sufficient to make that key ingredient, cathelicidin. Hence, a level above 30. He replied by saying, "Did you know that Crohn's disease is the #1 admission to Children's Hospital?". I thought that was a bit off the wall. I asked why that was relevant. He informed me that Crohn's had increased in incidence dramatically in the last 40 years. He was curious about Crohn's because as a pathologist, he knew that Crohn's is an illness with "granulomas" in the wall of the intestine. Only two other diseases make granulomas, tuberculosis, and sarcoidosis.
He asked, "Are you aware of Johne's disease". I had never heard of Johne's. It is basically atypical tuberculosis in cows. About 70% of dairy herds have at least one cow affected, and its hard to find. You have to culture the bug for over a year for it to be detected. Eventually, it kills the cow, but not before it infects other cows. Here's the rub. Pasteurization does not kill it completely. Some bacteria get through, especially in cheese production.
Now, there are increasing journal publications that are directly addressing the issue and using PCR (Polymerase chain reaction can detect just a few molecules of DNA and amplify it, thus permitting identifying its source.) and statistical methods to finger atypical TB with Crohn's. It's a very difficult illness to treat. Very indolent and persistent. There is virtually no cure. Did you know that one study showed that 100% of lactating women with Crohn's have atypical tuberculosis in their milk?
What's the rational conclusion? Every glass of milk you drink comes from 500 cows as milk is collected in large tanker trucks that mix the output of many cows. You will be drinking milk, eating cheese, yogurt, kefir or sour cream that is not completely sterilized for atypical tuberculosis. Johne's disease is not completely wiped out because we don't have a rigorous enough detection system in Wisconsin, or anywhere. There is broad consensus that some genetic predisposition exists. Vitamin D insufficiency is also clearly associated.
www.What will Work for me. I feel vindicated and frustrated. We have been talking about this topic for decades. The advent of PCR gives even more definitive proof. When will our suffering be enough? The only way to reduce our risk of Crohn's is to ask our elected government to insist on stronger identification of Johne's. PCR on cows would find it. It costs a little money. It saves huge medical costs and life-long misery for those affected. Otherwise, you are playing roulette with every dairy product you consume. It costs $ 37 to PCR test one sample for a cow. Wisconsin has a great lab. Politics makes it too expensive. Please, please take your Vitamin D and keep your level above 30....5000 IU a day will do it 99% of the time.
References: Science, World Jr Gastroenterology, J Immunology, Thera Adv Gastro., USDA, J Food Products, Inflamm Bowel Disease, Eur Resp Journal, MedRxIV, Wisconsin Vet Lab,
Pop Quiz
1. Crohn's disease is caused by what? Answer: Atypical tuberculosis in the small bowel.
2. The primary source of it is? Answer: Infected dairy products.
3. We have proof that you can't kill regular tuberculosis if your Vitamin D level is below. Answer: 30. The more skin pigment, the more sunlight you need to make sufficient D, African Americans in Wisconsin, not on D, will have levels of 5 ng in the winter and 20 in the summer....never sufficient. They have more Crohn's.
4. How long does it take to culture atypical tuberculosis? Answer: 1 year
5. Wisconsin requires that all its cows be tested for TB? T or F. Answer: False. It's voluntary. Bummer.
You can contact the Wisconsin Johne's Disease Lab and express your dismay by clicking here: Wisconsin Johne's Program. Better yet, contact your elected congressman. Make it an issue.
Myelin and IQ
The MRI scanner excites water molecules and uses that excitement to create its images. A very powerful magnet makes protons (a positive electrical charge) line up and then when the magnetic field is relaxed, the protons release their lining up with a smidgeon of released energy. The MRI scanner can read that. It is excellent at defining "soft tissue" in the body which has a lot of water in it.
The brain is floating in water but is mostly made of fat. Fat and water have quite different densities. The nerve cells of the brain are all connected to thousands of other nerve cells with some 4 quadrillion (estimated) connections called synapses. Each neuron cell is linked to some 3500-4000 other nerve cells with those synapses. The wires in between the cells and synapses are called axons. A naked axon conducts an electric impulse quite slowly. Eight weeks prior to birth, an infant human has very little myelin. All this can be proven by advances in MRI technology that can measure the quantity and quality of myelin. The human brain can't "afford" to be myelinated too much as that would make it "too large" for the exit canal. The brain has to wait for the last minute to be myelinated. Hence, babies are born with a huge myelin deficit and a big plasmalogen demand.
From the time to birth to age 3 months, the myelin doubles, and then doubles again in the next 6 months. There are many, many more wires laid down in the brain that are "needed" and the brain has a sorting process of discovering which axons are active, and conduct electricity and thereby need to be "hooked up" and connected. All that takes sorting out and pruning, wrapping, and wiring. A myelinated nerve that is sending signals conducts those signals at speeds in proportion to the density of myelin. Mothers paying attention see that maturation process as their infants learn to focus their vision and recognize their face. That happens early and is an important developmental event. Same with voice. Infants don't figure out their hands till later.
The axons in the brain are wrapped with progressively more layers of myelin. Like an onion, they mature, with efficient axons having many, many layers of myelin wrapped around and around the axon, making it faster and faster. The oligodendrocyte, the cell that does the wrapping, actually has pseudopods that reach out to multiple axons to wrap. That wrapping process doesn't happen in just a week or two. It is ongoing well into the 3rd and 4th decade of life, with "peak myelin" being achieved between 40-50. (Yes, children, your parents are smarter than you.). The more myelin, the faster the transmission speed.
The analogy with computers is compelling. Faster computers are better. They compute faster. We want to make quantum computers so that we can catapult computing time massively allowing us to solve heretofore unsolvable problems, like your bank account password.
That's what the frontier of MRI scanning is now achieving. As the layer upon layer of myelin is laid down around the axon, a tiny bit of water is trapped between the lipid layers. A tightly wrapped axon will have just a tiny bit of water. It is detectable as a tiny bit. A damaged axon, for any number of reasons, will have more water. And that variation is also detectable. Multiple sclerosis, concussions, autism, manic depression, ADHD, all have shown vhttps://www.medicalnewstoday.com/articles/adhd-brain-vs-normal-brainariable alterations of myelin density on MRI. This is obviously a developing field and more information is to follow.
But what about a high-functioning brain? Is a brain that is perfectly myelinated better than one that isn't? Here is the dilemma. The answer is probably yes, but not quite proven yet. Making myelin requires having sufficient plasmalogen lipids, the building blocks for constructing all those onion layer upon layer of myelin lipids. Making plasmalogen lipids is a delicate task that is put off by anything that damages cells' mitochondria and peroxisomes (where the plasmalogen backbone is constructed. MRI scans of twins suggest there is some genetic link with intelligence.....or is that link because the twins ate the same food? But preliminary studies are now beginning to confirm, more myelin, thicker axonal layers all correlate with better IQ. Hmmmm. Want your child to have one up on the competition?
www.What will Work for me. Prodrome Glia is the first compound to be on the market that has been proven to act as an engine to drive myelination in the brain. It has been proven to repair RDCP, the rare genetic disease of absolute plasmalogen production failure. This story has legs. We can fix the badly broken brain. Can we optimize it as well? Goodenowe's autism study is predicated on resolving the lack of healthy myelin easily documented in the brains of autistic folks, as well as in ADHD. It is clear that one of the "choke points" of human metabolism is the ability to manufacture plasmalogens. Yet, they play a massive role in the ability of our brains to function optimally. We can treat brain injuries of any source, including post-concussion syndrome. We are going to repair autism. Alzheimer's is next. Can we optimize our kids' brains with a little boost? (Answer? Probably yes)
References: Neuroimage , NIH, Frontiers In NeuroSci, ScienceDirect, eNeuro, Cell, Dev Neurobiol, KJR, WJP, Medical News Today, Intelligence, Brain Pathology,
Pop Quiz
1. A newborn baby has a fully functioning brain? T or F. Answer: Absolutely false. It is just starting to wrap its axons. Huge deficit in plasmalogens at birth.
2. The richest food source for newborns is what? Answer: Mother's breast milk. It provides about 30 mg/kg per day of plasmalogens. Cow's milk and formula provide zero.
3. The more breastfeeding, the less autism. T or F. Answer: True as proved by many, many studies.
4. If giving plasmalogen supplements repairs a disease called autism, what does giving, even more, do for otherwise normal kids? Answer: It makes sense to believe that it fixes a lot. SAT tests to follow.
5. Is there any toxicity to taking plasmalogen-building supplements? Answer: They are GRAS, generally recognized as safe. No toxicity.
Muscle Mass Defines Type 2 Diabetes
What does muscle mass have to do with diabetes? Very simple. You take up glucose in your muscles. If you lose muscle mass, you run out of places to put the glucose, so the glucose level in the blood starts to climb. Your insulin level then starts to climb. But as Grandma used to say, "You can't put five pounds of sugar in a four-pound bag." Insulin resistance ensues. Insulin is damaging to your kidneys and stimulates you to hang on to sodium. Blood pressure goes up. Metabolic syndrome develops. Voila. And it all started because you lose muscle mass. Conclusion: Muscle mass loss causes diabetes.
Does that sound too simplistic? What's the data? Actually, recently quite a lot. Studies have been conducted around the world, surprisingly, less so in the USA. From Japan, for example. In this study, two groups with 198 men, one with diabetes and one that was normal, had bioelectrical impedance analysis of their body to measure muscle mass. The men with diabetes had significantly less muscle mass. The loss was most pronounced in their legs.
A much larger study from Korea was comprised of 113,913 men and 89,854 women who were free of Type 2 diabetes at baseline. During 589,098 person-years of follow-up, 4,264 individuals developed Type 2 diabetes. Comparing quartile groups to relative risk, the next quartile still had a 2.2 fold increased risk for women and 2.0 increased risk for me....and dropping off with increasing muscle mass.
All of these studies speak to a more simple, global observation from the last 20 years. Muscle mass predicts longevity. The first research came out in just 2011 by Dr. Rosenberg indicating that "sacopenia" was a strong indicator of mortality. Loss of muscle makes for loss of places for glucose to be use. Blood levels of glucose rise. Insulin rises in response. Muscles become stuffed with glucose and insulin resistant.
This observation may explain why being "obese" isn't always so bad for you, if you have kept your muscle mass. It is bad for you the extra weight has increased your risk for diabetes, which it frequently does. But the core observation remains, more muscle, longer life. Muscle gives a place for glucose to go. Muscle burns calories around the clock shifting metabolism from glucose driven to ketone driven. Glucose helps you gain weight, make inflammation, make babies, but it doesn't help you live longer. Ketosis is always anti-inflammatory and supportive of building more plasmalogens. Plasmalogens are another strong indicator of longevity. And it all comes down to the amount of muscle you have.
www.What will Work for me? This line of logic makes physiological sense. The number one "anti-aging" activity we can all do is some form of exercise. All forms. Cardio has its own benefits. Weight lifting and resistance has its particular help with building muscle. And, as the time honored Hawaiian Retired Men's Study from 1998 showing that men who walked just 1.2 miles a day had a 20% reduction in mortality. Bike riding up an incline can be pretty cardio. We're going this afternoon. It's summer. Find a way to get out and do whatever that stretches your ability to exert.
References: Metab Syn Related Disorders, Open Access Govt, PLOS One, Am Jr Medicine, Sci American, NEJM, Clin Inter Aging,
Pop Quiz
1. Which comes first, muscle mass loss or diabetes? Answer: That is not apparent in these studies.
2. Muscle mass is dependent upon what main feature? Answer: Use it or lose it. Without use, your muscle shrink. With use, they grow
3. Why is muscle mass helpful for diabetes? Answer: it gives a destination for glucose.
4. Might I be correct in saying that diabetes is an indication of inadequate muscle? Answer: Yes. And inadequate exercise. Particularly in legs.
5. What can I do to change all that? Answer: Start. Do something. Every day. Consider Exercise Your #1 Anti-Aging Strategy.
How To Fix Autism: The Program, Part 4
We have reviewed the critical metabolic problems that promote autism.
1. Mitochondrial distress from an overload of elections and NADH leads to loose electrons that make reactive oxygen species. Cause of this? Anything that causes inflammation, reduces Nitric Oxide. High fructose corn syrup and table sugar are both right up there. Those reactive oxygen species make peroxide.
2. Too much hydrogen peroxide overwhelms all the safety systems to neutralize and we end up making too much OH-, the hydroxyl anion. The final evil ion.
3. The hydroxyl anion damages plasmalogen lipids that are the coating of your nerve fibers, and axons. You make malondialdehyde, and you lose plasmalogen coating and protection of your nerve fibers. (Remember this key factor because this is how we get to cure.)
4. Malondialdehyde activates microglia which attack the damaged axons and demyelinate the "white matter" in the brain. That can be seen and proven on MRI in autistic "victims". The microglia damage the methylation system by flooding the damaged cells with glutamate. Brain cells suffer and may die, but certainly don't have their wires communicate the way they were meant to. Autism ensues. (Or, if less affected, ADHD, manic depressive disease, or long COVID.....all have similar pathology.
5. Young children are most often affected because they have the least myelin. As children age and eat healthy food, they progressively develop more layers of myelin in their brains. The more layers of myelin, the faster your brain transmits signals. And yes, the more myelin, the faster and smarter your brain is. Eventually, the brain becomes so myelinated that autism doesn't happen in its fullest forms, but other lesser forms occur that are called ADHD, manic depressive disease, etc
There you have it. That's the physiological process of making a healthy kid's brain into an autistic brain. Knowing that, what are the steps to fix it?
A caveat. An autistic child has been deprived of normal brain function for a period of time. Their brain hasn't learned how to process language, emotions (love and trust), culture properly. Their learning has been delayed. Fixing all the metabolic problems doesn't repair that deficit and the child will need to learn to love, and be loved, to read and talk normally, to trust and be trusted.
We are going to learn how long all that takes....but a healthy brain can do that.
Step 1. Consider avoiding problematic foods containing sugar (particularly fructose), fried food using vegetable Omega 6 oils, A1 milk, and ultra-processed foods (more than 5 ingredients, wheat).
Step 2. Support the Mitochondria. Carnitine, CoQ10, B1, B2, B3, NAC
Step 3. Methylation Support. Creatine, egg yolk lecithin, B12, folate, betaine, B9, NAC
Step 4 General Nutritional Support. Sugar in the form of trehalose, Egg yolk oil, Whey Protein, Vitamins A, E, D3, K2, B6
How do we get all of those supplements into a child? Special Milk available to all children in the Autism Trial and generally available later this year. Or dig in and give it a try.
Step 5. Plasmalogen replacement and Myelin Repair. Prodrome Glia, 8 capsules a day (This has been the missing link. Now we have it. Everything else is part of the orchestra. This is the Maestro.). The whole program depends on this foundation. Prodrome Glia is essentially the basic skeleton building block for the brain to get to work and remyelinate those damaged neurons.
www.What will Work for me. I am awaiting the start of the trial. Families will get 4 bottles of Prodrome Glia for free, that will last a month and a reduced rate thereafter for participating in the trial. This is the missing link we have not had available to us until now. Now, we can prove that Prodrome Glia gets into the brain and stops the demyelination very rapidly. Days to weeks. Then, with metabolic repair in progress, it will take time, love, and caring to teach the child to love, trust, learn, remember....and all that happens in time.
References: PLOS1, Eur Rev Medpharm Sci, Epigenetics, Amino Acids, Goodenowe, Int Journal Mol Sci, Cell Metabolism, Nutr Res,
Pop Quiz
1. It has been proven in the lab that each step of the metabolic pathway of autism can be addressed, resolved, and repaired. T or F. Answer: True
2. It has been proven in large, placebo-controlled trials of autism that Prodrome Glia cures autism. T or F. Answer: False. Very exciting anecdotes holding promise.
Hence starting an open-label study as it was deemed unethical to withhold treatment when the real option of success was so close.
3. Prodrome Glia is toxic and should be studied further. T or F. Answer: false. No toxicity. Generally recognized as safe and sold as a supplement. It's essentially the core building block you make yourself to coat your own nerve cells. Prodrome Glia has been proven to safely reverse and repair the metabolic defect of RDCP children that are born without the ability to make any plasmalogens. Very rare condition but nature's example of absolute and complete plasmalogen deficit. That has been published in the peer-reviewed literature.
4. A treated autistic child will recover in weeks into a normal child. T or F. Answer: False and not claimed by the program. Early adapting parents report that it only takes weeks to notice calmer behavior, beginning play with siblings, less repetitive motions. The "computer" that is the brain has to get its wires insulated and functioning properly before it can create memories, culture, trust, language. That's a complex task.
5. More myelin in a brain makes for faster functioning? T or F. Answer: True. Hmmm. Do you want your child to have a better functioning brain. Will Prodrome Glia become brain food for all children? (Next week: Myelin and IQ)
Autism is a Disease of Microglia Activation that Damage Nerve Fibers - Part 3
Ok, last week we learned the incontrovertible proven fact that kids with autism have mitochondria that are being overwhelmed and are unable to handle the volume of electrons they are being presented. Some escape and make reactive oxygen species that cascade down to the hydroxyl ion. All the salvage steps in between; superoxide dismutase, catalase, and glutathione, get overwhelmed, as can be proven by lab tests showing dramatic alterations in autistic kids' blood.
All of those natural "anti-oxidants" are not sufficient to protect against the making of the hydroxyl ion (OH-). The hydroxy ion attacks the double bonds in the plasmalogen molecules and makes malondialdehyde, which is elevated in autistic kids as well. Now we have damaged membranes in the axons of our nerve cells. That malondialdehyde is a potent stimulator of microglia. Microglia are the garbage trucks of your brain, your macrophages, tasked with fighting invading germs, cleaning up unused synapses, dead cells, and damaged axons.
Wups! Cleaning up damaged axons? Yes. They are just doing what microglia are meant to do. When they see a damaged axon, that speaks to a diseased cell that needs to be tidied up and cleaned out before it sets off more inflammation that damages other cells. In autism the microglia just got sucker-punched by an internal problem of too many electrons and inadvertently started attacking the wrong thing.
Malondialdehyde is elevated in autistic kids' siblings too, just not as much as in the affected child. That is what argues for some genetic susceptibility in autism, or common environmental exposure. The microglia kill the cells they attack by flooding them with excess glutamate. At the same time, astrocytes in the brain frantically try to suck up the extra glutamate to calm the fire down. All of those phenomenon have been proven in lab tests.
An epic struggle ensues. Younger children have much less myelin in their brains, giving them a much smaller reservoir of reserve to battle oxidizing events, followed by microglial attack. (This is why autism starts in early childhood when the least bit of extra inflammation sets it off.). In the experimental model of autism induced by the chemical cuprizone, you can identify that females get much less demyelination in their brains to the same dose of cuprizone, accounting for the 3:1 ratio of autism in boys to girls. And yes, in the animal model of cuprizone-induced mouse autism, the tiny bit of estrogen that female baby mice have over baby male mice is sufficient to protect the females. What levels do human boys have compared to girls? Human girls, 0.6 pg and boys 0.08. Human adult women have 100-175 pg.) And estradiol is especially protective against glutamate toxicity.
Aha! It's glutamate secretion by microglia that kills off the neuron. It gums up and stops the methyltransferase system (B12, folate, homocysteine) and makes homocysteine jump. The cell starves to death and dies. Kids with autism have horrible methylation problems and need a ton of supportive supplements to get over the hump and fix the defect. More B12, folate, Betaine, B6, choline, creatine, and finally.....the kid's brain can calm itself down and get back to normal behavior.
Take-home summary. Autism is the endless cycle of microglia activation set off by overwhelmed redox systems. Microglia activate and attack the damaged, plasmalogen-deficient axon, thereby activating more microglia. Round and round, never escaping. The overwhelmed brain needs extra plasmalogens to rebuild and protect the nerve fibers, methylation support, and extra mitochondrial support to put out the fires....and that is all possible.
Guess what happens when you give plasmalogen precursors to make more myelin? Just guess. Yup! The Lone Ranger comes riding over the hill. You can almost instantly (within weeks) turn off demyelination in every mouse and animal model ever studied. This turns out to be the key. More plasmalogen building blocks. Pulls the rug out on all the extra stress and vicious cycles the brain is in.
That is Goodenowe's genius. He designed and is now making the plasmalogen precursor to make more myelin. It turns off microglial activation just like that. It's called Prodrome Glia. In effect, it provides sufficient building blocks for the brain to repair itself and break the neverending cycle of reinforcing microglia activation and demyelination.
www.What will Work for me. I am all in. Goodenow is launching his nationwide Autism study with his collaborating doctors, of which I am one. We are just waiting the details of how to sign people up. And all the "drugs" we sure are actually just supplements. GRAS. Generally recognized as safe. We just haven't had the Prodrome Glia until now. Now we do.
And it's not just autism. This mechanism is probably also what ADHD is actually all about, but with a slightly more mature brain that has just enough materialto stay a little bit ahead. Many are beginning to argue they are just different parts of the same spectrum. Got that? ADHD too....
References: Biomarker Insights, Annual Review of Immun, Neurosci., MDPI, Neurobio of Disease, Jr Clin Investigation, J Neurosci, J Immunology, PLOS One, Molecular Autism, Spectrum News,
Pop Quiz
1. Ok, keep it simple. What happens when you get too much hydroxyl ion? Answer: You damage plasmalogens in the myelin sheath around nerve axons and you make malondialdehyde and lose plasmalogens.
2. Autistic kids have more or less malondialdehyde? Answer: Way more (meaning dramatic loss of total plasmalogen pool)
3. Malondialdehyde is a potent trigger for what? Answer: Microglia (brain's garbage trucks) activation. You turn on the garbage trucks that come and attack the damaged membranes, stripping off the myelin and killing the cell with flooding glutamate.
4. Glutamate does what? Answer: Too much of it and you shut down the methylation cycle, and you starve the cell to death.
5. Can I fix that? Answer: Yes. You can give the plasmalogen building blocks to rebuild myelin and methylation vitamins and building blocks to give all the extra nutrition the autistic kid needs.
6. Wait, wait, wait.....I have more questions. Is ADHD and Autism part of the same spectrum? Answer. YES. and Prodrome Glia will probably help both syndromes in a similar fashion. Maybe even faster for ADHD as it is a milder form.
7. Wait, wait...... Answers: next week. (See why I argue that Goodenowe is going to get a Nobel Prize in Medicine? This is a major emerging story.)