What is Your APOE4 Gene and How Does it Work

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.