#395 - Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer's disease risk, and the effects of lipid-lowering therapies on brain health | Tom Dayspring, M.D.

“that gets talked about for brain health which is the role of EPA and DHA. And again they're readily available as supplements over the counter. And there are certainly some brands out there that are legitimate, which is to say you're getting what the label says you're getting, and they're free of contaminants.”

“So since we can't produce omega-3 fatty acids, we have to eat them. And we're eating, when you eat them, they're mostly in the form of a triglyceride carrier or a phospholipid carrier.”

“could make lysophospholipids. But hey, if the remaining fatty acid on that lysophospholipid is an omega-3, it gets in. So once they're in the enterocyte, what happens to them? The enterocyte immediately re-synthesizes them to a full-blown fatty acid. And that's a phospholipid or attaches them to a triglyceride molecule, which goes in the core of the chylomicron.”

“lipid transfer protein. And the phospholipid transfer protein will bind to either a full phospholipid or a lysophospholipid. And it's that little delivery truck of an omega-3 phospholipid transfer protein, which goes up, butts into the blood-brain barrier. And there's a specific receptor in the blood-brain barrier that will internalize the lysophospholipid form of DHA or EPA.”

“vehicle you're ingesting an omega-3 with. We would prefer that you've established that a supplement actually has the amount of omega-3s they say they do. Don't trust the labels of every supplement you may buy.”

“that didn't work as well as the EPA. But once they get into the brain, the brain has its omega-3 fatty acids. Used to be all DHA, but I know the thought on that is changing. EPA is required there too.”

“And why wouldn't it be? Because where do omega-3s go in the cell membranes? And that's everything, cell membrane health in the brain cells. And I guess, where do you stack this in terms of evidence, right?”

“if you went through all of that data with omega-3s in the brain, you would find it. Bill Harris has studies relating it to brain size or at least certain sections of the brain size in omega-3 context, I believe in the hypothalamus or other areas of the brain. And I think it's a good idea to do that. So again, it's this plausible stuff, but there's no level one evidence.”

“he's pretty content that when you hit the 8 to 9% omega-3 index, you pretty much have the proper amount of omega-3s in the scenario cell membranes of your body. There is no study you can allude to that, hey, therefore, so it's so important in the brain, let's make it 10% other than if there's no harm to it, why not try for it?”⚑ Under review

“vehicle. And then the free EPA or free DHA, which joins with other lipids in the biliary micelles, gets absorbed by a fatty acid absorber, CD36. Interestingly, not only can a free fatty acid be absorbed, but a lysophospholipid can be absorbed.”

“controlled, the EPA is a little bit more important. And the DHA plus the EPA, there's a trial where that didn't work as well as the EPA. But once they get into the brain, the brain has its omega-3 fatty acids.”

“fatty acids. Used to be all DHA, but I know the thought on that is changing. EPA is required there too. Some people can convert EPA to DHA, but not everybody can. And that's how they get up into the brain.”

“serum or EPA-DHA level in the RBC membrane of 10% versus 6%? What's your level of confidence? Well, the data is all going to come from observational trials for the most part.”

“big trial that shows perhaps for preventing or lessening residual risk in people who have ApoB controlled, the EPA is a little bit more important. And the DHA plus the EPA, there's a trial where that didn't work as well as the EPA.”

“serum or EPA-DHA level in the RBC membrane of 10% versus 6%? What's your level of confidence? Well, the data is all going to come from observational trials for the most part.”

“with sudden death and increased atherosclerotic heart disease. Again, we lack the randomized controlled trials that changing that will reduce events other than that one trial of EPA and insulin-resistant high-risk people who had APL-B well-controlled. So you're in that gray zone,”

“Ezetimibe is a drug that really works outside the body, so to speak, right? It works in the gut. It blocks the Niemann-Pick C1-like-1 transporter.”

“You could probably pull it out of a biobank for an existing study that was already done on Ezetimibe. So we could at least get the suggestion of that from such a study, because we do have at least one.”

“It certainly can get into the brain. maybe a little less slowly than lipitor, lipophilic statin, can, but if you're in a steady state, they're all in. They all have the ability to reduce cholesterol synthesis in the brain.”

“Yes, basically, CETP inhibitors of which OB-Cetropib is the latest have been investigated to see what they do to atherosclerotic heart disease and LP-little A and maybe brain functioners.”

“They're packaged in as a triglyceride. Typically, one of the fatty acids on a synthesized triglyceride would be an omega-3. And there is a product that delivers omega-3s as a phospholipid from krill oil. So now once you ingest a triglyceride or a phospholipid, remember, the only thing that can really be absorbed is free fatty acids.”

“So that's the quick story with Obicetrapib. Yay for its ApoB ability. We're all going to certainly be using for that. That'll be its FDA indication.”

“But if I took one fatty acid off of a phospholipid, it's called a lysophospholipid. It's actually a smaller molecule and they're easily absorbed. So the lipases either makes free fatty acids or could make lysophospholipids.”

“in real-world practice, Rosuvastatin, a hydrophilic statin, is used more commonly, it certainly can get into the brain.”