One of the things I wanted to cover that has changed since we last talked is you had really gone deep and published a paper around the phospholipid form of omega-3s and its benefits. I was wondering if you could bring us up to speed on that and what your current thinking is on omega-3 supplementation. So when it comes to— if we're talking about phospholipid DHA, when it comes to DHA in general, DHA is one of the omega-3s. Uh-huh. It's predominantly found in marine sources. Really what I care about is, you know, getting it to the brain. That's like my number one interest.

And the only type of DHA that crosses the blood-brain barrier is DHA that is bound to albumin, which is a protein found in your bloodstream, transports a variety of, you know, goodies in addition to DHA to other tissues including the brain. But there are 2 forms of DHA that are bound to albumin. And, these 2 different forms are transported by different mechanisms. So, the first is DHA that is not esterified. It's not bound to anything other than albumin, so it's in a free fatty acid form. And, I often refer to that as DHA-free. It's free. It's not bound to anything aside from albumin. Mm-hmm. It gets transported across the blood-brain barrier via this mechanism that's passive diffusion, which just means it's passively crossing the blood-brain barrier. Yeah.

And the blood-brain barrier, there's a variety of things that, you know, make it up, but one of the things that's important in this discussion is that endothelial cells line the blood-brain barrier and they're— the endothelial cells are attached to each other by tight junctions. So this passive diffusion mechanism where free DHA gets across the brain depends on the integrity of the blood-brain barrier. Unfortunately, as we age, the blood-brain barrier becomes compromised, and this is even more of an issue in people that have an ApoE4 allele. ApoE4 is just a gene, and allele just means, you know, one copy of the gene. You have 2 copies of every gene, one from your mom, one from your dad, so you have 2 alleles of every gene.

And just to bring people up to speed, if you have one copy of this gene, you are how much more likely to get Alzheimer's disease? People that have one copy of the APOE4 allele are about twofold more likely to get Alzheimer's disease than people that have no copies of it. People that have 2 copies of it, it's not very common. So, about 25% of the population has at least one copy of it. 2 copies, much, much less common. I don't know the percentage off the top of my head, but you can figure the math out if 25% has one copy, what 2 copies would be. But, that increases the risk for Alzheimer's disease from anywhere between 10- to 15-fold. And, and what percentage of the population that is diagnosed with Alzheimer's disease has at least one copy? Anywhere between 65 to 85%. Wow. Yeah.

So this is a pretty big indicator then. It is. And we could spend like hours talking about the reasons why that is. And I do talk a lot about that in my paper that I published last October in FASEB Journal. But basically, to get back to the whole DHA part of the story, I mentioned that there's 2 ways it can be transported in the brain. This one form that's free, you know, not bound to anything other than albumin, it goes through passive diffusion. However, ApoE4 actually disrupts that because it does compromise the blood-brain barrier and that even gets worse with age. Things like traumatic brain injury also compromise the blood-brain barrier. The good news is there is another form of DHA that is bound to albumin.

It's a form that is a specific type of phospholipid form called lysophosphatidylcholine DHA. Or DHA lysopC as I like to call it for short. And, that's also transported across the blood-brain barrier through an entirely different mechanism. It uses a transporter called MFSD2A. And basically, when this phospholipid form of DHA binds to the transporter, the transporter flips it across the outer membrane into the inner membrane of the blood-brain barrier and it potentially bypasses any defects, for example, in tight junctions. Hmm. In the endothelial cells that I was just mentioning, which, by the way, ApoE4 does disrupt tight junctions in lining the blood-brain barrier.

So, I sort of argue in my latest publication that this specific DHA lysopC form of DHA may be a nice way to bypass that defect that ApoE4 causes or even just normal brain aging causes. Is there a hypothesis here that lack of this DHA is a cause, potential cause of dementia? Yes, specifically making people with ApoE4 more susceptible to it. So DHA plays a lot of important roles in the brain. It plays a role in preventing and ameliorating a couple of the hallmarks associated with Alzheimer's disease, tau tangles and amyloid beta plaques. And, that's been shown in clinical studies. It's been shown that DHA supplementation can lower the amyloid burden and also tau tangle pathology in people that have them, specifically people with Alzheimer's disease.

And, it also can improve cognitive function. The other thing that DHA does, it's really important for transporting glucose across the blood-brain barrier. And, this is a really major hallmark of Alzheimer's disease. not gating glucose into the brain, basically. That is actually something that can be observed before any other clinical features of Alzheimer's disease, and it's specifically found early in people with ApoE4. So, DHA is important for increasing levels of the transporters that transport glucose across the blood-brain barrier, the glucose transporters. So, I always thought that, you know, people for a while were calling dementia like, or Alzheimer's disease, like potentially type 3 diabetes. I'm sure you've heard it called that before.

I always thought an increase or too much glucose in the body would be a bad thing, but here you're saying the brain getting a lack of glucose is a bad thing. What I'm saying here, yeah, is that getting— not having glucose in the brain can be a bad thing, but that's separate from, you know, obviously from like dysregulated blood glucose levels and insulin insensitivity. Like those things are all hallmarks of aging and cause multiple, multiple problems for sure. It's kind of a different thing that I'm talking about here. So, like, brain glucose levels are important for preventing a lot of the hallmarks associated with Alzheimer's disease. And this has to do with a lot of, like, very specific molecular mechanisms having to do with, like, forming tau tangles and stuff like that.

So, not being able to get glucose into the brain can play a causal role in Alzheimer's disease. And perhaps that is also linked to this type 3 diabetes that you're referring to. That would be a completely separate but sort of parallel mechanism. Got you. As DHA, I think it could play a role in addition, right? So, DHA is important for getting glucose in the brain, but also some newer research does indicate that insulin insensitivity can reduce glucose getting into the brain as well. So, those 2 things could even possibly synergize. Who knows? I mean, it'd be nice to see data on that. Yeah.

But, in terms of getting the DHA in the brain and the question you kind of asked at the beginning and I'm sure people are wondering is, well, what are the dietary sources of these different types of DHA, the free DHA versus this lysopC DHA, the one that's a phospholipid form that's transported across the blood-brain barrier? And, the simple answer actually is that all dietary forms can form Either of those forms of DHA. That's the simple answer. There's there's definitely a much more complicated answer that you know involves even getting down to the chemical level. So DHA, looking at dietary sources like fish, fish roe, krill oil—those are all sources that have DHA in phospholipid form predominantly. You find phospholipid form being phosphatidylcholine as as the phospholipid.

Triglyceride form is found in fish, also in fish roe, and also in higher-quality fish oil supplements or DHA supplements. There's also other forms that you could find in supplements. A majority of supplements that are molecularly distilled, which is the process used to purify fish oil to purify away contaminants like mercury, PCBs, etc. A lot of fish oil supplements are found in ethyl ester form. Some are even in free fatty acid form. Those forms are a little less bioavailable than triglyceride form fish oil supplements. Uh-huh. But the main thing here is actually the difference between ingesting it in phospholipid form versus any of those other forms because those other forms to some degree are metabolized in a very similar manner.

Compared to phospholipid form, and the reason for that is because phospholipid form, again found in fish, fish roe, a variety of different you know eggs, fish eggs, caviar as people call it, and also krill oil have DHA in this phospholipid form, predominantly phosphatidylcholine. And the phospholipid form has this backbone; it's a glycerol backbone. And the thing that differentiates it from the other forms is that there's actually two DHAs attached. There could be a DHA attached at. 2 positions on it, positions meaning different carbon atoms, one on the SN1 position as it's called and one on the SN2 position. And so, the triglyceride, ethyl ester, all those forms have DHA on the SN2 position. Uh-huh.

And, there's a difference between the way DHA is metabolized on the SN2 versus SN1 position. On the SN1 position where it's found in this phospholipid form, You can actually metabolize it and it retains its phospholipid form throughout metabolism. It's then bound up into HDL and it gets cleaved by an enzyme and it forms DHA lysopC, that form that bound to albumin crosses the blood-brain barrier through a transporter. The DHA on the SN2 position, which is found in all forms, is cleaved by an enzyme. It forms a free DHA. molecule which then is bound up in LDL instead of HDL. An enzyme cleaves it out of the LDL and it can form either free DHA bound to albumin or it can form the DHA lysopC. So, it can form either.

But, the bottom line here is that for the phospholipid form, the dietary phospholipid form you're consuming, you're going to get more bang for your buck in terms of forming that DHA lysopC form that you want to cross the blood-brain barrier. Okay. Uh-huh. That's the bottom line. So the majority of supplements that you see out there are mostly— is it triglyceride form? Is that right? The high-quality ones are triglyceride. Most of them— Okay. Are actually ethyl ester. Oh, really? Yeah. Yeah, because there's an extra— it's more costly, you know, when you're molecularly distilling these fish oil supplements.

They're removed from their triglyceride form which is what they originate in and— and they're put on this ethyl ester backbone and— and that's how they like run it through this column where they're purifying it and doing all this chemical Cool stuff, and then at the end of the day, a lot of people just leave it in that form because the enzymes in your pancreas and small intestine things like that they can recognize that ethanol backbone and cleave DHA off of that. The higher quality fish oil supplements after that whole molecular distillation process then reesterify it to a triglyceride form. So it's an extra step. So extra step means more money, right? Right. And so that's why I say higher quality. Higher quality usually also means.

What are your thoughts on, say, eating salmon roe versus getting a krill supplement versus finding a form of omega-3 that is phospholipid? I know Nordic Naturals came out with one not too long ago. What do you recommend there? So I should probably start with this. Fish contain around 1 to 1.5% of their DHA in phospholipid form. The remaining is triglyceride form. Fish roe, and this includes salmon roe, herring roe, pollock roe, flying fish roe, they contain between 38 to 75% of their DHA in phospholipid form. I didn't know this was flying fish roe as well. That's great for sushi fans out there. Yes, it is. Now each— Because that's the easiest to— Yeah, like the easiest to down because it's smaller.

It doesn't have that like very pungent, you know, fishy— Yeah, they're just little poppy things, yeah. Right, yeah. I know— I know you have a harder time than I do. to eating salmon roe, for example. You're probably like more like my husband. He's like, oh, it's like medicine to him, you know. Yeah, I take it like pills. I like put a scoop in my mouth and then just like drink water real quick or pop them real quick to make sure they get all out and then it's horrible. Well, I like to eat mine. I put mine on a little bit of seaweed with a slice of avocado and some lemon, sometimes a little ginger, and it really— I really like how that tastes. I give it to my son. Now, he likes it with this type of cheese called Boursin, B-O-U-R-S-I-N. It's like this cream cheesy garlic herb stuff.

That sounds great. And, it masks the salmon roe taste. And so, he gets that almost every morning and Dan is getting that. He likes it on this paleo waffle with some sour cream and that cheese and the salmon roe. And, that totally masks it. Yeah. For me, I can just eat that stuff. But, I probably should mention that this form, this DHA lysopC form, in addition to be what I argue in my most recent publication to be really important for brain aging and preventing Alzheimer's disease, particularly for people with APOE4 alleles, also it's been shown in multiple animal studies to be a preferred source of DHA to be taken up into the developing brain. In fact, it's taken up in some cases 10 times better than DHA in free fatty acid form. So that's kind of why I mentioned my son.

You know, he's still in the brain developmental stage, and so that's why I'm trying to get him the salmon roe. But back to the whole important question that you asked, because it really is— it is an important question. I mentioned, you know, 38 to 75% of DHA in these, you know, in these different roes from fish are found in phospholipid form. Krill oil is another phospholipid form you mentioned, and about 35% 90% of the DHA in krill oil is phospholipids. Krill oil supplements are not very high in terms of their concentration. So if you look at a majority of krill oil supplements out there, consumer-available supplements, you'll see that between 60 to 80 milligrams, you know, per 2 softgels or something like that— Uh-huh.

Is what you'll find compared to like what I take in my fish oil supplement which is each pill has 500 milligrams of highly purified DHA. So 2 pills have a gram. So 1 gram compared to 60 to 80 milligrams. I mean, even regardless of the fact that there, you know, more of that DHA is bioavailable to be— to form the phospholipid DHA form, the DHA lysopC, you're gonna get more from, you know, a gram of fish oil. Yeah. What I choose to do is I actually take fish oil and I take— I eat salmon roe and I eat fish. So I do all of those things. Do you have any preferred sources of where you get your supplementation oil? So I take a fish oil. It's called N-Pure 3. So it's, it's basically Nordic Pure 3, and it's a, it's a friend of mine.

He, he makes it in Norway, and he's basically convinced me that it's one of the most purest forms of fish oil. He doesn't add any lemon or strawberry or anything to mask the fish. One little trick in the industry is unfortunately it can mask the smell of rinse. you know, when something's rancid. Uh-huh. You can smell it. And if you pop open a fish oil pill, you can definitely— you don't even have to pop it open sometimes. You can smell it. You can definitely taste it. That's hard to do when you got lemon and strawberry flavors and stuff like that. Right. He doesn't put any of that stuff in there. And it's funny, like when I first— when I first met him, I popped open one of his pills and tried it and it was like the best tasting. I couldn't believe I could just eat it.

Like it was— Oh, you actually chewed it up? I just— yeah. I did. Yeah, that's my litmus test. That's my— that's usually my litmus test. But he's also shown me— Crazy. Like, my dog Toaster does that. It's like, it's really— I get my dog— I always wonder because I hand them to— I give omega-3s to Toaster and I'm always— I watch him chew them up and I'm like, is that good? He's like my little tester. Yeah, totally. Um, I, I actually pop open those pills and I put it in, in my son's oatmeal and I mask it with lots of butter. So— so he's getting the DHA pills in his oatmeal as well where— and again, it is— it tastes good so it's not like, you know, gross. And I should mention that I don't have any ties to this fish oil company. I don't get any kickbacks. I'm not affiliated with them.

But he is a friend of mine. And you do a gram of that a day? I actually take 3 grams a day. Wow! Yeah. So that's a great point. Like what's the upper limit of this? Like have you read about any downsides, any potential downsides of doing high dose? The only potential thing I've seen has been for high-dose EPA, and it is— and it is really possibly because it can inhibit with like leukotrienes and stuff, things that are involved in like blood clotting, that maybe it can thin the blood a little bit. So it could, you know, contraindicate people that are taking blood-thinning medications.

But there's also randomized— large randomized controlled trials coming out now showing that highly purified EPA in high doses up to 3 grams a day are like dramatically reducing triglycerides and lowering the risk of cardiovascular disease. And so it's— Wait, that's for DHA or EPA? That was for EPA. EPA, right? EPA, yeah. That's more like— EPA is more linked to heart health, right? Well, it's also a really potent anti-inflammatory which is linked to brain health. Inflammation— Hmm. in the brain. So there's also been some evidence showing that it may help with depression, specifically EPA as well. Hmm. So how do you balance that?

If you're doing 3 grams of DHA, do you do a gram of EPA or— So the high DHA that I get, so he— so he makes 2 different versions, a high DHA, high EPA, and the high DHA does still have EPA in it just to a much, you know, smaller degree. I don't remember off the top of my head. Recently, now Yeah. I was really, you know, while I was breastfeeding, you know, I was like super hardcore about getting tons and tons of DHA, you know, through the salmon roe and also, you know, like taking the 3 grams which is— turns out to be 6 pills of these high DHA. And— and because there's studies showing that like women that take in— in a dose-dependent manner, DHA in breast milk increases and like— and there— it's really like it reaches a limit but it's a super high dose.

It's like 10 grams or something like that. Wow. Now I'm trying to do high DHA and high EPA, but I take— I take one in the morning, like one— I sort of like take them at different times of the day. But DHA has basically been my, you know, my number one thing for a while just because of pregnancy and breastfeeding and all that. But, but I'm trying to take both actually.