The ApoE4.Info Podcast: Episode 5

Dr. Hussein Yassine: The ApoE4 Mechanisms that Lead to Disease

Dr. Hussein Yassine joins Julie Gregory to discuss the work his lab at the University of Southern California has been doing to understand brain biochemistry with special emphasis on interactions with APOE genotype.


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00:00:25 Julie

Hi friends, I’m very excited to have Dr. Hussein Yassine, an associate professor at the University of Southern California, as our guest today. The Yassine lab works on understanding how changes in brain lipid metabolism predispose individuals to develop Alzheimer’s disease pathology.

Dr. Yassine is an expert in brain lipid metabolism. The Yassine lab approach combines imaging studies, clinical trials, observational cohorts, and animal models with a focus on Alzheimer’s disease as it relates to APOE and is actively funded by the National Institute of Health.

Dr. Yassine is the leader of the research and education core of the University of Southern California, Alzheimer’s Disease Research Center. He’s also the current co-chair of the Nutrition, Metabolism, and Dementia professional interest area of the Alzheimer’s Association.

The Yassine lab has uncovered important structural and functional changes and lipoproteins from both cerebral spinal fluid and plasma of patients at risk of Alzheimer’s disease based on the ApoE4 genotype. Dr. Yassine is the principal investigator of Prevent E4, a randomized clinical trial testing whether high dose omega-3 supplements can slow down cognitive decline in ApoE4 carriers, when started before the onset of clinical disease.

Dr. Yassine’s basic science lab investigates mechanisms of ApoE4-associated brain pathology focusing on APOE / ABCA1 interactions, brain inflammation, and develops biomarkers and drugs based on APOE and brain lipoproteins metabolism.

Welcome Dr. Yassine. Thank you so much for joining us. I was really looking forward to our discussion today. In order to prepare for it, I was listening to your previous interview with Dr. Peter Attia that was really an epic discussion. I’d like to start by learning more about you. Tell me a little bit more about your background and how you became interested in studying ApoE4.

00:03:04 Hussein

Right, so my background is I I got training into endocrinology specifically within endocrinology, lipids,  and then within my niche of lipid specialties I was studying lipoproteins in the blood. And we were interested on the function of HDL particles, otherwise known as good cholesterol. We stumbled across important roles for APOE in the blood, and at that time I moved from Tucson to Los Angeles to join USC, and USC had a very strong Alzheimer’s program. The chair of Neurology at USC came to me – Helena Chui – and she said, “Well, do you know that APOE has a major role in Alzheimer’s disease?” – and we’re talking 2012 now – and I said, “Well, yeah, I’ve heard about it; it seems to have many roles.” And she said, “Would you be interested in getting some small funding to look at what APOE is doing in the brain?” And I said, “Why not?” And it was a slippery slope from that time until now, almost a decade.

And my lab has focused on APOE since in the brain and trying to understand what it does, how it works, and if there’s anything we could do to prevent or change the course of ApoE4 on an aging brain.

00:04:35 Julie

Well, interesting, my interest in ApoE4 began at the same time because in 2012 is when I learned I carried 2 copies of the gene, and back then, as you know, much, much less was known, and in terms of clinical advice given to patients there was very little information. At that time, we were told to eat a very low fat diet, and we were told to do crossword puzzles and square dancing. And I thought, really? That’s what the medical community has to offer us.

So things have evolved, thank goodness. And thank you for your interest in this gene. We we need more people like you.

I’m going to start with a really monster question, but we’re going to break it down into bite sized pieces. What do you perceive to be the top three mechanisms by which ApoE4 leads to dementia and or cardiovascular disease? And then I’ve got little follow-ups for each of those mechanisms. So if you want to go one by one, we can do it like that. Or you can share all three at the top. Whatever you prefer.

00:05:50 Hussein

So these are great questions, and I don’t claim to have the answer to those questions. All what we have is some bits and pieces of this puzzle, and we’re trying to piece it together. So I think more and more research is coming. And proving to us that we have to be humble.

00:06:06 Julie

Oh, I totally appreciate that. And I share your humility. I am learning more every single day.

00:06:14 Hussein

Right, so let’s maybe start by asking what APOE is and then possibly get to the answer right after.

So APOE as you probably know is a gene. And encodes its APOE protein. Now our interest in APOE is because in nature APOE is found three in common variants with three forms, what we call E2, E3, and E4. E3 is by far the most common – approximately 70% of people have the variant. Less so would be E4 – 20 to 25% and that can actually vary by ethnicity as well. So whites and Africans may have different population frequency. The common example is in Nigeria, up to 50% of the people are E4 carriers. E2 is less common. Approximately anywhere from 5 to 20% depending on the population. E2 is protective against Alzheimer’s and in fact is one of those very few genes that has been shown to be associated with a longer lifespan. E3 is neutral, and E4 increases the risk of Alzheimer’s. One copy slightly increases the risk of Alzheimer’s and two copies significantly increase the risk of Alzheimer’s. That is what APOE gene and protein exist. These are the forms that they exist.

Part of my interest in this APOE is because it makes HDL particles, meaning that it can get lipidated. It carries lipids like fats and cholesterol and becomes a truck carrying those fatty molecules both in the blood and in the brain, and are the most common mechanism for people to attribute or are interested in APOE is by their lipid carrying capacity. So the initial view of APOE mechanism as an AD or Alzheimer’s disease risk factor was tied to its ability to carry lipids between different cell types in the brain. For example, between the helper cells known as astrocytes and the neurons, which are the main brain cells responsible for our ability to a have a cognition or to fire to make memories.

So that’s the first impression of how it works, but as we learn more and more about APOE, more things have evolved and more important now than carrying lipids is the ability of APOE to regulate inflammation. And those two mechanisms are not separated from each other, meaning that the ability to carry and exchange lipids is associated with the ability of cells to become more inflammatory or less inflammatory, and those two mechanisms are coupled. And now most people, some people at least, believe that this inflammatory process in the brain could be playing a big factor in the evolution or development of diseases like Alzheimer’s dementia.

There are other mechanisms that have been attributed to ApoE4 that are related to both lipids and inflammation, and they include blood vessels changing their behavior, becoming leaky, or having atherosclerosis or stiffening up because of lipid accumulation. Other mechanisms also include the response to trauma, the ability of the brain to respond to trauma, whether it’s injury falling, epilepsy or any of that. E4 carriers tend to respond by being more inflammatory and producing more disease in response to trauma.

So I would say yeah, the ability to exchange lipids and the ability to modulate inflammation would make the ApoE4 brain more prone to getting disease, and maybe finally ApoE4 as a third mechanism – if you’re looking for three – it has ways that it interferes with the metabolism of nutrients, including fat and carbohydrates and that could possibly also put the aging brain at increased risk of neurodegenerative diseases.

00:11:01 Julie

OK, I love all three of those mechanisms. They’re really, really good. Let’s start with the first one. The exchange of lipids and how ApoE4 carries lipids differently than the other APOE genotypes. Help us better understand that.

00:11:19 Hussein

Yes, so lipids are not soluble in water. The classic example like it is you’ve got this meal. You decided to use your pan, then you started to cook and you had great greasy meal full of fat and then you want to clean the pan after frying the meat for example, you turn on the water faucet, but you’ve realized that the water is not able to efficiently extract the fat sticking to it because water and fat are not mixing.

So what do we do to solve this problem? We add some soap right? So APOE is behaving like soap. So what APOE does it takes the fat and the water and allows them to form particles or missiles or lipid droplets. And then they can dissolve and become entities which can circle it. So fat he will not get suspended, it just cannot. It will crash out of the solution. The blood solution.

So to be able to get transported whether it’s going to be in the blood or across the cells in the brain, it requires to be packaged in droplets, and APOE is efficient in doing that. And that’s my principle that APOE does the packaging of fat and its distribution between different samples.

00:12:46 Julie

Interesting, so let’s talk about how ApoE4 does that perhaps less well than ApoE2.

00:12:55 Hussein

Right, so I would not say less well or worse or better because it differs by ethnicity. It differs by, so I would argue that in Africans who are ApoE4 probably descended from a tree of lineage in Africa and then we started exchanging genes ApoE4 is very functional and not associated with Alzheimer’s.

The mismatch happens because we live in an environment now that is more sterile, less infections, and we were able to get to 80, 90, 100. But if we did not age and we were living in rural areas where our exposure is to parasitic infections, other infections is prevalent. In fact, if you were an E4 carrier, you will have a survival advantage.

So we would have to look at ApoE4 as a mismatch as opposed to being less efficient but more efficient. It’s quite an efficient system. In fact, our ancestors, based on genetic studies of the past, suggested that all of them had E4 and was time you started getting E3s and E2s. So in that regard, I wouldn’t call ApoE4 good or bad. It’s just a mismatch. So the mismatch happens when E4 carries lipids differently than E3 or E2. E4 tends to carry less lipids than E3 and E2 and because of that amino acid substitution that makes E4 E4, it tends to aggregate, meaning that the ApoE4 particle tends to clump and carry less lipids.

Now, why is that the problem? Well, it might be a problem because the ApoE4 system, when it clumps, can induce a greater inflammatory response. And in populations exposed to infections that greater inflammatory response would clear the infection and will assist the body in getting getting rid of sepsis in case a pregnant woman is getting septic, unfortunately, because of her exposures to infection and that term in pregnancy is known as puerperal sepsis. An E4 female can effectively fight puerperal sepsis and deliver infants compared to an E2 or an E3 female. And an E4 carrier living in rural Ghana or in the Brazilian slums is more efficiently fighting parasitic infections than others.

Now we move now to northern latitudes and let’s specifically talk about Northern Europe where ApoE4 is predominantly transmitted to whites, and they’re living in environments where there isn’t really much infections. The inflammatory response that ApoE4 is supposed to be fighting infections is now misdirected and it is leading to a sterile inflammation that manifests in the accumulation of amyloid in the brain or some form of atherosclerosis and blood vessels outside the brain. So here are examples where we see the mismatch between ApoE4 in different ethnicities depending on the environment that exists.

00:16:29 Julie

Right, we actually know of several primitive hunter gatherer tribes like the Tsimane in Bolivia, and certain groups in Nigeria that are ApoE4 carriers, and they do extraordinarily well and because of everything that you just described.

I kind of want to get back to a APOE to better understand that mechanism though. So my understanding is that ApoE2 carriers have higher levels of peripheral APOE compared to ApoE3 carriers and ApoE4 carriers. Does that play a part in this mechanism? Is MORE better?

00:17:14 Hussein

Not necessarily. Part of the response or part of what APOE does can be assessed by the levels of APOE. But the reason why I’m a little ambivalent and not strong about the answer is because that doesn’t translate into the levels of APOE in the brain. In the brain, E2, E3, and E4 levels are not different as much as they are in plasma, and that has to do with the clearance and how APOE is cleared from the blood. ApoE2 is cleared at a much slower rate in the liver compared to E3 and E4, but in the brain the clearance pathway is different. And changes in the levels of APOE in the blood may not translate to changes in the level in the brain because these are two different compartments. APOE in the blood is made in the liver to a large extent, less extent is made in macrophages and other cell types, but in the brain the large production site for APOE is going to be your astrocyte and to lower extent your microglia or immune cell [inaudible] parasites and other subtypes.

So these are two different pools of APOE and their levels may actually differ based on whether they’re in the blood or in the brain. So yes, you’re correct in that ApoE2 has greater levels in the blood, but that doesn’t translate to changes in the brain.

And increasing ApoE2 in the blood may or may not result in changes in APOE levels in the brain. This is a good area of study, and more research is needed to understand this crosstalk between the brain and the blood.

00:18:56 Julie

Right, are you familiar with research done by Katrine Rasmussen from Denmark?

00:19:04 Hussein

I have seen some of that, but … you have a specific …?

00:19:08 Julie

Well yeah, so she took a very large data set. I want to say over 70,000 people over a very long period of time for a clinical trial. I think it was over seven years, and she looked at peripheral levels of APOE and she found a very strong correlation. Those that had low peripheral levels of APOE, regardless of APOE genotype, tended to develop dementia as they aged. So people that had higher levels of APOE appeared to be protected, and that kind of follows the APOE 2/3/4 story.

So you know, I know that we don’t know how that translates to APOE in the brain, but it makes me wonder if that’s a biomarker worth tracking. I think she’s written a few papers about it.

00:20:05 Hussein

Yes, I’ve heard that story and I can tell you it’s an interesting concept that needs to be tested. Now, here’s what we don’t know. What we don’t know is: does lower levels of equally in the blood mean means that there is something in the brain that’s also happening at the same time that is making the risk of Alzheimer’s bigger and the higher levels of APOE in the blood also means the same process that’s leading to higher levels of it in the blood is causing APOE in the brain to function better. So we don’t know whether that same reason why you have higher APOE levels in the blood or lower APOE levels in the blood is causing something else in the brain that leads to less or more dementia.

00:20:53 Julie

You’re right, it’s just a correlation now. We don’t understand the connection right?

00:20:57 Hussein

That’s why we have to be careful in moving to the next step and assuming that higher levels of APOE in the blood means we should give people APOE. We know that when you increase the levels of APOE too much in the blood, you can get very high triglyceride levels.

00:21:18 Julie

I noticed that. So it actually predisposes you to cardiovascular disease. So it seems like there’s a fine line. It’s a balance, yeah?

00:21:26 Hussein

It can’t be too little or too much just right.

00:21:32 Julie

Right, oh boy, you know I kind of want to go back to the mismatch theory. So if you were me, an ApoE4 homozygote of European ancestry, should I get some parasitic infections and play in the mud?

00:21:51 Hussein

Should your children be exposed to more infectious environments, and I I would argue that it may not be a bad idea. We need to develop, we need to tune down our immune responses and we know in conditions like asthma we might talk a little bit about the autoimmune nature of Alzheimer’s.

In conditions of asthma, communities that are exposed to hay and other allergenic responses at a very young age are protected from asthma than communities who live instead in sterile environments.

00:22:23 Julie

Interesting, yeah, and it’s same with children that are exposed to pets. They are healthier, right?

00:22:30 Hussein

Yes, exactly.

00:22:31 Julie

So there certainly is something to that for sure. Let’s move on to inflammation. Come talk to us about how that mechanism works as far as it relates to ApoE4.

00:22:47 Hussein

Right, so inflammation is a very difficult area of research to study because it’s it’s not as simple as we think it is. The definition of inflammation varies from one setting to another. There’s an inflammation that happens after you get an acute infection. There is an inflammation that happens with chronic conditions like cardiovascular disease and Alzheimer’s, and they may not be the same thing. What we know is that inflammation is a way for the body to adapt to injury so when there’s a chemical injury or a construction agent or a traumatic injury, the body responds by creating first an acute inflammatory response where the immune cells try to circle the agent or the injury side and then slowly that inflammation resolves and the inflammation goes away.

The problem with ApoE4 is that it associates with … when the inflammation happens, associates with poor resolution, so instead of resolving quickly it lingers and stays for a long time and that lingering, unresolved inflammation now becomes the problem.

There is no evidence that ApoE4 by itself creates inflammation. In fact, the more we learn about ApoE4, the more we understand that ApoE4 mishandles inflammation. When you look at all ApoE4 carriers, you would find a lot of ApoE4 carriers with no inflammation. Where is this cross talk or interaction? This interaction happens when an ApoE4 carrier has inflammation. The risk of disease gets higher.

00:24:43 Julie

And that’s actually been shown in one study that was pretty poorly designed regarding COVID-19 in ApoE4 carriers. I don’t know if you saw that, but we had poorer outcomes, and I say it was poorly designed because I think the data set was all people who were in the hospital, so we have to assume that there were many ApoE4 carriers who got sick and stayed at home and did fairly well.

So it makes me wonder, as an ApoE4 carrier, what inflammatory biomarkers should I be tracking to make sure I don’t have inflammation in my body?

00:25:09 Hussein

We don’t really have the answer to that, but we may have tools.

00:25:26 Julie


00:25:27 Hussein

So in the Framingham cohort north of Boston they looked at the C Reactive Protein as a measure of blood inflammation, and they found out that E4 carriers had possibly less levels of C Reactive Protein, less inflammation.

But that’s not the story. The story in ApoE4 carriers who had higher C Reactive Protein for some other reason, they decline and progress to have Alzheimer’s disease at much faster rate than those E4 carriers without high C Reactive Protein. So the nuance is that ApoE4 is not causing the high C Reactive Protein because more ApoE4 carriers have lower C Reactive Protein, but those unlucky ApoE4 carriers who for some reason have chronic inflammation, whether it’s diabetes, cardiovascular disease, some form of response that the body is now turning to an inflammatory state, they do not do well.

00:26:41 Julie

Wow. So there aren’t other specific inflammatory biomarkers that you would track like TNF Alpha or any of those – IL-6?

00:26:52 Hussein

IL-6 and TNF Alpha are produced by the same mechanism in the liver that leads to … in fact, IL-6 gets converted to C Reactive Protein so they have [inaudible].

00:27:00 Julie

OK, so in our community lots of people tracked our C Reactive Protein, and many of us try to keep it below 1. And as you noted, and as the Framingham study showed, that seems to be pretty easy for many of us. But occasionally I do see members of our community that have really high numbers kind of inexplicably, and so that’s probably an indication that something else is going on.

00:27:28 Hussein

Right, and ApoE4 does not know how to respond to inflammation, and that’s why it gets into trouble.

00:27:34 Julie

Right, and we would basically treat that by tracking down whatever the root cause is. If it’s obesity and metabolic syndrome, we would address that and … or whatever, I would imagine.

I kind of want to go backwards ’cause I should have asked you this before. So, we know that ApoE4 carries lipids poorly. Are there any biomarkers surrounding lipids that you would pay particular attention to if you’re an ApoE4 carrier?

00:28:09 Hussein

The answer to that is yes. We know that ApoE4 carriers, not all of them, a portion of them inefficiently carry cholesterol, and when I say inefficient, I mean that the ApoE4 protein goes to the liver and sticks to the LDL receptor. And when it does that it forces the LDL receptor to function less. And the LDL receptor has an essential mechanism in clearing cholesterol from the blood. So some ApoE4 carriers may have higher levels of LDL cholesterol, and that can tell you that the ApoE4 system is not efficiently able to clear or get rid of cholesterol. And it’s another indication of how this ApoE4 is not efficiently allowing the metabolism [inaudible].

00:28:59 Julie

Right, so many of us track our standard cholesterol panels, but we also do the advanced panels to see what those lipids look like as well. And certainly I’d say we have a pretty high percentage of people in our community that do end up having high LDL cholesterol. But sometimes not a high LDL particle number, which makes it less concerning, especially if oxidized LDL is low.

I love your focus on HDL. My understanding of the research, and I know nothing is conclusive, seems to be that a higher HDL would be protective for ApoE4 carriers. What do you think?

00:29:47 Hussein

Let’s take a step backward and talk HDL first. HDL is a particle that carries lipids, including cholesterol. HDL cholesterol is not the same as HDL particles. You could have higher HDL cholesterol with not more number of HDL particles; you could have lower HDL cholesterol and a lot of HDL particles. The other example is you can have a lot of buses with no people riding them, and you could have a lot of buses with tons of people riding them. And the cholesterol here is the rider of the bus.

So a large number of HDL cholesterol does not necessarily mean that the traffic of cholesterol is faster or slower. Sometimes when you have disease states that block the exchange or transport of cholesterol, you can have an artificially high HDL cholesterol that’s not protective. And sometimes the high HDL cholesterol is a measure of a lot of traffic going to deliver for this excretion.

So I realize that doesn’t fully quench your thirst about, is high HDL cholesterol good or bad? And I think my answer to that – it depends on the context. And somebody who is exercising, good genes – their parents lived to 100 – a high HDL cholesterol reflects the status of active flux of cholesterol from tissues to the liver for excretion. But in somebody who has, for example, type I diabetes, drinks alcohol, and has other problems, the high HDL cholesterol reflects a dysfunctional state

And low HDL cholesterol also holds the same concept. You could have low HDL cholesterol. And be in a disease state, and you could have low HDL cholesterol, but your HDL flux is high and you could be functional, so that’s why I would argue for people not to put so much money on what the HDL cholesterol level is, because that has to be interpreted with caution.

00:31:49 Julie

It has to be interpreted with the whole clinical picture in mind. I certainly appreciate that. How about the HDL particle number? Would you say a higher particle number or lower particle number would be more protective for ApoE4.

00:32:07 Hussein

We don’t know that. I think it’s a great question, and I think we need to study that in more detail. And my lab is certainly interested in this question, and we’re measuring HDL particles in people with and without ApoE4 carriers. We’re not really finding a big hooray answer, but what we will hopefully publish soon – it’s in review right now – is if lowered HDL particle numbers in the brain associates with features of Alzheimer’s disease?

00:32:35 Julie

OK, and are lower HDL particle numbers in the periphery correlated with lower HDL particles in the brain?

00:32:44 Hussein

It did, but it was not as strongly associated with what’s happening in the brain compared to HDL particles in the blood.

00:32:52 Julie

OK, so HDL, of all the lipoproteins, is there any crosstalk between the periphery and the central nervous system with HDL?

00:33:05 Hussein

We just published a review on this last month. So the dogma says there is no [inaudible] because these are two different components. But we’re finding in our studies that the small HDL particles, because HDL exists in many different sizes, we’re finding that the small HDL particles are correlating between blood and CSF, which is a measure of brain HDL for cerebral spinal fluid, and we’re hypothesizing that those small particles might be exchanged.

00:33:36 Julie

Right, I think I’ve read some hints about that in the literature before, and I wondered if the small particles were able to cross the blood brain barrier. So that’s a paper that you’ll be publishing soon it sounds like.

00:33:50 Hussein

I’m hoping – it’s in review it now in Alzheimer’s and Dementia. We would find out in the next two to three months what the fate of that paper is, but we’re hoping that the scientific audience will appreciate this one.

00:34:04 Julie

Oh, I’m sure that they will. That’s something that our communities paid a lot of attention to – HDL.

So let’s move on to that third mechanism. You mentioned that ApoE4 carriers metabolize nutrients differently. Fats and carbohydrates. Can you expand on that mechanism?

00:34:28 Hussein

Sure, so this is where also my lab works on understanding.

One of the features of ApoE4 and its ability to modulate metabolism associates with changes in how mitochondria may be peroxisomes, and these are subcellular organelles that metabolize fatty acids. It affects how these areas in the liver possibly, and in the brain too, oxidize and metabolize fatty acids, specifically polyunsaturated fatty acids. So our study suggests that ApoE4 carriers tend to oxidize or break down polyunsaturated fatty acids at a higher rate than non-E4 carriers. In this process, it’s more pronounced with aging and as disease state ensues.

So what we specifically find, if we give an ApoE4 carrier and omega-3 rich diet, they tend to have less increases in their blood and the brain as measured by CSF compared to non-E4 carriers, meaning that the ApoE4 system is consuming more omega 3s than ApoE3 and E2. And that also to us means that ApoE4 carriers not consuming enough omega 3s is at a higher risk of omega 3 deficiency.

So we proposed a few years back, in 2017, 2016 that the ApoE4 brain could be hungry for omega 3s and would require a higher intake of omega 3s compared to the non-ApoE4 brain decades before the onset of disease.

And we also propose that as a disease ensues, the brain switches through a system that hyper oxidizes or increases the catabolism or destruction of omega 3s, that it becomes futile to start these supplementations after disease ensues because it’s no longer using them in the right direction.

So what we mentioned in the 2017 paper in JAMA Neurology is that we think E4 carriers, decades, decades we were talking from 20s to 60s consume more omega 3s because the ApoE4 brain is hungry for those. But once you develop the disease status, it may not make a difference because you switch now into a different metabolism state where omega 3s can no longer be protective.

That’s one aspect that my lab is doing, and in fact we got funded by both NIH and the Alzheimer’s Drug Discovery Foundation to launch a relatively large trial. We call it Prevent Before where we’re giving ApoE4 carriers relatively higher doses of omega 3 supplements over two years. But we struggle to find those E4 carriers because 1) you have to be ApoE4; 2) you have to not like eating fish because we’re looking for people who do not consume omega 3s; and 3) you cannot have dementia or cognitive impairment, so we’re looking for people between the age of 55 and 80 who happen to carry an E4, not eat a lot of fish and don’t have disease. And the reason why we’re looking in this age range is because if you look at younger people, you won’t find changes in cognition. So we wouldn’t know if it’s going to be working well. So we want to catch them a year or two before they have disease to see whether the supplementations with large doses of omega 3s can alter or or make a dent in the progression towards disease.

So that’s one aspect of the answer to your question. There’s another aspect.

00:38:22 Julie

Yeah, OK, let me ask a quick question. So you say high dose of omega 3. What is the dose that you’re giving people in the trial?

00:38:33 Hussein

We’re giving them two grams per day of DHA.

00:38:36 Julie

DHA. OK and what type of DHA?

00:38:41 Hussein

It’s produced in algae and it’s vegan and it is what’s known as triglyceride based DHA.

00:38:43 Julie

OK, and why did you choose to do a vegan based DHA?

00:38:56 Hussein

I didn’t specifically choose to do a vegan based, but this form of DHA has been studied extensively before, it’s available, and we know that this form of DHA efficiently raises the amount of DHA in the blood.

00:39:03 Julie

Got it. So I know that we need to move on to part two of your answer to this question, but I sort of want to stay here for just a moment. So if you were an ApoE4 carrier like me, I’m 59 years old and not showing symptoms at the moment, it would be a reasonable suggestion that I would not want to skimp on my omega-3 fatty acids at this part of my lifespan. I would imagine.

00:39:43 Hussein

Let me also reflect humbleness because we don’t know, and I do not want to give you information that’s not supported by strong evidence because if we had evidence this should be a recommendation, not a trial. We wouldn’t put E4 carriers on placebo.

But to answer your questions, I think if I were an ApoE4 carrier, I would possibly want to increase my omega 3 consumption from fish. And I think the reason why I’m focusing on fish because fatty fish contains so many other nutrients besides omega 3s that makes the body’s consumption of omega 3 much more efficient.

00:40:18 Julie

Right, absolutely. So let’s move on to Part 2 of how ApoE4 carriers metabolize nutrients differently.

00:40:36 Hussein

So the second part has to do with body weight and insulin resistance.

00:40:39 Julie

Can you repeat that?

00:40:44 Hussein

Insulin resistance. ApoE4 we know is associated with more insulin resistance and lower body fat. Typically ApoE4 carriers can be skinnier, but they are more insulin resistant, meaning that they don’t really know how to metabolize glucose.

So one of the things we are interested in studying is what is the effect of maybe modulating insulin resistance on the ApoE4 brain? And one way to alter insulin resistance is through exercise. One way to alter insulin resistance is through a low carb diet. One way to alter insulin resistance is through weight loss.

Now we don’t really fully understand what the recommendations should be like, but we have hypotheses, and please take this with a grain of salt, because it’s a hypothesis. We don’t think caloric restriction or losing weight is a good idea for ApoE4 carriers, despite the fact that it improves insulin resistance, based on basic science studies suggesting that ApoE4 adipocyte Is not able to tolerate weight changes graciously, so an ApoE4 carrier who loses more weight might be at higher risk of diseases than an ApoE4 carrier who maintains or even gains weight.

00:42:14 Julie

Wow, and overall that applies to everyone of every APOE genotype. It’s been a little surprising, but it seems like people that are of a slightly heavier weight seem to be protected somewhat.

00:42:31 Hussein

Yeah, I can’t tell you how it works by genotype because the studies have to be done and they’re not done yet.

But we have enough epidemiology observational [inaudible] suggests that older ApoE4 carriers with heavier weight do better than older ApoE4 carriers with [inaudible]. This is an association or a correlation. We don’t fully understand that, but we know that in mice models, when you feed a mouse to a diet that’s rich in elements that can make the mouse diabetic or insulin resistance, the ApoE4 mouse tends to gain less weight but become much more insulin resistant than the ApoE3 or ApoE2. Because they cannot expand their depots efficiently.

00:43:22 Julie

That is fascinating. So we also know that as ApoE4 carriers become insulin resistant, they’re less able to use glucose in the brain, and I guess imaging studies have shown that we have issues with that starting as early as age 20 if you’re going to look at the studies from Eric Reiman and Richard Caselli. And in the same regions of the brain as Alzheimer’s patients, even though these 20 year olds aren’t showing symptoms, they still have that deficit of being able to use glucose efficiently in the brain.

00:44:00 Hussein

I have to caution you that these findings don’t apply to heterozygotes. Those findings are largely driven by homozygotes and have not been reproduced yet. In fact, larger studies which have happened decades or maybe years after Eric Reiman published these findings didn’t reproduce his findings.

The majority if not all studies that came later do not show that younger ApoE4 carriers have deficits in brain glucose uptake.

00:44:31 Julie

Very encouraging.

00:44:32 Hussein

So when you look at large cohorts, hundreds of people, you realize that, for example, a study by Knopman from the Mayo Clinic suggested that the changes in glucose metabolism in the brain in ApoE4 carriers do not appear before the age of 60, and he studied approximately 800 individuals. And if you want to dig deeper into what Eric Reiman’s findings where 20s and 30s they might have been biased toward ApoE4 homozygotes in a very small subset of patients, so we don’t know whether it just happened by luck, that those ApoE4 carriers had more severe disease, but in general there is no evidence that younger ApoE4 carriers have strong deficits in brain glucose metabolism at this age. It appears to happen at older age and perhaps five years before non-carriers.

00:45:34 Julie

Right, that’s very encouraging, and I think you’re right, Dr. Reiman’s data set was certainly rich in ApoE4 carriers, and it was certainly people at very high risk and probably more homozygotes than heterozygotes, but so that would make sense. And I also wondered about the metabolic health of that data set because that finding was so surprising.

00:46:01 Hussein

Yes, and you know, since that publication we’ve had many papers that do not show a clear signal that ApoE4 is doing that to the brain at that age. Now, ApoE4 may have a lot of effects on the brain, and it is possible that in some ApoE4 homozygotes you could clearly see some signal, but in general it’s diluted out.

In fact, we have published the paper in 35 year old ApoE4 carriers showing increased omega-3 brain uptake. And what we and again, it’s a small subset, 35 individuals. We still have to reproduce it in a larger group, but what that suggested to us is that the ApoE4 brain is consuming more omega 3s than the non ApoE4 brain, possibly because it prefers fat over glucose.

00:46:54 Julie

Right, and many people in our community and we know we don’t have definitive research, but many of us are using a low carb approach and very regular exercise. And you know, certainly trying to make sure we have enough omega 3s on board so everything you’re saying beautifully dovetails with what people in our community are doing.

I guess that brings me to my next question. If you were an ApoE4 carrier – and I don’t know that you’re not – but what diet or lifestyle strategies would you be using to protect yourself from the effects of ApoE4?

00:47:38 Hussein

Right, it’s a great question. Let me start by saying we need to do more research into it, and I think the ApoE4 community should stand up and work together to support more ApoE4 research. We’ve had decades of research into amyloid and tau, but we’ve only started to scratch the surface of ApoE4. And we know that ApoE4 is by far the strongest genetic risk factor for late onset Alzheimer’s disease. So that’s why fundamentally if there’s anything that the community can help with, it is to spread the word, support ApoE4.

Coming back to your question is, if I knew that I was an ApoE4 carrier, what can I do to change my life span risk of having dementia or cognitive diseases with age?

One I would probably consume more fat than carbohydrates, and when I talk about fat, I’m more referring to healthy fats and not saturated. That includes nuts; that includes fatty fish, avocados, and olive oil and so forth.

I would consume less simple sugars. Simple sugars come in the form of sodas, cakes. Because we know there’s an association of simple sugars with diabetes at this moment.

I would definitely not smoke because we know that smoking would worsen vascular biology and make it higher likelihood that there’s vascular dysfunction in the ApoE4 system.

I would develop an exercise strategy where I would engage in at least 150 minutes in a given week. That’s 30 minutes a day, five days a week with some form of exercise. Doesn’t have to be high intensity. Could be as simple as an aerobic exercise where I stretch myself, walking fast, running, swimming – any form of exercise is good.

I would engage in some form of meditation that would clean up my thought processes and help me to reorganize.

Music and anything that can possibly de-stress and not cause any increase in stress.

Importantly, I would take any chronic disease in middle age seriously. So if I had diabetes, hypertension; if I had, you know low vitamin B’s. If I had anything that could possibly put my brain at risk, I would deal with it when I’m asymptomatic. Between the ages of 20 and 60, not wait until after 60.

There are other things that we haven’t talked about, which is the importance of vitamin B for brain health. I’m not advocating for supplements. But what I’m trying to say is that the vitamin B has an important role in the transport of omega 3s to the brain. Vitamin B can be found in fish, could be found in green leafy vegetables, and other sources.

00:50:40 Julie

And I want to make sure I understand what you’re saying. Vitamin B.

00:50:43 Hussein


00:50:44 Julie

B, as in a baby book, OK, and there’s so many forms of vitamin B, so which are you referring to – vitamin B12?

00:50:55 Hussein

B12 and B6 and folic acid.

00:50:57 Julie

And folate, right absolutely. And you know, a lot of people in our community pay attention to those three to keep homocysteine down.

00:51:05 Hussein

Yes exactly. So we want to do that because also we understand that the omega-3s to be able to get to the brain, they have to be on phospholipids and that reaction requires folic acid and B12.

These things go together and that’s why fish is a more complete source of omega 3s than supplements because the actual fish itself will have vitamin D, vitamin B, vitamin E, which is an antioxidant, lutein, which is an antioxidant. So that’s why sometimes just taking one supplement may not be sufficient.

00:51:43 Julie

Absolutely, it’s always best to get nutrients from food, as opposed to a supplement.

My final question for you is, do we know enough to do APOE testing? Should we be testing people?

00:52:00 Hussein

Yeah, I used to get asked that question a few years back, and then my answer was no. But my answer has evolved to yes, because we have a little bit more information than a decade ago.

And with the information we have today, I would tell the ApoE4 carrier exactly what we just talked about. If they knew that they were ApoE4 and they had a family history of dementia, they would have plenty of time to prepare and to do the best they can to avoid getting into later risks. You don’t want to certainly have this discussion at the age of 75.

00:52:37 Julie

Oh, absolutely. And you don’t want to learn later in life. It’s always better to know sooner. And I completely agree with you. We think everyone should know their APOE status. For instance, I wish I knew my son was an ApoE4 carrier before he decided to engage in extreme skateboarding and get a bunch of concussions on his head. I mean, so there’s lots of preventative things we could do.

I also would have paid so much more attention to omega 3s had I known when he was young. Although we are paying attention now. So yeah.

00:53:12 Hussein

Exactly. For the exact reasons that sometimes knowledge is bliss. In this case we are trying to make the argument that this should be part of a [inaudible] where when we see ApoE4 carriers we include genetic counseling, nutrition, exercise, lifestyle.

So it’s all good. To deal with ApoE4, we need a good understanding what it does, and that understanding will be influenced by many other things, including family history of dementia, including race, including age, including disease stage, the recommendation may differ for somebody who is 75 and someone who is 30.

So there’s a lot of research that needs to happen, but we’re starting to see the tip of the iceberg, and I think we’re heading in the right direction.

00:54:08 Julie

Oh, absolutely, and you shared a beautiful PDF with me that gave some advice, essentially for ApoE4 carriers. And you echoed it, much of it, in this discussion. But in our show notes, I plan to share that with our community if you don’t mind.

And I did have one question about that. I noticed that you recommend a lot of omega-3 rich foods that are plant sources, and you only recommend seafood like once a week. Why do you prefer the plant sources?

00:54:45 Hussein

I don’t prefer plant sources. It’s at least one time, one serving, so at least one, so you could have two or three or four. The evidence is really toward zero versus one is much bigger than one versus four.

00:55:02 Julie

Wow, OK.

00:55:03 Hussein

The people who do not consume any fish – the epidemiology evidence supports that they have greater risk of dementia compared to people who have one or two servings. But as you go from one or two servings to four, the risk reduction is not as steep.

00:55:18 Julie

Oh interesting, OK.

00:55:20 Hussein

I’m not saying that omega 3s is found in nuts is superior or inferior to omega 3s found in fish, although there is the argument that the human body may not efficiently make the fish derived omega 3s. From the plant-derived omega 3s, we cannot convert alpha linoleic acid, which is found in flaxseed or walnuts, to DHA and EPA.

But nevertheless, levels of alpha linoleic acid correlate with better outcomes. So people who consume nuts seem also to provide their brains with a nutrient that the brain likes.

Again, I’m not saying one is superior to the other. It appears that consumption of omega-3s – not binging on them – but just consumption at least seems to be protective for the brain.

00:56:14 Julie

OK, wonderful. Well I can’t thank you enough for sharing your expertise with us. If you would like, we’d love to help you recruit people for Prevent E4 if you’re still trying to get folks enrolled in the study, we can make an announcement on the site.

00:56:31 Hussein

Absolutely, so you can go to our website, and has the phone numbers, the protocol, the age group, inclusion / exclusion criteria, and you can support us by joining the study, spreading the word, talking to your friends, your family members.

This is an NIH funded study, which means it has been peer reviewed by people who are experts in the field. That also means that the budgets tends to be modest, so we wouldn’t have a big budget to fly people in, but we do the best we can to get them into the study with our resources.

I have to disclose that I have no conflict of interest for supplements – I don’t get paid by the supplement industry, and I’m not advocating for taking supplements. And if we knew that supplements worked, we would not do this trial.

The paper that you are going to upload on your website is not really an evidence based recommendation. It’s more of: we think this is where the science is today; this is the best available evidence we have today, but it might change; it does not guarantee that you do this and you don’t get disease; you may still get disease; it does not replace talking with your doctor.

But it’s the best available evidence we have today. And you know, if I made mistakes I will admit them. And if some of the recommendations need to be changed, they will be changed. We keep an open mind, and we realize that science is evolving. And new information will come in the future that makes this changeable.

00:58:09 Julie

Absolutely, and as I said earlier, we share your humility. We’re on this ApoE4 journey together and we’re learning more every day. And what I thought was helpful yesterday may not be the same as what’s helpful tomorrow, and so I’m always looking for new research. I’m looking to understand more and thank you once again for sharing your expertise. You’re very welcome to come back anytime you have new findings or want to share results of your clinical trial. And we will help you spread the word.

00:58:44 Hussein

Thank you so much, thank you.

00:58:44 Julie

Well alright thank you. Alright take care Hussein – bye bye.


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