What APOE4 Means for Brain Health

Dr. Rhonda Patrick: Moderate alcohol consumption in people that don't have any APOE4 allele doesn't seem to be harmful most of the time. When you have that APOE4 allele, it's definitely harmful.

One of the biggest SNPs, the biggest bang for your buck in terms of learning if you have it and actionables that you can do to alleviate the disease risk, would be APOE4. It's pretty common. It's actually one in four people have at least one allele. In other words, they have one copy of it from one of their parents. If you have just one of those alleles, you have about a twofold higher risk of Alzheimer's disease. If you have two copies, you mentioned homozygous, that means you have a copy from both your mom and your dad. That means you have about a 10- or 11-fold risk of Alzheimer's disease.

Now, just having a baseline risk of twofold higher is even a lot. And as I mentioned, one in four people have at least one of those alleles. That's a significant percentage of the population, right? This is a big one because it's not only involved in neurodegenerative disease, it's also involved in cardiovascular disease risk as well because it has to do with cholesterol clearance. People with that allele don't recycle their cholesterol back to the liver as readily, and so they at any given point have higher levels of LDL in their circulation than someone who doesn't have that allele.

Cardiovascular health is very related to brain health, right? If your arteries are clogged up, blood's not getting to the brain. Your brain's not getting enough oxygen and nutrients and glucose and everything, right? There's a very big relationship there between your cardiovascular health and your brain health.

Aside from that, though, people with an APOE4 allele have to realize there are other lifestyle factors that play a role in your Alzheimer's disease risk that are very important, that you have to consider and be more fastidious about than someone who doesn't have one of those alleles, one of those SNPs, the APOE4 SNPs. A big one is alcohol consumption. There's all this mixed data out there looking at alcohol and neurodegenerative disease risk, dementia risk. You may have come across the study that says, "Oh, moderate alcohol consumption actually lowers dementia risk." Or you may have come across a study that says, "Oh, moderate alcohol consumption actually increases dementia risk." Pick or choose, which side are you on? Let's see, what do you want, right?

Well, it turns out the data is nuanced. It is, right? When it comes to anything nutrition, lifestyle-related, any observational data, right? Protein consumption. We started the podcast talking about protein consumption and meat versus vegans, right? Well, it turns out when you start to look at people's genetics, then it goes, "Oh, okay. Moderate alcohol consumption in people that don't have any APOE4 allele doesn't seem to be harmful most of the time. When you have that APOE4 allele, it's definitely harmful. It's increasing your risk," right?

Derek: Do you have both copies?

Dr. Rhonda Patrick: I have one. I have one copy. That was the biggest thing that I learned from my genetic data. People with an APOE4 allele, there's really no amount of alcohol that is safe for your brain and for neurodegenerative disease risk. There's a variety of reasons for that. One has to do with your blood-brain barrier breaking down earlier. Repairing damage doesn't happen as well. You have every reason to really not drink alcohol, and certainly not drink it frequently.

If you do this, there's other factors that are important. Exercise also hugely important. I should mention there are a lot of people that have an APOE4 allele that do not get Alzheimer's disease. That is important to realize. It's not a sentence that you're going to necessarily get this disease, okay? There are things you can do to decrease your risk. It just becomes more important for you to focus on those things. Alcohol consumption, exercise really helps negate APOE4's increased risk on Alzheimer's disease. That's why I'm really focused on brain health and exercising for my brain as well.

Derek: And what is the mechanism? With MTHFR, we know it's inhibited capacity for—it's like functionality of the gene that encodes for that enzyme that's severely inhibited, and there's ways you could backfill micronutrients to try and attenuate it, or at least offset the burden significantly, too. You'd have extra creatine supplementation, you could have methyl donors, et cetera. With APOE4, is it like you mentioned the cholesterol clearance? I don't think I've ever heard somebody break down succinctly what exactly is happening that's wrong that's causing the problems.

Dr. Rhonda Patrick: Yeah, there's multiple things that are happening with APOE4. It's essentially affecting the ability of the LDL receptors on your liver to interact with apoB, which is that key protein that people measure to look at their particle number, LDL particle number. What's happening is that the interaction's not connecting as well, and so the LDL particles are not getting taken back up into the liver and being recycled, right? They stick around in your vascular system longer. What happens when they stick around longer? They get modified. Then they get lodged into your artery walls, and you get this cycle of, okay, inflammation, foam cell, atherosclerosis, right? That is one aspect.

APOE4 is also in our brain, so we actually make it in our neurons as well. Essentially, there's lots of things going on. One thing that's happening is it plays a role in what's called neurite outgrowth, which is anytime there's any type of damage, alcohol, you're drinking alcohol, you're causing damage to your neurons, okay? Your neurons repair that damage. That's the adaptation, the response, right? It's like, okay, a little bit of damage, got to repair it. Well, part of that repairing is neurite outgrowth, and that's not happening well in people with that APOE4 allele.

That's why people with traumatic brain injury that have an APOE4 have such severe outcomes, right? They do not recover well from TBI. Their Alzheimer's disease risk, even if they only have one allele after one TBI, goes up dramatically. It's not just twofold, then it becomes like fourfold, then it becomes tenfold, depending on how many TBIs they've had, right? You're not repairing that damage to the brain. Hugely important.

It affects cholesterol production, trafficking in the brain as well. APOE4 is also affecting the blood-brain barrier integrity. The blood-brain barrier actually starts to break down earlier in life in people with APOE4 alleles. You have to do everything in your power to have a healthier blood-brain barrier. The biggest factor that helps maintain a blood-brain barrier is exercise.

We have these tiny little blood vessels, like the size of hairs, and they sort of fall off and die off if you're not increasing blood flow to them because it's really hard to get blood flow to them. They're very small in diameter. Exercise kind of forces blood flow into those tiny little vessels, and it really helps maintain that blood-brain barrier. As those tiny vessels start to break down and break off when you're not physically active, that begins the process of breaking down the blood-brain barrier. Exercise is so important for maintaining that blood-brain barrier, and that's why people with APOE4 have to obsess about exercise and exercising for their brain, right? That is another one.

And then there's diet that plays a role as well. Sleep. Sleep is very important for a lot of things. One thing is also clearing out all the gunk that's in the brain. When you're in the deep sleep state, when you're in that slow-wave sleep state, this activates something called the glymphatic system, which is essentially this series of vessels that are coming at—the cerebrospinal fluid comes up, gets into the brain, and squirts, like cleaning out, like washing and squirting away all the gunk, like proteins that build up.

Protein aggregates like amyloid beta, which play a role in Alzheimer's disease, or pieces of DNA from cells that are dividing and fragments of DNA, just gunk, right? Trash. Got to get rid of it. It's got to get out of the brain. Sleep is important to do that. When you're not getting enough sleep, that gunk isn't getting taken out. In fact, APOE4 also affects that process. You really need sleep, and you have to really optimize the sleep.