COMMENTARY

Omega-3s to Prevent Alzheimer's: Who Benefits?

Richard S. Isaacson, MD; Hussein Yassine, MD

Disclosures

September 14, 2020

This transcript has been edited for clarity.

Richard S. Isaacson, MD: I'm Dr Richard Isaacson, and on behalf of Medscape, I'm here interviewing someone whose work I've really admired and followed for years now: Dr Hussein Yassine.

He's an associate professor of both medicine and neurology at the University of Southern California Keck School of Medicine. He's an internist and an endocrinologist by trade, but we somehow tricked him into helping us figure out the complexities around Alzheimer's and in the brain.

Hussein, thanks so much for being here today on Medscape.

Hussein Yassine, MD: Thank you. My pleasure. I appreciate the invitation.

Isaacson: I saw you speak about 4 or 5 years ago now at the Clinical Trials in Alzheimer's meeting. You also had a paper in JAMA Neurology back in [2017] showing that with omega-3 fatty acids, whether it's DHA or EPA, you may not want to take a one-size-fits-all approach when it comes to Alzheimer's prevention, which your brand-new paper suggests as well.

Take us back a couple of years and give a summary of what your research found and why, in patients who are at risk for Alzheimer's disease, or even in patients in the earliest stages, omega-3 fatty acids may be a really important therapeutic target.

Yassine: Thank you, Richard. That's a wonderful question. Let's step back a little bit and ask why we are even interested in omega-3s.

There has been a very consistent association between omega-3 intake and the incidence of Alzheimer's disease. That's not just in the US but in many different cohorts in Europe as well. We're talking about a large number of cohorts with lower levels of omega-3s that are associated with increased risk for Alzheimer's disease.

We know that the human body cannot efficiently make omega-3s. We don't have the enzymes to make them, so we have to take them in with food. We also know, by elegant PET scans, that the brain needs a very tiny amount of omega-3s to keep going. This is the adult human brain, unlike the baby brain, which needs more. The brain needs about 3 mg per day, which is a tiny amount.

The question is, is there a relationship with omega-3 intake that we could use to prevent or stop Alzheimer's disease? Our studies have shown that, yes, there is; however, as you said, the relationship is not one-size-fits-all. Not everybody will benefit from supplementation.

Our studies suggest that people who do not consume omega-3s are the most likely to get benefit because a lower omega-3 level is associated with greater brain amyloid plaques. Also, not everybody is going to get Alzheimer's.

We know that about 5-6 million Americans have AD. Let's assume that you give omega-3s to people who will never get AD. You're not likely going to see an effect because those people are not going to cognitively decline.

Who are those people who might get AD and benefit? Over the past 8 years or so, we've done many studies on a genetic risk for AD known as APOE4. People who carry one risk allele have a fourfold increase in the risk for AD, and people who have two have an approximately 12-fold increase.

We tracked APOE4 carriers, and our studies suggest that if you catch an APOE4 carrier early before they have any disease, we have evidence that the brain is using a lot of omega-3s. This means the brain is pulling those omega-3s from plasma. There is no evidence of cognitive decline. We think this APOE4 brain is going to run into trouble if the levels of omega-3 in plasma are low.

The implications are that younger APOE4 carriers who do not have enough omega-3 intake have a higher risk of developing cognitive decline. I think it's not everybody, but it's a specific population. Finally, should an APOE4 carrier go and get an omega-3 supplement from the store, and would that be okay?

We just completed a study published in eBioMedicine showing that 400 mg, or any dose less than a gram that you can find over the counter, will probably not do it because the majority of those omega-3s are getting oxidized in the liver and lost. The tiny little fraction that goes into the brain is lost when the dose is low.

Maybe an over-the-counter dose can help if taken across many years, but if you want short-term effects — short term could be a couple of years or maybe 3 years — you'll need higher doses to get those omega-3s into the brain.

Isaacson: Your work has really elucidated all of these important points. First of all, it's not just about the dose but about which type. There's DHA vs EPA — different types of omega-3 fatty acids.

There are different ways to get it. As you said, there are supplements that are over the counter. Some of the purities may be terrible; they may have gone rancid. They may not even be good anymore when you look at the expiration dates.

There are FDA-approved omega-3 fatty acids available by prescription. They're the same omega-3s, but they're regulated and they've been studied — in this case, in cardiovascular disease trials.

You've brought up so many good points. When a practitioner like me is on the front lines and seeing a person, they may say, "Doc, is there anything I can do to reduce my Alzheimer's risk?" My usual answer is, "Well, yeah, there are a lot of things you can do. We may not be able to prevent it entirely, but if we can delay it by a few years and then the blockbuster drug comes, well, then guess what? By doing these different things, you've delayed or prevented your own Alzheimer's."

Honestly, omega-3 fatty acids, I believe, have to be part of this conversation. Also, you mentioned that not everyone's going to get Alzheimer's. Also, not everyone needs omega-3 fatty acids. We do a red blood cell (RBC) level because RBC levels of omega-3s are really important. If they're low, those people really need to be supplemented

From a practical clinical perspective, I think physicians out there need to take a step back and say, wow, there's been an explosion of evidence. What I read 10 years ago, when we tried omega-3s in randomized trials for treating Alzheimer's disease that failed, may be different now. Maybe they're not going to work because of the dose, and maybe when patients already have dementia, they're not going to work.

For prevention and risk reduction, I think it's honestly one of the most important things. We obviously also have exercise, nutrition changes, blood pressure control, sleep modification, and stress reduction. But omega-3 fatty acids, I think, really need to be prioritized in the conversation.

Yassine: These are great remarks, but I do have to usher in some caution. I would personally say that, yes, I am convinced that having seafood, such as fatty fish like salmon once a week may make a difference based on large, good-quality epidemiology studies that may not be replicated by short-term clinical trials.

When it comes to supplements, we do have to take this with a little bit of caution because, yes, we have some signals that it may work in prevention in certain populations. But we still have to nail that down and we still need to do more research to give a supplement the same recommendation that we give to a statin, aspirin, or to any well-researched medication in the setting of clinical trials for the clinical recommendation.

Supplements, as you mentioned, are all diverse. Some of them are bad, some of them are great. We don't exactly know what dose. We don't know exactly how long to give them.

You mentioned RBC DHA. Does increasing the RBC DHA translate into lower cognitive decline? That's a great question. We don't have the answer to that yet. I think the answer is not to throw the omega-3 into the bin, but rather do more research to figure this out. There is really a good signal that needs to be refined in better trials and more tailored to specific populations.

Isaacson: I couldn't agree with you more. We have to be cautiously optimistic. More research is definitely needed. You can get omega-3s from fatty fish like wild salmon — which is likely better than farm-raised — mackerel, albacore tuna, and sardines. You almost can't eat enough sardines because they're very brain-healthy. There are many different types of fatty fish out there.

You can also get omega-3s through a prescription or potentially through a supplement. This has to be a one-on-one discussion with the physician and the patient.

I agree with you that we need to track outcomes. In our clinic, we track cognitive trajectory every 6 months, we track RBC DHA, we track cholesterol markers, and we track advanced cardiovascular markers. Omega-3s are an FDA-approved treatment for high cholesterol. I think these are really key.

I wanted to wrap up with one question. When it comes to one-size-fits-all, the terms "pharmacogenomics" and "nutrigenomics" underscore the importance that certain people with certain genes may respond to something and other people with different genes need a different plan because they're not going to respond the same way.

When it comes to the APOE4 variant, how do you think about the dose and the duration for someone who has one variant vs two vs no copies?

Yassine: That's a great question. Again, whatever I'm going to say is not based on strong clinical evidence and we need to do more trials. It is my suggestion. Having two copies means you're going to get severe disease at a younger age. The implications to that mean interventions have to be much earlier than if you have one copy.

Homozygotes should probably start maybe in the 20s or 30s with lifestyle interventions, whether it's exercise or eating seafood. You don't have to eat much seafood to get omega-3s. Once a week would probably be enough if you have a good-sized piece of salmon.

All of the preventive measures we're talking about should be more aggressive, a higher dose, and earlier in homozygotes compared with heterozygotes, who actually may have a larger window of time before they get the disease.

In addition, you have to take into consideration family history. Having a family history in addition to APOE4 increases the risk for cognitive decline because not all heterozygotes will get AD. In fact, the majority of heterozygotes may not get dementia. Of the population, 25% carry one copy. Again, having two copies means we have to start early.

Isaacson: Hussein, thank you so much. I've been an admirer of your work and I really appreciate you taking the time to educate the folks on Medscape.

Yassine: I appreciate it. Thank you, Richard.

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