Can You Improve Your Memory With A Jellyfish Protein?

Some colleagues of mine recently asked me about Prevagen, a supplement that is being advertised heavily on television as a memory booster. It's everywhere, they said–but what is it? And does it work?

Both questions are pretty easy to answer. On the first question, the TL;DR version is that Prevagen's primary ingredient is a protein called apoaequorin, which is found in a species of jellyfish that glows in the dark. These jellies produce two proteins, apoaequorin and green fluorescent protein (GFP), that help them fluoresce. It’s an amazing biological system, and the three scientists who discovered and developed the chemistry of GFP were awarded the 2008 Nobel Prize in chemistry.

Cool science! But what does this have to do with human memory? Not much, it turns out.

First let's examine what Prevagen's manufacturers, Quincy Bioscience, say about it. Their website claims that:

"Prevagen Improves Memory* 

Prevagen is a dietary supplement that has been clinically shown to help with mild memory loss associated with aging.* Prevagen is formulated with apoaequorin, which is safe and uniquely supports brain function.*"

Sounds pretty clear, right? But note the asterisks by each of these claims: if you scroll all the way down (or read the small print on their packages), you'll find out that:

"*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease."

You may recognize this language: it's what all supplement manufacturers use to avoid getting in trouble with the FDA. It means, essentially, that the government hasn't approved Prevagen to treat anything, including memory loss.

Despite Quincy’s claims, I see no reason why eating this protein would have any effect at all on brain function. First of all, it’s not even a human protein, so it's unlikely to work in humans. Second, even if it did work in humans, eating it would not deliver it to our brains, because it would be almost certainly be broken down in the stomach. And third, the connection between any protein and memory is very complex, so simply having more of a protein is very, very unlikely to improve memory.

Quincy's website points to a single study that they themselves conducted, which they argue showed benefits for people with mild memory impairment. However, others have pointed out that the experiment (which was never published in a scientific journal) didn't show any such thing: overall there was no difference between people who took Prevagen and those who took a placebo, but the manufacturer's did some p-hacking to extract a subgroup that appeared to get a benefit. As Dr. Harriett Hall and others have pointed out, this kind of p-hacking is bogus.

And what about my observation that the jellyfish protein will simply be digested in the stomach, and never make it to the brain? It turns out that the company itself admits that I'm right. On their website, they have a "research" page pointing to several safety studies, designed to show that Prevagen won't cause an immune reaction. One of these studies explains that

"Apoaequorin is easily digested by pepsin."

Pepsin is the chief digestive enzyme in your stomach. So Prevagen's main ingredient never gets beyond the stomach, which is why it's probably quite safe. (Joe Schwarcz at McGill University recently made the same point.)

Back in 2015, I asked Ted Dawson, the Abramson Professor of Neurodegenerative Diseases at Johns Hopkins School of Medicine, what he thought of Prevagen’s claims.

“It is hard to evaluate Prevagen as to the best of my knowledge there is no peer-reviewed publication on its use in memory and cognition,” said Dawson. “The study cited on the company’s web site is a small short study, raising concerns about the validity of the claims.”

Finally, a word to those who are still tempted to try Prevagen: it isn't cheap. Their website charges $75 for a bottle of 60 pills, each containing 10 mg of apoaequorin, or $90 for 30 pills of the "Professional formula," which contain 40 mg. (Note that there's no evidence that taking a higher dose will work any better.)

The FTC sued Quincy Bioscience in 2017 for deceptive advertising, arguing that claims that Prevagen boosts memory are false, and that claims it can get into the brain are also false. Just a few months ago, a judge ruled that the case can proceed. Meanwhile, though, the advertising and sales of Prevagen continue. The FTC case states that Quincy sold $165 million worth of Prevagen in the U.S. from 2007 to 2015.

So the bottom line is: jellyfish proteins are very cool, but eating them won't improve your memory. If you're interested in brain food, perhaps you just eat more fish, which might actually work.

(Note: I wrote about Prevagen in 2015, and some elements of this article are based on my earlier one.)

Fish really is brain food

Everyone has heard that eating fish is good for the brain. This notion goes back at least a century; the famous humorist and novelist P.G. Wodehouse often mentioned it in his books. In one scene, after Jeeves (the butler) describes a clever scheme to escape a ticklish problem, Bertie Wooster reacts:

I stared at the the man.
'How many tins of sardines did you eat, Jeeves?'
'None, sir. I am not fond of sardines.'
'You mean, you thought of this great, this ripe, this amazing scheme entirely without the impetus given to the brain by fish?'
'Yes, sir.' [From Very Good, Jeeves, (c) 1930 by P.G. Wodehouse]

A century ago, the evidence that fish is brain food was virtually nonexistent. Researchers have been looking at this question ever since, and the evidence has been mixed. Even if fish is good for the brain, the mercury content in some fish might have the opposite effect.

A new study that appeared last week in JAMA answers this question: fish is indeed good for the brain. More precisely, eating fish regularly was associated with a reduced risk of Alzheimer's disease. This benefit occurred despite the fact that people who ate more fish did have higher levels of mercury in the brain. Apparently, the levels of mercury were too low to cause harm, and the benefits of eating fish easily outweighed any risks.

The new study, by Martha Clare Morris and colleagues at Rush Medical Center in Chicago, looked at 554 Chicago residents, all part of a long-term aging study, who died over a ten-year period. The scientists conducted autopsies to look directly in the brain for physiological changes such as neuritic plaques, which are signs of Alzheimer's or other disease. They used questionnaire data, which they collected for everyone in the study, to measure how much fish people had been eating–an imperfect way to measure eating habits, but it's often the only realistic way to gather this information.

Here's what they found: people who ate seafood at least once per week had lower levels of three different physiological signs of Alzheimer's, but only in people with a genetic marker known as APOE ε4, which itself carries an increased risk of Alzheimer's. (None of the people in the study had dementia when they first enrolled, starting in 1997.) Somehow, then, eating fish seems to counteract the effects of this harmful genetic mutation.

Bad news for fish oil supplement makers: the study found that "fish oil supplementation had no statistically significant correlation with any neuropathologic marker." In other words, people who took supplements got no benefit. You just have to eat fish.

This isn't the first study to show a positive benefit to brain health from eating fish. The authors cite 13 previous studies that reported "protective relations between seafood consumption and n-3 fatty acids with cognitive decline and incident dementia." The JAMA study is the first to include mercury levels, brain changes associated with Alzheimer's, and diet all in the same study. It's reassuring to learn that despite the increased mercury caused (probably) by eating more fish, the overall effect is beneficial.

The authors also pointed out that as we age, our brains lose DHA, a critical lipid in the brain, and that therefore "fish consumption may be more beneficial with older age." The FDA already recommends that pregnant women and young children eat more fish for its nutritional benefits. Now there's evidence that older people should eat fish regularly too.

So it seems that Wodehouse's character Bertie Wooster might have been right: fish really is brain food.

Jellyfish proteins: modern snake oil for brain health

Watching ABC's World News Tonight this week, I saw an impressive-looking ad for a pill that claimed to improve memory and cognition. The ad showed several adults, all looking very happy, presumably because they didn’t forget where they left their keys. In appearance, it looked like many of the drug ads that run on the evening news in the U.S. these days.

The ad described a product called Prevagen, which is sold as a supplement, not a drug. This is a critical distinction: supplements are almost completely unregulated, unlike real drugs. The FDA isn’t allowed to regulate supplements and their claims, thanks to Congress and the 1994 DSHEA law.

I was curious about what this memory pill could be. The Prevagen ad, website and packaging make a number of very strong claims, scientifically speaking. The biggest claim is that Prevagen improves memory*, something pretty much everyone would like. The website also includes the more specific claim that “Prevagen can improve memmory within 90 days.*” The package adds that Prevagen “supports healthy brain function*, [a] sharper mind*, and clearer thinking.*"

How can they make these claims if they aren’t true? Simple: every claim has a little asterisk (*) next to it. If you scroll all the way to the bottom of the Prevagen webpage, you’ll find what that means:

“*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”

Behind this blanket escape clause, supplement makers hide all kinds of unsupported claims. Thus Quincy Biosciences–Prevagen's manufacturer–can state that “Prevagen significantly improves learning,” add the asterisk, and voila! the FDA can’t touch them, as long as they don't make a claim to cure a specific disease.

And by the way, they also claim that “Prevagen improves the quality of sleep.*” There’s that asterisk again.

So what is Prevagen? It’s a pill that contains a protein called apoaequorin, which is found in a species of jellyfish that glows in the dark. These jellies produce two proteins, apoaequorin and green fluorescent protein (GFP), that help them fluoresce. It’s an amazing biological system, and the three scientists who discovered GFP were awarded the 2008 Nobel Prize in chemistry.

How (you might be wondering) this can be sold as a dietary supplement? After all, we don’t eat apoaequorin, and isn’t a supplement supposed to be related to something we normally eat? It sounds more like a drug. The FDA agrees with me–I’ll get to that below.

Despite Quincy Bioscience’s claims, I see no reason why eating this protein would have any effect at all on brain function. First of all, it’s not even a human protein, so it's unlikely to work in humans. Second, even if it did work in humans, eating it would not deliver it to our brains, because it would be almost certainly be broken down in the stomach. And third, the connection between this protein and memory is complex, so simply having more of it is not likely to improve memory.

Prevagen isn’t cheap, either. If you order direct from the company, a month’s supply of pills will cost you $66 with shipping. There’s even an “extra strength” version, though I cannot see how twice as much of an ineffective pill will be twice as effective. On the other hand, two times zero does equal zero.

I wrote to ask the president of Quincy Bioscience, Mark Underwood, if his company is claiming that Prevagen will provide any benefits to people suffering from dementia or Alzheimer’s. He didn’t answer that question, but he did respond that “our scientific basis for the claims we make related to Prevagen are on pretty solid ground.” He was careful to qualify this first, though, writing that

“Prevagen is intended to assist people with mild memory issues related to aging. Prevagen is not a pharmaceutical, nor is it approved by the FDA for the treatment of any neurodegenerative disease (Alzheimer’s, Parkinson’s, etc.).  We do not wish to confuse mild memory loss related to aging with Alzheimer’s disease or dementia in our advertising.”

I also asked Underwood if he could provide any peer-reviewed studies supporting his company's claims. He sent me several studies, but none of them was peer-reviewed: they include company-sponsored studies that are unpublished, and one published abstract from 2011, in the Journal of Alzheimer’s and Dementia. Abstracts, though, are not peer-reviewed: they are short summaries typically presented in oral form at conferences, and sometimes published (as this one was) in special supplements to journals. This abstract seems to be the basis of the claim on Prevagen’s website that “Prevagen was tested in a large double-blind, placebo-controlled study using computers to assess brain performance. 218 adults over 40 years old participated in the three month study. Prevagen significantly improved learning and word recall.*” (Note the asterisk again.)

Prevagen’s claims should be easy to test. If Prevagen really does improve memory, then it would be relatively cheap to run large, well-controlled studies on randomized subjects, and I’d expect to have seen multiple studies published since 2011. But because Prevagen is being marketed as a supplement, Quincy Bioscience doesn’t have to prove anything. They just have to be careful not to cross the line in their advertising.

I asked Ted Dawson, the Abramson Professor of Neurodegenerative Diseases at Johns Hopkins School of Medicine, what he thought of Prevagen’s claims.

“It is hard to evaluate Prevagen as to the best of my knowledge there is no peer-reviewed publication on its use in memory and cognition,” said Dawson. “The study cited on the company’s web site is a small short study, raising concerns about the validity of the claims.” 

Treating dementia, Alzheimer’s, Parkinson’s, and other age-related brain disorders is truly difficult. If you want to see what real scientists (not supplement maker) are doing to try to stave off or cure dementia, here’s a short video narrated by Dr. Dawson:

Dr. Mark Sager, a scientist at the Wisconsin Alzheimer’s Institute and a Professor at the University of Wisconsin, has been quoted saying that he does not recommend Prevagen “primarily because there’s no evidence that it does any good.” He recommends adopting a Mediterranean diet instead, which does have some scientific evidence to support it.

I’m not the first person to raise questions about Prevagen. In 2012, a class action lawsuit was filed against them in California, in which the plaintiffs argued that the Prevagen didn’t work and that the advertising campaign was false and misleading. Earlier this year, another class action lawsuit against Quincy Bioscience argued that Prevagen’s active ingredient, apoaequorin, "is completely destroyed by the digestive system.” And in 2012, the FDA sent Quincy Bioscience a warning letter (see it here), pointing out that the company was marketing Prevagen as a drug, not a supplement. The FDA stated that:

"Apoaequorin is not a vitamin, mineral, amino acid, herb or other botanical, or dietary substance for use by man to supplement the diet ... nor is it a combination of dietary ingredients. Therefore, the synthetically produced apoaequorin used in your Prevagen products is not a dietary ingredient as defined in section 201(ff)(1) of the Act.... Accordingly, your Prevagen products could not be marketed as dietary supplements even if they were intended only to affect the structure or function of the body and not for use in the cure, mitigation, treatment, or prevention of disease."

Somehow, though, Quincy continues to sell Prevagen as a supplement. Their website claims they are the #1 selling brain health supplement in the U.S. today.

The appeal that Prevagen is making to consumers is a very old one: basically, they want you to think that if a protein is used in your brain, then eating that protein will make your brain healthier (even though apoaequorin is not a human protein). By this argument, I could package up hundreds of different proteins (perhaps thousands–the brain is a complex organ) and sell them as “brain food” This simplistic principle has been used for centuries in folk medicine: it’s the reason why some people think that eating the body parts of bears and tigers will make them more virile. But eating tiger organs doesn’t make you more like a tiger. It's a form of magical thinking, and there's simply no science to support it. In short, it's just wrong.

Human health isn’t that simple. You don’t acquire the properties of the food you eat. Eating chicken won't make you fly, and eating tuna won't make you a fast swimmer. Eating jellyfish proteins (Prevagen's main ingredient) won't improve your memory, nor will it allow you to emit green fluroescent light. There's no magic brain food, or supplement, that will make you smarter. But you can be a tiny bit richer by not spending your money on ineffective supplements.