When it comes to dietary supplements, few have the type of advertising budget needed to run national TV commercials.

Aside from Qunol, during the past few years it seems that Prevagen is the only other supplement dedicating serious ad dollars to get their message out there.

To be clear, Prevagen is not a prescription drug. It is not meant to be used for any disease. It is only a dietary supplement, which of course means it’s available for sale over the counter.

How is it sold and marketed in the north? If we knew where to buy Prevagen in Canada, we could answer that question. No drugstores there appear to carry it.

It appears it’s only available in Canada indirectly, through online sales which are shipped from the US. Likewise for sales to Mexico, UK, and other international buyers.

So any product claims revert back to US jurisdiction.

bottles of ginkgo biloba for sale at Whole FoodsYou may remember – no pun intended – that during the 90’s it was ginkgo biloba which was being hyped for memory. The “GEM study” was conducted, which was the largest clinical trial ever for it, involving a total of 3,069 people (1).

The results? Taking 120 mg of ginkgo biloba twice daily did not improve the rates of Alzheimer’s or dementia.

Does that means it’s a scam? No, not necessarily. There is a lot of other research suggesting there might be something to it. Possibly at higher dosages and/or for certain segments of the population. It’s still an unknown.

What the GEM study does mean is that clearly, ginkgo was overhyped.

That was disappointing for longtime users and you certainly don’t want to be setup for another letdown. That brings us to the question, does Prevagen work for memory?

Here’s what we found out…

What is Prevagen made of?

You’ve seen the commercials where they say the protein comes from a jellyfish. In a 30 second ad spot, they’re not going to get into the nitty-gritty on that, but we will right now.

aequorin molecule

Apoaeuorin is one two distinct units found in the aequorin protein, whose structure is shown above. Image by Yikrazuul [CC BY-SA 3.0], via Wikimedia Commons

Technically, it’s made of apoaequorin (pronounced a-po-e-kwor-in). This is a protein found in bioluminescent jellyfish, which gives them their signature glow. It’s not a new discovery, as scientists have known about it since 1962.

What is the jellyfish species which Prevagen gets this protein from? The answer can be confusing.

Aequorea victoria, or more commonly known as the crystal jelly, is the species cited on their website as to where it originally comes from.

You can find Aequorea victoria in the Pacific ocean, off the coast of North America.

When you consider that, it would make sense why it’s somewhat expensive. The cost of Prevagen at Walmart, Walgreens, CVS and other brick and mortar stores is not exactly cheap

Online you might find it for sale cheaper, but that’s on a relative basis.

As it turns out though, the manufacturer Quincy Bioscience no longer sources their apoaequorin from jellyfish. They synthetically create it in the lab, as mentioned in a 2012 FDA letter (2):

“Apoaequorin is no longer extracted from the jellyfish, rather rapidly dividing host cells are ‘taught’ to grow the unique protein”

So today, when you pop one of these pills you’re not eating a part of a jellyfish. It’s the isolated protein which has been synthetically created in a lab.

It’s made in the USA. Quincy Bioscience is based in Madison, WI.

When it comes to foods, synthetic is often viewed as being bad for you. However with dietary supplements which just consist of one type of molecule, being synthetic can be a good thing.

It means purity and less chance for contamination. For an ocean-derived ingredient which normally comes from fish, if it’s synthetic – and 100% molecularly equivalent – would would agree it’s preferred. Especially considering the issue of heavy metal pollution in marine life.

How much apoaequorin is in a capsule of Prevagen?

  • Regular strength = 10 mg
  • Extra strength = 20 mg

Since your typical-sized gelcap can hold about 500 mg of a dry powder, it means the majority of Prevagen ingredients will be inert substances. The supplement facts label lists white rice flour, cellulose, salt, magnesium stearate, and acetic acid as the other ingredients.man with handful of supplements and water glass

Is all the filler a bad thing?

Maybe, or maybe not.

You can’t really base the answer off the ratio of a purported active ingredient versus the inactive. For some things, a lot more of a compound is needed for benefits. For others, very little is all it takes.

For example with the medication Singulair for asthma and Zyrtec for allergies, each tablet only contains 10 mg of its active ingredient.

Now to reiterate, Prevagen is NOT a medication. It’s only a dietary supplement which means it’s supposed to contain a “dietary ingredient” intended to add further nutritional value to (supplement) the diet (3).

The Dietary Supplement Health and Education Act defines them as a category of food (4). They’re not approved by the FDA and as the boilerplate disclaimer goes, they’re not intended to diagnose, treat, cure, or prevent any disease (5).

What is Prevagen used for?

Legally, it can’t be marketed for Alzheimer’s disease or dementia. As a dietary supplement, any claims which can be made are quite limited.

The bottle’s label currently say it supports:

  • Healthy brain function
  • Sharper mind
  • Clearer thinking

But how well does Prevagen work for support of those things is the question. Not an answer based on unscientific customer reviews, but rather clinical research related to those purported benefits.

How Prevagen might work

Before diving into the clinical research, it’s important to understand the bird’s eye view of the science involving calcium and the brain.

How Prevagen works is purported or theorized to be due to calcium homeostasis. In other words, it is believed to help promote healthy levels of calcium. While we typically associate this mineral with bone health, it also plays a crucial role in our central nervous system.

In its free unbound form, it acts as a signaling molecule, cofactor, and second messenger. It forms a coenzyme and a protein in its bound form (6).

Age-related decline of neuron function has been found to correlate with unhealthy calcium levels in the brain (7).

According to a study published in Molecular Psychiatry (8):

“…altered Ca2+ [calcium] homeostasis play a key interactive role in the cascade of signaling events leading to autism: their modulation could provide new preventive and therapeutic strategies.”

So calcium levels in the brain might play some role in autism.

After a traumatic brain injury, the large influx of calcium into the cells is said to “initiate cell death signaling cascades” by turning on various degrading enzymes (9).

What about psychiatric illnesses? In bipolar disorder and schizophrenia, researchers have discovered higher neuronal calcium sensor-1 (NCS-1) protein (10). It’s found in a specific location – the cerebral cortex (11).

In short, too much or too little calcium in your brain is not good for you.

How much of this mineral you eat or drink might have little effect on the levels. Why? Because we have naturally occurring calcium-binding proteins flowing throughout our body to promote homeostasis (balance).

calcium homeostasis in the bodyKnown as EF hand proteins, these bind to excess calcium and our body then excretes it. There are at least several dozen types within the human body (12).

However research suggests that the levels of these natural calcium-binding proteins are lower in older brains (13) (14) (15) (16).

Additionally the “calcium pumps” in aging brains, which are another mode of regulating levels, don’t seem to be as active in older brains (17) (18) (19).

This is where apoaequorin enter the picture. It’s not the same as the human forms, but it’s a very similar calcium-binding protein. It’s categorized as an EF hand protein, like the human forms are.

This apoaequorin – which is used in Prevagen supplements – is what makes jellyfish glow. When the apoaequorin of the fish binds to the calcium ions in the water, it produces their famous luminescence.

Going back to age-related cognitive decline, it has now been nearly three decades since the calcium hypothesis has been put forth. There will always be some who disagree, but what’s the conclusion scientists are leaning towards?

The “normal” decline in cognitive function with age is probably due to synaptic restructuring, not neuronal death or unhealthy calcium levels in the brain – however those two things are still believed to play a role in Alzheimer’s disease (20). Many conclude (21):

“…the “Ca2+ hypothesis” is not directly applicable anymore to the process of normal aging, but retains much of its explanatory power in the context of Alzheimer’s disease.”

But as pointed out, using Prevagen for Alzheimer’s is definitely not what it’s marketed or intended for. It’s not a drug or medication.

So even if – and we emphasize the if – Prevagen works by promoting balanced calcium levels in the brain, then is it of any use for supporting “healthy brain function” and “clearer thinking” in healthy individuals?

One way to possibly address that question is with the 2016 clinical study, since it used healthy individuals. We will get to that in a just a minute.

The blood-brain barrier

neurons, brain cellsImagine a bouncer at a nightclub entrance. He doesn’t let the rest of the blood circulating throughout your body into the club (your brain). In order for anything to get in, they need to go through the bouncer AKA the “selective permeability” of the barrier.

The bouncer will kick your sorry butt to the curb if you are a:

  • waste product
  • large molecule
  • low lipid soluble molecule
  • glucose
  • plus other things

But guess what? You can still get into the club, even if you are one of those!

The secret? You need a hot date on your arm as an accessory, also known as a transporter protein. With one of those attached, glucose can enter the brain, as well as other needed molecules which would otherwise be rejected on their own.

That brings us to the EF hand protein from the jellyfish. Does apoaequorin cross the blood brain barrier?

We have been unable to find research proving one way or another.

That spurs the next question, if we don’t know if it gets into the brain, then how can we know if Prevagen works?

That’s a good question. We feel the answer as to whether or not it cross the blood-brain barrier should be addressed publicly or if it already is, the answer should be publicized better (we and many others online can’t seem to find it).

But let’s assume the worse… even if apoaequorin didn’t cross into the brain, in theory it still might help regulate calcium levels in the brain, albeit indirectly.

How that would work is purely theoretical, so keep that in mind while reading the next paragraph.

If apoaequorin is able to bind to excess calcium in the blood and usher its removal, then even if that’s taking place outside of the brain, it might promote healthier levels in the blood. That blood flows everywhere, including reaching the BBB. So in theory, it might mean less calcium in the blood = less opportunity for it to end up in the brain.

Again, that’s just our speculative theory.

Digestion

The second question mark about apoaequorin is that it’s a protein.

When you eat proteins, it doesn’t matter if they’re coming from a chicken or broccoli. Your body breaks down most proteins into their individual amino acids before absorbing them.

That’s why whether you eat meat or vegan protein is irrelevant to your body, assuming you’re getting enough of it.

process of digesting protein

Image by OpenStax College [CC BY-SA 3.0], via Wikimedia Commons

While that agnostic approach to protein processing is good for eating, it’s bad if we want a specific type of protein to stay intact and make its way into our bloodstream without being altered.

That’s why diabetics have to inject their insulin using a syringe, rather than taking it in pill form – because it would be broken down during digestion if they ate it as a pill.

In a 2014 safety assessment about apoaequorin, it says (22):

“Apoaequorin is easily digested by pepsin, a characteristic commonly exhibited by many non-allergenic dietary proteins. From these data, there is no added concern of safety due to unusual stability of the protein by ingestion.”

That paper was authored by Quincy Bioscience, the manufacturer of Prevagen. The good news is that the paper’s findings suggest that even though it was originally found in jellyfish, it’s a protein which doesn’t seem to have a propensity for allergic reactions in humans.

But does the above quote mean as humans, we might digest apoaequorin and break it down into amino acids, before it has a chance to make its way into our bloodstream? To us, the answer does not seem clear.

To the best of our knowledge, we are not aware of published researched which specifically answers exactly how it is digested in the human body. However since it is called calcium-binding, and assuming the protein would have to be at least partly intact to fulfill that binding role, one would guess or hope that it does remain intact.

The research

Anyone who’s a regular reader of Superfoodly knows that we love using PubMed in almost every article we write. It’s our go-to source for information. Maintained by the NIH, this database has nearly 30 million pieces of research compiled for just about anything you can think of.

Rather than search for the brand name of this supplement, let’s search more broadly by looking for the claimed active ingredient, apoaequorin.

apoaequorin research in PubMed database

While that may seem like a lot of results, it’s important to realize much of it is unrelated to what we want to know about it.

For example, it’s safe to conclude you don’t give a crap about “Reconstitution of holo-aequorin with apoaequorin mRNA and coelenterazine in zebrafish embryos” (23). That has nothing to do with enhancing memory, let alone the human brain!

Even for the pieces of research which are related, Petri dish experiments can only tell you so much, right?

What you’re going to be most interested in seeing are clinical trials. When you filter the results to that category, here’s what you get…

apoaequorin clinical trial on PubMed

One result and it’s recent at that – from the winter of 2016.

Now you may be saying to yourself:

“Wait a second, that’s from 2016! I saw commercials long before that for Prevagen which said it was clinically studied?!”

That’s correct – it was clinically studied in a 2009 open-label study with 56 healthy individuals. They used the product over a period of 90 days.

However, that one is not on PubMed. To be included, it’s needs to be accepted and published in a peer-reviewed medical journal. It seems the 2009 study must not have met the requirements, either for that reason or another.

Whatever the case, we prefer to stick with what has been accepted into PubMed and hence, this new 2016 study will be the one we will review here.

The Madison Memory Study (2016)

The objective of the study was to see if apoaequorin supplements would have an effect on cognitive function (24).

The 2009 study was open label, meaning both the participants and the researchers knew exactly what was being given. That’s far from ideal, since people can experience placebo benefits – feeling or believing something works, simply because they think it will work.

Fortunately, this 2016 study was a randomized, double-blind, and placebo controlled trial. That’s exactly what we want to see.

  • 218 individuals who were “community-dwelling ” from Madison, WI and the surrounding area participated.
  • Ages ranged from 40 to 91 years.
  • All had “self-reported memory concerns” but were healthy men and women.

These participants were divided into two groups; one receiving the supplement, another receiving the placebo. Here’s the full breakdown of how the 218 people were divided out…

Group Participants Age Range Mean Age ± SD
Apoaequorin 126 40 to 90 62.54 ± 11.79
          Male 43
          Female 83
Placebo Control 92 40 to 91 62.39 ± 10.98
          Male 27
          Female 65

So in each group, the average age was around 62.5 years.

Why more women volunteered to participate is unclear, perhaps they take their neurological health more seriously and hence, are more likely to admit to themselves (and others) if they feel like they have memory issues?

Who knows.

Whatever the cause may be, it doesn’t really matter. Even though there were more women, they divided out the groups in a way which kept them comparable. Both the Prevagen and placebo group have roughly a 1/3 male to 2/3 female ratio.

Establishing baselines

Before being divided into those groups, everyone did an AD8 screening interview.

AD8 = Ascertian Dementia 8-item Informant Questionnaire

Developed by Washington University, it’s considered to be a brief, yet effective way of how to distinguish who has “very mild” dementia and who doesn’t have it at all.

The lower the score, the worse the person’s cognitive ability.

The test is agnostic to etiology, so if someone tests as having subpar performance, the test is not meant to diagnose or infer what’s causing it. Whether the cause is normal age-related cognitive decline, Alzheimer’s, or something else is not to be construed from the test results (25).

Here were the AD8 test results before placebo or Prevagen treatment started…

AD8 Score
Group 0 to 2 2 to 5
Apoaequorin (# out of total participants) 59 (46.5%) 68 (53.5%)
Placebo Control (# out of total participants) 38 (40.4%) 56 (59.6%)

A score of 2 was used as the cutoff point for normal vs “some level” of cognitive impairment.

If you run the numbers, you will see 59 + 68 = 127 (not 126) and 38 + 56 = 94 (not 92).

126 and 92 were the numbers reflected in the prior table for the total in each group.

The reason for the discrepancy is unclear. But presumably, the extra 1 person in apoaequorin and 2 people in placebo were not counted in final results, and hence, why the breakdown of participants reflects a lower number than the pre-treatment AD8 score results.

If that’s the reason, it’s quite normal. Clinical studies regularly have people who drop out or can’t be counted at the end, due to an injury/illness incurred while the trial was taking place.

In addition to the AD8 test, computerized cognitive tests were used which came from Cogstate. They’re a company which specializes in cognitive testing for research and medical purposes.

  • Cogstate International Shopping List (ISL) – This test randomly generates a 12-word list and is presented to a participant 3 times. The goal is to measure how many of the words the person can remember during the 3 times it’s given. It’s trying to gauge if there is impaired verbal memory.
  • Cogstate ISL-Delayed Recall (ISL-DR) – This seeks to evaluate how well the person remembers the shopping list from the 3 ISL tests given around 25 minutes earlier. It’s looking at verbal learning and delayed memory.

The ISL is really looking at verbal learning, which is not just about memorization. It’s looking at how well you can learn information verbally (because if you can’t learn it, then of course you can’t recall it later on).

The ISL-DR is looking at verbal working memory. That’s your ability to remember verbal instructions and use them for a task.

These were given prior to treatment to establish baselines for each group.

In addition to those, Groton Maze Learning (GML), Groton Maze Recall (GMR), Detection and Identification (DET), and One Card Learning (OCL) are reported in the study published on Quincy Bioscience’s website. They discuss those in detail, as well as additional data points on the ISL and ISL-DR tests.

However we are using the PubMed article, which was published in the journal Advances in Mind-Body Medicine (26). In that peer-reviewed article, only the ISL and ISL-DR are evaluated and hence, we are only reviewing those two tests and the data presented about them in the article.

Measuring effects

Using capsules which were identical in size and color, participants were given either a 10 mg Prevagen dosage or a placebo which contained nothing but white-rice flour. These were taken once daily.

The ISL and ISL-DR tests were given 8, 30, 60, and 90 days after treatment started.

charts of Prevagen clinical trial results

The above charts depict the results for those who scored 0 to 2 on the initial AD8 test (which suggested they had “very mild” impairment).

chart of Prevagen vs. placebo for AD8 2-5 in ISL-DR cognitive testFor those who had normal cognitive ability according to the AD8 test (scoring 2 to 5) the third chart depicts their ISL-DR test results.

As far as ISL results for those with normal AD8 scores, a data table or chart depicting those was not presented in this particular article.

Presumably, this is because they were most interested in the results for those who had originally tested low (0 to 2) on the AD8 test. There is a lot more data presented for those people in the article.

For those who understand statistics, it worth noting the P values in the above charts.

Side effects?

One person reported an adverse event in both the supplement and placebo group. They were not considered serious.

The Prevagen side effects were “feeling owly” or irritable. Or at least, that’s according to 1 person out the 126 in that group.

For the man in the placebo group complaining, he said it made him “despondent and tired all of the time.” That just goes to show you the power of the placebo effect and why it’s important to have studies be randomized and double-blinded, as this one was.

Conclusion?

This is what the article’s authors stated:

“In the current study, daily use of an oral apoaequorin-containing supplement or capsule had a statistically significant effect on verbal learning in a population of older individuals with little or no self-reported cognitive impairment. Those results indicated a strong relationship between apoaequorin and improvements on a measure of cognitive function, specifically verbal learning. The results imply possible utility for apoaequorin to reduce the declines in cognitive function associated with aging.”

Admittedly, the Prevagen results versus the placebo group seem to be quite interesting. However, we are not going to opine one way or another on the results, or if we think Prevagen works, as we feel those things are best left to others in the field.

Hopefully the company is or will be doing additional randomized, double-blind, and placebo controlled trials, since this is the first one published. It would also be useful for them to address/clarify the concerns some critics are raising about whether it crosses the blood-brain barrier and how the human body digests the apoaequorin protein after oral consumption.
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.