Prevagen®: A Most Curious Dietary Supplement for Your Brain

Dietary supplements are a large part of the alternative medicine universe, with annual sales of more than $70B in the United states and much more than that in the rest of the world.  I have followed the supplement business since tryptophan, a canonical amino acid marketed as a sleep aid, caused an outbreak of eosinophilia-myalgia syndrome (EMS) in the United States in the late-1980s.  The complex tryptophan biosynthetic pathway (gif) is a triumph of conventional biochemistry that causes flashbacks in generations of biochemistry students.  But this incident was probably caused by an unrecognized minor contaminant co-produced by a strain of bacteria tweaked to increase tryptophan production.  Some evidence also suggests that large doses of tryptophan are not healthy for some people who may be susceptible to adverse effects, including EMS.

Dietary supplements are not regulated by the Food and Drug Administration (FDA) in the United States.  Perhaps the 1,500 cases and 37 deaths from EMS would have been avoided if they were.  But as the FDA gets “downsized” in the current DOGE Craze, even to the extent of reducing routine food inspections, that is unlikely.  In any case, dietary supplements should be used with care at all times.  It can be impossible to know what is in the bottle.  This long, fascinating history is covered well in Choose Your Medicine: Freedom of Therapeutic Choice in America (2022) by Lewis A. Grossman, previously discussed here.

I was reminded of the sometimes-strange status of dietary supplements earlier this year when I was channel surfing in a hotel with “cable” TV, which I have not had at home in years, and the United States Figure Skating Championships were on ESPN.  The artistry and athleticism of figure skating remain astonishing.  I was also astonished that Prevagen^®, is of the sponsors of the US Figure Skating Championships.  It turns out that Prevagen^®, also sponsors USA Gymnastics and USA Track & Field.  What is Prevagen^®?  In the words of the company:

• Prevagen^® is an over-the-counter supplement for your brain.*
• Prevagen^® is a unique supplement for your brain. Prevagen^® has been tested to be safe according to published studies.  The unique ingredient in Prevagen^®, apoaequorin (‘a-po-ah-kwor-in’), originally discovered in jellyfish, is an ingredient that is only found in Prevagen^® and is now produced in a controlled scientific process.  (The jellyfish in the photograph is the common moon jelly Aurelia aurata, not the much less common Aequorea victoria)
• Safety Study 1. Apoaequorin, was evaluated for safety using a toxicity study, a common method for evaluating dietary supplements. Apoaequorin has been found to be safely consumed in amounts much higher than recommended (4,000 times the recommended daily amount of Prevagen^® Regular Strength).
• Safety Study 2. In a separate safety study, apoaequorin has not shown to have any significant risk of allergic reactivity when ingested.
• Safety Study 3. The protocol followed was very similar to Safety Study I, however, in this instance, the amount was increased. Apoaequorin has been found to be safely consumed in amounts much higher than recommended (16,000 times the recommended daily amount of Prevagen^® Regular Strength). [1]

Important footnote: *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.

So, Prevagen^® is safe to take in the form of a tablet.  Good to know.  But what does Prevagen^® actually do?  The marketer’s answer was published in a paper entitled “Effects of a Supplement Containing Apoaequorin on Verbal Learning in Older Adults in the Community (2016).  This paper from a journal called Advances in Mind Body Medicine is behind a paywall (InnoVision Professional Media).  The following is taken from the online Abstract in PubMed:

Context: The changes in verbal learning and working memory that often occur with aging may result in reduced social and intellectual interactions.  These changes significantly affect an individual’s quality of life.  As humans age, the body’s ability to regulate and maintain calcium levels is diminished.  Pharmacological manipulation of the entry of free calcium (Ca2+) has been shown to be effective in increasing some aspects of cognitive function in the aged brain.  Apoaequorin has been shown in laboratory studies to regulate levels of intracellular calcium in neuronal cells and to provide protection against ischemic cell death.

Objective: The study was designed to assess the effects of a supplement of apoaequorin on verbal learning and working memory.

Design: The current study, the Madison Memory Study, was a randomized, double-blind, placebo-controlled trial.

Setting: The study occurred in Madison, WI, USA.

Participants: Participants were 218 community-dwelling adults, aged 40-91 y, with self-reported memory concerns.

Intervention: Participants were randomly assigned to receive either apoaequorin (apoaequorin group) or a matched placebo (control group) for 90 d.

Outcome measures: The study used quantitative, computerized tools for cognitive assessment the CogState International Shopping List (ISL) and the CogState ISL-Delayed Recall (ISL-DR).  Scores from computerized cognitive tasks were measured at baseline and at several points during the 90-d study.

Results: No significant differences existed between the intervention and control groups in any parameter at baseline.  The intervention group (apoaequorin group) showed a statistically significant improvement in verbal learning and recall on the ISL and the ISL-DR, respectively, during the 90-d study. Apoaequorin was tolerated very well in the study.

Conclusions: The results indicated a strong relationship between apoaequorin and improvements on a quantitative measure of cognitive function, specifically verbal learning. The study found that apoaequorin is a well-tolerated supplement that improved cognitive function in aging adults.  The results suggest potential utility for apoaequorin in addressing the declines in cognitive function associated with aging.

So, what is apoaequorin and why might it “improve cognitive function”?  The answer explains why I had been following this story at a distance, until I saw those few minutes of the US Figure Skating Championships.  Without going into the details of my long apprenticeship in biochemistry and cell and molecular biology, suffice it to say the photoprotein aequorin is a pre-charged enzyme-substrate complex (apoaequorin + light emitter + oxygen = aequorin) that upon binding to calcium ions produces a flash of blue light in the jellyfish Aequorea victoria. [2]  However, the light emitted by the jellyfish is actually green because the energy from the aequorin is directly transferred to the accessory “green fluorescent protein” (GFP) [3].  As noted before here, this is only one of thousands of reasons why basic scientific research should be funded.  One never knows where the next great advances will be found.

To return to Prevagen^®, I have kept up with the literature of bioluminescence long after I last purified, cloned, or assayed a bioluminescent protein or even used GFP to see “my favorite protein” in a cell.  This includes the literature, such as it exists, that apoaequorin improves “brain health.”  Yes, apoaequorin binds to calcium ions, although with less affinity than the complete, ready-to-glow aequorin.  These calcium-binding sites are similar to those in other calcium-binding proteins in animals (and plants) that are essential in the brain and every other cell type.  Still, how can we explain the results reported in the paper?  From the primary author, Daniel L. Moran, who is associated with Quincy Bioscience LLC, the manufacturer and only marketer of Prevagen^®:

Calcium-binding proteins are ubiquitous modulators of cellular activity and function. Cells possess numerous calcium-binding proteins that regulate calcium concentration in the cytosol by buffering excess free calcium ion. Disturbances in intracellular calcium homeostasis are at the heart of many age-related conditions making these proteins targets for therapeutic intervention.  A calcium-binding protein, apoaequorin, has shown potential utility in a broad spectrum of applications for human health and well-being. Large-scale recombinant production of the protein has been successful; enabling further research and development and commercialization efforts.

This sounds “scientific,” but:

• Yes, about calcium-binding proteins and the regulation/modulation of cell function.
• No, about numerous calcium-binding proteins that buffer calcium concentrations in the cytosol. Too much information, but those proteins are in a cellular organelle called the endoplasmic reticulum (ER) that is a membrane-bounded cellular compartment distinct from the cytosol. Resting free calcium concentrations are very low in the cytosol.  When they are stimulated to rise transiently the calcium ions come from the ER.
• Yes, about disturbances in calcium regulation and disease.
• About the “potential utility (of apoaequorin) in a broad spectrum of applications for human health and well-being, uncertain at best.

The single relevant question in all of this is why would a jellyfish protein (albeit one that binds to calcium ions) that produces a flash of light when the jellyfish is disturbed lead to “improvements (in) cognitive function, specifically verbal learning” in adults?  There is certainly no likely mechanism that could account for a protein supplement taken by mouth making its way to the brain and affecting memory.  In the first place, the protein would get digested like all other proteins in our diet.  It would first get partially fragmented in the acidic environment of the stomach, while the remainder would be turned into small peptides and single amino acids by pancreatic digestive enzymes in the small intestine. [4]  In the second place, it is a very long stretch to think a fragment of an exogenous light-emitting calcium-binding protein from a jellyfish would have any function in the human brain.

This remained a puzzle as I attempted to parse the data in the Advances in Mind Body Medicine paper.  Extraordinary claims require extraordinary evidence, and that an infinitesimal dose of jellyfish protein taken by mouth improves memory is an extraordinary claim.  One might suspect p-hacking, which “occurs when researchers collect or select data or statistical analyses until nonsignificant results become significant.”  This is unfortunately not uncommon and a previous analysis in Science-Based Medicine goes into detail on apoaequorin and brain health.

Finally, after many years, the Federal Trade Commission (alas, not the Federal Drug Administration) has prevailed in its case against Prevagen^® as of December 6, 2024 (pdf).  This I had read, and this is why I was surprised that the US Figure Skating Championships were sponsored by Prevagen^® in 2025, up to today.  Still, the lesson has apparently not been learned by Quincy Bioscience LLC (bold sections in the following press release, which though undated seems to be a response to the December 2024 decision):

Today the FTC released a statement regarding a ruling by the U.S. District Court for the Southern District of New York in its case (along with the New York Attorney General) against Quincy Bioscience.  Notably, the FTC’s statement did not refer to the portion of the Judge’s order that once again confirmed the jury’s findings that the principal claims for Prevagen^® (e.g., Prevagen^® improves memory,” “Prevagen^® is clinically shown to improve memory within 90 days,” and Prevagen^® provides other cognitive benefits, including but not limited to healthy brain function, a sharper mind, and clearer thinking,” etc.) are not materially misleading.

The statement also neglected to refer to the Judge’s findings that there was “no intent to harm” – an indication of his belief that the Company has acted in good faith – nor did it refer to his rejection of the NYAG’s efforts to obtain statutory penalties, disgorgement and/or statutory costs.  And of course, there has never been a health issue here – no one is disputing that Prevagen^® is safe.

The order merely requires certain changes to Quincy’s advertising on a going forward basis. While we strongly believe this requirement is based on a misreading of the law and science supporting the advertising statements, and will appeal the Judge’s decision, Quincy has already started to transition its marketing campaign for Prevagen^®.  We are pleased that the judge clarified-as we requested-that the Company will be afforded a reasonable amount of time to launch its new advertising.

The Company is excited about the upcoming launch of its refreshed Prevagen^® branding and is pleased that it will be able to continue to market Prevagen^® in the U.S. – bringing a gold-standard supplement to every state in the country.

So, here we are.  Quincy Bioscience had “no intent to harm” and will apparently continue to market Prevagen^® (accessed 20 April 2025) to consumers, in every sense of the word, who are unaware they are taking a pill containing an inactive jellyfish protein produced in bacteria, while “bringing a gold-standard supplement to every state in the country.”  We are not a serious people.

And yet my colleagues continue to wonder why “science” is losing its authority.  I can respond only by noting the very few and essentially uncited “apoaequorin and brain health papers” have been published for the most part in legitimate scientific journals.  This is the only basis of their authority.  Who were the editors?  Reviewers?

But it is also past ridiculous that marketers of “dietary supplements” are not required to show their products are both safe and effective.  That, however, is a topic for another time during another presidential administration.

In the meantime, someone should ask USA Gymnastics, USA Track & Field, and US Figure Skating why Prevagen^® remains one of their sponsors.  And all of us should remember our due diligence in the dietary supplement store or aisle in our local supermarket.  The placebo effect can be strong.  Nevertheless, it is very unlikely that eating 40 milligrams (i.e., 0.0014 ounce) of apoaequorin can hurt you.  The science says Prevagen^® is safe, aside from the cost.  But this is not true of every product on offer, inert and active ingredients included.

Notes

[1] Note that the two journals in these links are published by reputable scientific publishers whose products are generally considered authoritative.  Elsevier is “part of the RELX Group, known until 2015 as Reed Elsevier, a publicly traded company.  According to RELX reports, in 2022 Elsevier published more than 600,000 articles annually in over 2,800 journals.  As of 2018, its archives contained over 17 million documents and 40,000 e-books, with over one billion annual downloads.  Researchers have criticized Elsevier for its high profit margins and copyright practices.  The company had a reported profit before tax of £2.295 billion with an adjusted operating margin of 33.1% in 2023.   Much of the research that Elsevier publishes is publicly funded; its high costs have led to accusations of rent-seeking, boycotts against them, and the rise of alternate avenues for publication and access, such as preprint servers and shadow libraries.”  Sage Publishing is similar to Elsevier, only smaller.

[2] A. victoria (class Hydrozoa) is found along the Pacific Northwest coast of North America from Oregon to Alaska.  I have heard that populations have declined, possibly due to increases in water temperature that have affected the hydrozoan life cycle.  These jellyfish do not sting, and they are remarkable creatures.  Anyone out on a dark night in a kayak or small boat, especially in the San Juan Islands, will see them when they are disturbed by turbulence, along with sparkles (dinoflagellates) and other jellyfish (Obelia, Phialidium, Halistaura, each of these jellyfish have produce their version of aequorin) and bioluminescent ctenophores (comb jellies).

[3] GFP revolutionized research in cell biology by providing cell biologists with a marker for protein location in living cells.  Three scientists were awarded the Nobel Prize for Chemistry in 2008 for the discovery and use of GFP in biomedical research.

[4] To be fair, a paper was published in 2017 showing that cholesterol could protect apoaequorin and calmodulin (a calcium-binding protein ubiquitous in animals and plants) from digestion in the gut but concluded that “our results suggest that a physiological calmodulin-cholesterol complex, not cholesterol-free jellyfish protein, may better serve as a dietary supplement to facilitate memory maintenance.”  The paper has been cited twice, once in a review of jellyfish as food and another unrelated to anything apoaequorin or jellyfish related.  To my knowledge, the apoaequorin in Prevagen^® does not come coated with cholesterol.