Alan R. Gaby, MD

Age-related cognitive decline is a common problem, for which few effective treatment options are available. Randomized controlled trials have demonstrated that some natural products, such as acetyl-L-carnitine and Ginkgo biloba extract, can provide benefit with respect to slowing the progression of (or in some cases reversing) cognitive decline.¹ In addition, according to clinical observations, a small minority of patients experience substantial improvement from a series of intramuscular vitamin B₁₂ injections. However, these treatments are not well known to the mainstream medical community or the general public.

What are well known to the public are several heavily advertised products – such as Prevagen and Neuriva – which are promoted as memory boosters. Prevagen entered the market in 2007, and as of the year 2015, total sales had reached an estimated $165 million. Neuriva entered the market in 2019 and is said to be the second best-selling memory product (behind Prevagen), with $100 million in sales. Neuriva reached prominence largely because it was promoted in advertisements by Mayim Bialik, who is well known for her role on the television show The Big Bang Theory and as the co-host of the TV show Jeopardy. The average cost for each of these products is around $30-$40 per month.

Prevagen

The main active ingredient in Prevagen is a synthetically produced protein, apoaequorin, which was originally isolated from the Aequorea victoria jellyfish. Aging is associated with a decreased capacity to maintain intracellular calcium levels. Apoaequorin has been shown to regulate levels of intracellular calcium in neuronal cells in vitro, which is the apparent rationale for its use as a memory-enhancing agent. However, this rationale is questionable, considering that apoaequorin is rapidly digested by pepsin at gastric pH (pH 1.2 or 2.0)² and is therefore unlikely to reach the bloodstream intact.

The only clinical trial of apoaequorin was a study conducted by Quincy Bioscience, the company that sells Prevagen. In that study, 218 community-dwelling adults (aged 40-91 years) with self-reported memory concerns were randomly assigned to receive, in double-blind fashion, 10 mg per day of apoaequorin or placebo for 90 days.^3,4 There was no significant difference between apoaequorin and placebo on nine different measures of cognitive function. Post hoc analysis of more than 30 variables revealed that, in the subgroup of subjects who had little or no cognitive impairment at baseline, treatment with apoaequorin was associated with significant improvements on two measures of cognitive function. However, nonsignificant improvement was also seen in the placebo group, and it was not stated whether the difference in the change between groups was significant.

When so many post hoc analyses are conducted, it is likely that some statistically significant results will occur by chance. Furthermore, in a subsequent analysis of the study, the differences between the apoaequorin and placebo groups were found not to be statistically significant.⁵ Demonstrating an improvement compared with baseline on tests of cognitive function is not necessarily impressive because people often improve on repeat testing as a result of increased familiarity with the test. Even if the reported improvements were real, their relevance to age-related memory decline is questionable because the benefits were seen only in the subgroup of individuals who had minimal to no cognitive impairment. Thus, the evidence supporting a memory-enhancing effect of apoaequorin is somewhere between pathetically weak and nonexistent.

Neuriva

The main active ingredients in Neuriva are coffee cherry extract (CCE; the residue after the coffee bean is removed) and phosphatidylserine. There is some evidence that ingestion of CCE can improve reaction time on cognitive tests (possibly by increasing alertness), although there is no clear evidence that it improves accuracy on those tests. Numerous randomized trials have found that phosphatidylserine derived from bovine brain can improve cognitive function in people with age-related cognitive decline or dementia. However, that form of phosphatidylserine is not available in the United States because of the fear that it could be contaminated with the prion that causes bovine spongiform encephalopathy (“mad cow” disease). Phosphatidylserine manufactured from soybean lecithin is available in the US, but its chemical structure differs from that of bovine-brain phosphatidylserine.

In two double-blind trials, soy-derived phosphatidylserine (300-600 mg per day for 3 months) had no effect on memory or other cognitive functions, compared with placebo, in elderly individuals with age-related memory impairment.^6,7 Two uncontrolled trials in elderly patients with age-related cognitive decline did find an improvement on tests of memory and learning after supplementation with 300 mg per day of soy-derived phosphatidylserine for 12 weeks.^8,9 However, as noted above, those improvements may have been due simply to increased familiarity with the testing procedure. The available evidence suggests that soy-derived phosphatidylserine is not an effective treatment for age-related cognitive decline or dementia.

Conclusion

There is no convincing evidence that either of these products are effective memory-boosters. People wishing to improve their declining cognitive function may be better off using products with demonstrated efficacy, such as acetyl-L-carnitine and Ginkgo biloba extract.

References

1. Gaby AR. Dementia/cognitive decline. In Gaby AR. Nutritional Medicine, 2nd Edition. Concord NH, 2017. www.doctorgaby.com, chapter 286.
2. Moran DL, et al. Safety assessment of the calcium-binding protein, apoaequorin, expressed by Escherichia coli. Regul Toxicol Pharmacol. 2014;69:243-249.
3. Moran DL, et al. Effects of a supplement containing apoaequorin on verbal learning in older adults in the community. Adv Mind Body Med. 2016;20(1):4-11.
4. Harnett DS. Memory supplements: television ads and the elderly. Am J Geriatr Psychiatry. 2022;30:737-739.
5. Anonymous. Apoaequorin (Prevagen) to improve memory. The Medical Letter. 2021;63:175176.
6. Jorissen BL, et al. The influence of soy-derived phosphatidylserine on cognition in age-associated memory impairment. Nutr Neurosci 2001;4:121-134.
7. Gindin J, et al. The effect of plant phosphatidylserine on age-associated memory impairment and mood in the functioning elderly. Geriatric Institute for Education and Research, and Department of Geriatrics, Kaplan Hospital, Rehovot, Israel.
8. Schreiber S, et al. An open trial of plant-source derived phosphatydilserine for treatment of age-related cognitive decline. Isr J Psychiatry Relat Sci. 2000;37:302-307.
9. Richter Y, et al. The effect of soybean-derived phosphatidylserine on cognitive performance in elderly with subjective memory complaints: a pilot study. Clin Interv Aging. 2013;8:557-563.

Dr. Gaby received his undergraduate degree from Yale University, his M.S. in biochemistry from Emory University, and his M.D. from the University of Maryland. He was in private practice for 19 years, specializing in nutritional medicine.

He is past-president of the American Holistic Medical Association who has given expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. He is the author of Preventing and Reversing Osteoporosis (Prima, 1994), The Doctor’s Guide to Vitamin B6 (Rodale Press, 1984), the co-author of The Patient’s Book of Natural Healing (Prima, 1999). Dr. Gaby has written numerous scientific papers in the field of nutritional medicine. He has been the contributing medical editor for the Townsend Letter for Doctors since 1985, and was contributing editor for Alternative Medicine Review from 1996 to 2010.

Over the past 36 years, Dr. Gaby has developed a computerized database of more than 28,000 individually chosen medical journal articles related to the field of natural medicine. He was professor of nutrition and a member of the clinical faculty at Bastyr University in Kenmore, Washington, from 1995 to 2002. He is Chief Science Editor for Aisle 7 (formerly Healthnotes, Inc.) and has appeared on the CBS Evening News and the Donahue Show. In 2010, Dr. Gaby completed a 30-year project: the textbook Nutritional Medicine. Over the past six years, he has worked on completing the updated second edition of Nutritional Medicine.