Dietary supplements marketed as cognitive enhancers generally fall into two primary categories: those that enhance memory in aging adults with cognitive decline, and those positioned as nootropics—supplements that improve one or more aspects of cognitive function in healthy people of different age groups, including students. Often, research on nutraceuticals used in either type of supplement is specific to an aging population or to nootropic goals. However, there are certain nutraceuticals for which research demonstrates efficacy for both. One such nutraceutical is a polyphenol-rich extract from French grape and wild blueberry, which is the topic of this article.
Age-related Cognitive Decline
Regarding the first category, I want to be clear that age-related cognitive decline (ARCD) is common, can occur in healthy aging individuals1 and should not be confused with Alzheimer’s or another dementia. ARCD is simply mild memory problems associated with normal aging (e.g. “Where did I put my keys?”). Even so, the memory loss and cognitive slowing associated with ARCD can interfere with our daily routines.2 In fact, according to a national survey, worries over retaining mental sharpness with age was the No. 2 health concern among consumers (second only to worries about continuing normal activities with age).3
So how common is ARCD? The results of the Health ABC study4 found that, after four years, most of a representative sample of 2,733 generally healthy men and women ages 70 to 79 years experienced cognitive decline. Specifically, 48 percent had experienced a minor decline in cognitive functioning, and 16 percent had had a major decline. What’s more, in the MIDUS I and II studies (Midlife Development in the United States Study)5 with 4,268 sample members, who were then ages 32 to 84 years, results showed that with each successive 5 years of age, there were lower average scores on tests of episodic memory and executive function for individuals. The fact is, ARCD is more prevalent in the United States than dementia.6,7
Polyphenol-rich Extract From French Grape and Wild Blueberry
There are myriad choices for cognitive enhancing nutraceuticals, so why polyphenol-rich extract from French grape and wild blueberry (PEGB)? So, first of all, its not one or the other. There’s no reason that other cognitive enhancers (e.g. Ginkgo biloba extract, phosphatidylserine, etc.) can’t be used in combination with PEGB. But in my opinion, PEGB (Memophenol by Activ’Inside/Seppic) offer something distinct regarding mechanisms of action—they have good research and they are very safe to use. Let’s start with a brief review of mechanisms of action.
Mechanisms of Action
There appears to be more than one mechanism of action for PEGB. Certainly polyphenols have significant antioxidant properties, but evidence also suggests that polyphenols modulate cell and molecular processes involved in learning and memory, including neuronal signaling pathways involved in synaptic plasticity (Note: plasticity is a term that refers to the brain’s ability to change and adapt as a result of experience).8 In animal research, key polyphenols, like those present in grapes and blueberries, have also been shown to increase markers of nerve development within the hippocampus (a complex brain structure that plays a major role in learning and memory).9,10
More specifically, rodent research11 was conducted on PEGB to help determine mechanisms of action. Nerve growth factor (Ngf), a substance produced by the body, is involved in memory processes. A PEGB-enriched diet was found to modulate Ngf genes, increasing Ngf levels in both adult and aged mice. In addition, aged mice fed the PEGB-enriched diet had a greater proportion of newly generated immature nerve/brain cells with dendrites (Note: dendrites are an extension of a nerve cell, along which information received from other cells at synapses are transmitted). Collectively, these mechanisms likely contribute to PEGB’s role in improving cognitive function. Now let’s take a look at epidemiological (population) and preclinical research.
Epidemiological and Preclinical Research
Epidemiological studies have examined the relationship between cognitive functioning (including dementia prevalence) and nutritional habits and status. In particular, the protective effects of phenolic compounds present in fruit and vegetables have been delineated.12 Polyphenols are natural compounds which include flavonoids, phenolic acids, stilbenes and lignans.13 Research indicates that the intake of berries or flavonoids for 10 or 13 years has been associated with slower rates of cognitive decline and better cognitive function in the elderly.14-18 The most recent epidemiological data19 shows that polyphenols, especially the consumption of flavonoids, decrease the risk of dementia by 50 percent. Preclinical research has confirmed these observations. In one rodent study,20 the consumption of polyphenol-rich berries, berry extracts, or isolated flavonoids reduced ARCD. Of course, the real proof of the pudding is the human clinical research.
Human Clinical Research: Grape or Blueberry Juice/Supplement
Two randomized clinical trials were performed with elderly subjects who had mild cognitive impairment (MCI). Subjects consumed polyphenol-rich grape or blueberry juices. The results demonstrated an improvement of spatial and verbal memory performances.21-23 Likewise, blueberry supplementation in healthy older adults improved working memory.24 Another dietary intervention with blueberry has shown that an easily achievable quantity of these berries into the diets of older adults can improve verbal learning and memory.25
Human Clinical Research: PEGB
To assess effects on memory, a randomized, double-blind, placebo-controlled trial26 was conducted with 215 healthy elderly subjects (60-70 years-old) who received 600 mg/day of PEGB containing 258 mg flavonoids (Memophenol by Activ’Inside/Seppic) or a placebo for six months. Results were that PEGB supplementation improved verbal episodic and recognition memory (VRM)-free recall. In fact, the total number of correct words at the immediate recall was significantly higher in the PEGB group than in the placebo group (p=0.006). Additionally, those subjects with advanced cognitive decline (decliners) who responded positively to the PEGB also had better VRM-delayed recognition. In addition to a lower polyphenol consumption, the urine metabolomic profile of decliners revealed that they excreted more metabolites. At the end of the study, urinary concentrations of specific polyphenol metabolites were associated with the memory improvements. This study demonstrates that PEGB improves age-related episodic memory decline in individuals with the highest cognitive impairments, and successfully met all safety parameters.
Another randomized, double-blind, placebo-controlled crossover study was performed on 30 healthy university students between 18 and 25 years old. Students received both the placebo and 600 mg/day PEGB in acute dose within seven days. Students were then placed under real exam conditions. This included being alone with no social interaction during a cognitive test, timed tasks and mental calculations required. The cognitive tests were performed 1.5 hours after taking the PEGB. Each battery of tests assessed students’ cognitive performance and was repeated six times. The sum of the cognitive tests assessed the global cognitive performance through the one-hour intense mental effort. In addition, students were asked to rate their feelings regarding their mental fatigue, anxiety, vigilance and cognitive performance. The results were significant.
PEGB enhanced cognitive performance by 36 percent 90 minutes after supplementation. Likewise, cognitive scores known as STS (the student has to mentally count backwards in three from a given number for 800 to 900) improved by 1.25 times at 90 minutes. In addition—although all students were more tired over time during the tests—those supplementing with PEGB felt 39 percent greater performance than those using the placebo.
PEGB offers unique mechanisms of action and has been shown in human clinical research to improve age-related episodic memory decline in older subjects. Furthermore, human clinical research has also demonstrated that PEGB is capable of enhancing cognitive performance in students. Consequently, PEGB qualifies both as a cognitive enhancer for older adults, and as a nootropic for younger adults. Additionally, Memophenol is gaining credibility in the scientific community. The Journal of the American Medical Association (Impact Factor 51), published an article27 about the memory booster effects of Memophenol, mentioning its clinical effectiveness.
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3 Sloan AE, Hut CA. Reading the Compass: Up-and-Coming Market Trends. Nutraceuticals World. October 1, 2013. Retrieved November 9, 2015 from www.nutraceuticalsworld.com/issues/2013-10/view_features/reading-the-compass-up-and-coming-market-trends/.
4 Yaffe KAJ, Fiocco K, Lindquist E, Vittinghoff EM, et al. Predictors of maintaining cognitive function in older adults: The Health ABC study. Neurology. 2009; 72(23):2029-2035.
5 MIDUS (Midlife Development in the United States). 2011. History and overview of MIDUS. Retrieved February 22, 2015 from www.midus.wisc.edu/scopeofstudy.php.
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7 Blazer DG, Yaffe K, Liverman CT (eds.), Committee on the Public Health Dimensions of Cognitive Aging, Board on Health Sciences Policy, Institute of Medicine. Cognitive Aging: Progress in Understanding and Opportunities for Action. Washington (DC): National Academies Press; 2015:75-108.
8 Spencer JP. The interactions of flavonoids within neuronal signalling pathways. Genes Nutr. 2007; 2:257–273.
9 An L, Zhang YZ, Yu NJ, et al. The total flavonoids extracted from Xiaobuxin-Tang up-regulate the decreased hippocampal neurogenesis and neurotrophic molecules expression in chronically stressed rats. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1484–1490.
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11 Bensalem J, Dudonné S, Gaudout D, et al. Polyphenol-rich extract from grape and blueberry attenuates cognitive decline and improves neuronal function in aged mice. J Nutr Sci. 2018 May 21;7:e19.
12 Bensalem J, Dal-Pan A, Gillard E, Calon F, Pallet V. Protective effects of berry polyphenols against age-related cognitive impairment. Nutrition and Aging. 2016;3:89–106.
13 Manach C, Scalbert A, Morand C, Remesy C, Jimenez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79:727–747.
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16 Kesse-Guyot E, Fezeu L, Andreeva VA, et al. Total and specific polyphenol intakes in midlife are associated with cognitive function measured 13 years later. The Journal of Nutrition. 2012;142:76–83.
17 Rabassa M, Cherubini A, Zamora-Ros R, et al. Low levels of a urinary biomarker of dietary polyphenol are associated with substantial cognitive decline over a 3-year period in older adults: the invecchiare in chianti study. J Am Geriatr Soc. 2015;63:938–946.
18 Root M, Ravine E, Harper A. Flavonol intake and cognitive decline in middle-aged adults. J Med Food. 2015;18:1327–1332.
19 Lefèvre-Arbogast S, Gaudout D, Bensalem J, et al. Pattern of polyphenol intake and the long-term risk of dementia in older persons. Neurology. 2018 May 29;90(22):e1979-e1988.
20 Rendeiro C, Vauzour D, Rattray M, et al. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One. 2013;8:e63535.
21 Krikorian R, Boespflug EL, Fleck DE, et al. Concord grape juice supplementation and neurocognitive function in human aging. J Agric Food Chem. 2012;60:5736–5742.
22 Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment. Br J Nutr. 2010;103:730–734.
23 Krikorian R, Shidler MD, Nash TA, et al. Blueberry supplementation improves memory in older adults. J Agric Food Chem. 2010;58:3996–4000.
24 Bowtell JL, Aboo-Bakkar Z, Conway ME, Adlam AR, Fulford J. Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementation. Appl Physiol Nutr Metab. 2017;42:773–779.
25 Miller MG, Hamilton DA, Joseph JA, Shukitt-Hale B. Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial. Eur J Nutr. 2018;57:1169–1180.
26 Bensalem J, Dudonné S, Etchamendy N, et al. Polyphenols From Grape and Blueberry Improve Episodic Memory in Healthy Elderly with Lower Level of Memory Performance: A Bicentric Double-Blind, Randomized, Placebo-Controlled Clinical Study. J Gerontol A Biol Sci Med Sci. 2019 Jun 18;74(7):996-1007.
27 Voelker R. How Certain Foods Affect Cognition, Seizures, and Cardiometabolic Disease: Food for Thought. JAMA. 2019 Oct 24. doi: 10.1001/jama.2019.16477. [Epub ahead of print]
Gene Bruno, MS, MHS, the dean of academics for Huntington College of Health Sciences, is a nutritionist, herbalist, writer and educator. For more than 30 years he has educated and trained natural product retailers and health care professionals, has researched and formulated natural products for dozens of dietary supplement companies, and has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. He can be reached at firstname.lastname@example.org.