Dietary Supplements for Cognitive Health: Matter over Mind

For people young and old, the possibility of one day developing Alzheimer’s disease is terrifying, to say the least. This fear is especially acute in those caring for loved ones already suffering from Alzheimer’s, which now accounts for 80% of dementia cases and affects an estimated 5.4 million Americans.

There’s good reason for concern. Alzheimer’s disease is currently the sixth-leading cause of death in the United States, according to the Alzheimer’s Association’s 2011 Alzheimer’s Disease Facts and Figures report. According to the report, while death rates have declined for most major diseases-including stroke, prostate cancer, breast cancer, heart disease, and HIV-deaths from Alzheimer’s disease have risen an alarming 66%. By 2050, the number of people ages 65 and older with Alzheimer’s may triple.

As people look for ways to preemptively stave off cognitive decline, many are considering dietary supplements. Karen Todd, RD, CISSN, CSCS, director of marketing for Kyowa Hakko USA (New York City), says that the company’s Cognizin citicoline ingredient targets Baby Boomers and those caring for them. “There are different life stages for cognitive health, but we’re addressing two of them: the Baby Boomers (the 50- to 60-year-olds) and their caregivers (the 30- to 40-year-olds). These are the very people who are watching their parents suffering from Alzheimer’s disease right now. They’re experiencing it firsthand.”

A look at the supplements on the shelf today reveals that products touch on a range of cognitive-health aspects, many more general in nature: “Supports Memory,” “Boosts Brain Power,” “Increases Brain Energy.” As research continues, companies are looking to narrow in on more-specific mechanisms of action.

“In reality, the expression of ‘a healthy brain’ is a relatively new concept that is really quite important in scope, as brain health is a difficult-to-describe and very subjective concept,” says Scott Hagerman, president of Chemi Nutra (White Bear Lake, MN). “Nevertheless, the aim of researchers, product development people, and marketing groups alike is to key in on products that effectively address the many facets of brain health.”

Could this affect whether products someday address more-specific benefits? “Right now, I don’t think a lot of supplements are targeting specific areas of brain health,” says Todd. “But, as research develops, they have the potential to do that. It really depends on how simple you want to make it for the consumer and whether they will understand the message.”

Performance Enhancers

In January, new data was presented on a study, not yet published, confirming that Cognizin citicoline helped to improve focus, concentration, and memory in human subjects. The six-week study was conducted at Harvard Medical School affiliate McLean Hospital (Belmont, MA) on 16 healthy human subjects ages 40 to 60, with either a 500- or 2000-mg daily dose of Cognizin.

While undergoing functional Magnetic Resonance Imaging (fMRI), subjects performed two task tests-a virtual water maze test and the Stroop test.

Designed to test spatial memory, the Morris water maze is generally performed on mice or rats. The subjects are placed in a pool of water that also contains a hidden, slightly submerged platform, as well as visual cues. The objective is that over time, subjects will come to remember where the submerged platform is located so they can stand on it. For Cognizin, the test employed a virtual-reality version of the Morris water maze test, in which subjects were “placed” in a virtual room and asked to locate a platform using visual cues such as images of a window, a shelf, a door, or a painting. “It involves spatial memory, like remembering where you parked your car in a parking lot,” explains Todd.

The Stroop test measured attention and reaction time. Among other things, and while being timed, subjects were shown a list of words naming various colors. Subjects were asked to either to read the word or, at a different stage, name the color of the word’s ink, regardless of the word itself. An interference task was performed between stages. “It’s overriding what the brain wants to do, which is to immediately identify with the word it sees, rather than the color of the word,” says Todd. “It helps to measure improved accuracy in generating correct responses, under time pressure.”

During both tests, fMRI measurements showed increased brain activation and metabolism, as well as more-accurate performance.

Citicoline is thought to benefit cognition in a number of ways. For one, higher levels of citicoline raise levels of acetylcholine, which is the neurotransmitter responsible for storing and recalling memories. (Citicoline is converted into acetylcholine.)

Citicoline also aids in overall brain health. It is broken down into choline once it crosses the blood-brain barrier, helping to increase ATP and thus brain energy and metabolism. It also helps promote the synthesis of neurotransmitters like phosphatidylserine and phosphatidylcholine. Todd calls citicoline’s action “a multifactorial approach.” She also cites a study showing that choline doesn’t absorb as well in older adults, which is when citicoline supplementation could help.

Todd says the company just completed another, larger human study on Cognizin. This time, the study did not include fMRI analysis due to the time that employing fMRI takes in these types of cognitive trials. However, like before, subjects were asked to perform tasks measuring memory and function.

Ginseng-specifically American ginseng (Panax quinquefolius)-and its active-compound ginsenosides remain on the cognitive-health map for touted benefits such as enhancing clarity. Last July, a study was published online in Psychopharmacology (Scholey et al., vol. 212., no. 3: 345-356) on Naturex’s (Avignon, France) American ginseng ingredient Cereboost. The company called it “the first clinical study confirming the traditional use of American ginseng for cognitive health.”

Performed at the Brain Sciences Institute at Australia’s Swinburne University, the randomized, double-blind, placebo-controlled crossover study on 32 healthy young adults showed that a supplement of Cereboost (100-, 200-, and 400-mg doses) improved attention and working memory, including attention accuracy, working memory speed, and working memory capacity. Subjects performed a number of task tests, including the Stroop test.

“This preliminary study has identified robust working memory enhancement following administration of American ginseng,” the researchers wrote. “These effects are distinct from those of Asian ginseng and suggest that psychopharmacological properties depend critically on ginsenoside profiles.”

In January, supplements brand Cardium Therapeutics announced plans to include Cereboost in its Cerex supplement, currently in development.

Cactus Botanics Ltd., a Shanghai-based supplier of American ginseng, recently warned industry about a possible future price spike for American ginseng due to policies now limiting expansion of ginseng plantations in China. (Typically, ginseng is grown for years before it can be harvested.) The company reassured its customers that its supply is protected.

Many consumers still have confidence in Ginkgo biloba for supporting memory function, despite a 2009 Journal of the American Medical Association (JAMA) study that concluded that ginkgo does not help slow the rate of cognitive decline in older adults. In fact, ginkgo continues to be a top seller, according to market researcher SPINS. (Regarding the JAMA study, industry members pointed out study-design flaws and urged consumers to remember ginkgo’s long history of science showing efficacy. American Botanical Council (Austin, TX) founder and director Mark Blumenthal stated, “There are more than 125 clinical trials published on ginkgo extract over the past two decades, with most of them supporting numerous important benefits related to improved circulation and mental function.”)

Ingredient supplier OptiPure (Los Angeles, CA) offers Ginkgo biloba ingredient Gbe 24/6, which provides consistent levels of ginkgo’s active ingredient ginkgolides-specifically ginkgolide B, which inhibits platelet aggregation. High levels of ginkgolide B help enhance cerebral blood flow, which in turn supports memory and cognitive function.

Cognisetin is an ingredient based on fisetin, a flavonoid commonly found in fruits and vegetables such as strawberries. It has been shown to stimulate the signaling pathways that enhance long-term memory.

The ingredient was introduced by Cyvex Nutrition (Irvine, CA) last year through a partnership with research institution the Salk Institute (San Diego, CA). Based on their research, Cognisetin recently received a U.S. Patent and Trademark Office Notice of Allowance covering fisetin’s role as a neuroprotector.

Most notably, says Cyvex president and CEO Matt Phillips, Cognisetin has been shown to actually generate neuron cells, even in the presence of damage, which is what the patent notice shows. In addition, it promotes antioxidant synthesis and reduces overactive brain– and spinal cord–specific immune defenses that contribute to age-related decline.

A few years ago, Salk Institute researchers published a study done on rats showing how fisetin “can activate signaling pathways in hippocampal slices that are implicated in the development of long-term memory.” Phillips says that Cyvex is now planning a clinical trial to study these mechanisms in humans.

RFI Ingredients (Blauvelt, NY) conducted a trial on Chocamine, its patented cocoa extract, following studies reporting that chocolate intake can improve cognitive function. Forty subjects were asked to take a control, a supplement containing 1000 mg of Chocamine, or a supplement containing 1000 mg of Chocamine Plus, which contains caffeine. Subjects were then asked to perform the IMPACT cognitive-assessment test designed to judge aspects such as nonverbal problem solving, attention span, reaction time, and working memory. RFI says that those who took Chocamine and Chocamine Plus showed improvements in reaction time and impulse control/response inhibition. Those who took Chocamine Plus alone showed enhanced visual processing speeds, learning, and memory.

The company says these results support an earlier, preliminary cognitive study on Chocamine using the Audio-Visual Multi-Processing Test (AVMT) that showed that Chocamine consumption resulted in improved reaction times to auditory, visual, and multisensory stimuli and information-processing speeds.

RFI CEO and president Jeff Wuagneux says the company is not positioning Chocamine as a long-term cognitive-health ingredient, but rather as one that provides more-immediate, short-term cognitive benefits.

“The cognitive-health market has mostly addressed cognitive decline associated with aging, and it is difficult for supplements to make big claims or promises about one’s long-term cognitive health,” he says. “We, on the other hand, are looking at more-immediate cognitive benefits that can be experienced and measured shortly after consumption. We feel these are the types of claims that are more defensible and more in line with consumers’ real expectations.”

Staying in Tune

It goes without saying that maintaining brain cells and their function is crucial to preventing decline.

The phospholipid phosphatidylserine (PS) is supported by a strong history of research and two FDA qualified health claims supporting its role in reducing the risk of dementia and cognitive dysfunction in the elderly. PS is an important building block of cell membranes, protecting cell structures and ultimately their functions, such as controlling signal transmission and enhancing memory and attention in patients with cognitive deterioration.

Chemi Nutra’s Hagerman notes that researchers are now also exploring the link between mental performance and other diseases. Hormone replacement therapy (HRT) is one example. He says that Chemi Nutra’s SerinAid PS has been evaluated in a research study at the University of Guadalajara in Mexico on its ability to reduce the incidence of memory loss that accompanies HRT in women. PS is also being considered a natural alternative to pharmaceutical interventions for behavior modification for conditions such as Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD).

Chemi Nutra describes SerinAid PS as “assisting proteins that manage membrane functions that are involved in the transmission of molecular messages from cell to cell, helping nutrients enter cells and helping harmful stress-related waste products to exit the cells.”

The company also offers AlphaSize A-GPC (alpha-glycerylphosphoryl choline), which increases the formation of acetylcholine, the cell’s primary neurotransmitter chemical. Hagerman explains that acetylcholine plays many important roles in cognitive function, including the transmission of impulses from neuron to neuron.

“In fact, A-GPC is sold by Italfarmaco S.p.A., our parent company, in many parts of the world for use in Alzheimer’s disease, dementias, stroke, coma, brain injury, etc., competing against well-known prescription acetylcholinesterase inhibitor drugs,” says Hagerman. “Published clinical papers in fact indicate that A-GPC works as well or better than this class of drugs.”

Last year, a placebo-controlled study cosponsored by Chemi Nutra was published in the Journal of the International Society of Sports Nutrition (Hoffman et al.) showing that a formula combining SerinAid PS (50 mg) and AlphaSize A-GPC (150 mg), as well as other ingredients, helped improve focus, reaction time, and alertness in 19 college-aged subjects.

Other companies are also touting their PS and a-GPC ingredients. Soft Gel Technologies’ (Los Angeles) Smart PS is touted for its stability. The company says that PS is in general highly unstable and prone to degradation during shelf life. However, Smart PS has demonstrated to show no degradation after 24 months.

Enzymotec (Israel) recently announced a new brain-health product, Life Extension’s Cognitex Basics, containing Enzymotec’s high-grade PS as well as its a-GPC ingredient Sharp-GPC.

CapsuleWorks (Ronkonkoma, NY) offers Neuro-PS. The company also markets Neuro-PS Gold, a version combined with omega-3 fatty acid docosahexaenoic acid (DHA).

DHA is an important nutrient to the brain. The brain is rich in fatty acids, notably DHA and omega-6 fatty acid arachidonic acid (ARA).

“The fatty acid makeup of the brain neurons is different compared to other cells in the body, mostly due to the high concentration of the omega-3 fatty acid DHA and ARA,” says Baldur Hjaltason, strategic business development and sales manager for EPAX AS (Aalesund, Norway). The company markets its EPAX 1050TG, which provides a minimum, high-DHA amount of 430 mg/g, as well as a maximum of 150 mg/g of eicosapentaenoic acid (EPA).

“The lipids provide the brain membrane with a high degree of elasticity,” he continues. “The reason for this is not well understood, but it is generally agreed that a high concentration of DHA and ARA are closely linked to the basic functions of the neurons, such as the speed of electrical impulse trafficking and the release and uptake of neurotransmitters. DHA also serves as a substrate for the production of compounds that have anti-inflammatory effects to prevent degenerative destruction and brain-function delay.” He says that people with dementia have been shown to have lower-than-normal levels of DHA in their brains.

Hjaltason points to a study the company had done to determine whether its high-DHA EPAX 1050TG would positively affect the development of cognitive decline in early-stage Alzheimer’s disease. Performed at the Karolinska Institute in Sweden, the six-month placebo-controlled study was performed on 174 patients. While EPAX 1050TG did not help those who already had Alzheimer’s disease (mild to moderate AD), results did show that DHA played a role in slowing the onset of the disease, in those with very mild AD. The study was selected for inclusion in the National Institutes of Health’s Office of Dietary Supplements’ 2006 Annual Bibliography of Significant Advances in Dietary Supplement Research.

The company is now running another study on DHA and dementia at the University of Malaysia. The study will finish later this year.

Maintaining blood glucose in the brain is also an important aspect of brain health. According to Nutrition 21 (Purchase, NY), which has just started marketing its Chromax chromium picolinate ingredient for cognitive health, “If people cannot manage the glucose metabolism in their brain, they risk cognitive decline, as impaired glucose metabolism precedes the appearance of clinical symptoms associated with Alzheimer’s.” In fact, the company says, a greater percentage of people with type 2 diabetes also develop Alzheimer’s, leading some researchers to dub Alzheimer’s as “type 3 diabetes.”

A study published last year in Nutritional Neuroscience (Krikorian et al., vol. 13, no. 3: 116-122) examined 26 older adults with indications of early memory decline. Subjects were given an intervention chromium picolinate supplement containing 1000 mcg of elemental chromium, or placebo, for 12 weeks, and were administered tests, including the California Verbal Learning Test, to evaluate memory function. At the end of the study, researchers found that chromium picolinate supplementation helped improve memory function in those with early memory decline.

Protection

Antioxidants play a role in protecting against inflammation and oxidation in the brain. A number of new and established ingredients on the market are supporting this arm of cognitive health.

“Current research points toward the accumulation of damage resulting from oxidative stress as a major cause of cognitive decline,” says Jeremy Bartos, PhD, ingredients product manager for pTeroPure (Irvine, CA), a 99%-pure, nature-identical pterostilbene launched last fall. “One of the hallmarks of aging diseases such as Alzheimer’s is reduced hippocampal function caused in part by accumulative damage brought about by oxidative stressors. Antioxidants are a good theory to help alleviate this damage accumulation.”

Bartos points to a rat study on pterostilbene and cognitive health, done collaboratively between scientists at Tufts University and the USDA research station at the University of Mississippi and published in 2008 in the Journal of Agriculture and Food Chemistry. The study showed not only that pterostilbene protected cells against oxidative stress both in vitro and in vivo, but that this protection significantly correlated with increased cognitive function in aged rats. Bartos says that the rats with the highest pterostilbene levels in their hippocampus demonstrated significantly better results when performing the Morris water maze test. A human study, however, is yet to be done. “The data on pterostilbene and cognitive research is relatively new,” he says.

ChromaDex, pTeroPure’s parent company, is currently licensing a patent from the University of Mississippi for the use of pterostilbene in reducing cognitive decline through its role as a neuroprotector.

Bartos also says that pterostilbene as an antioxidant may be more bioavailable than other ingredients. “Some of the best antioxidants have hydroxyl groups that give them their antioxidant potential but also reduce their lipophilicity, or oil solubility,” he explains. “Oil-soluble compounds generally have higher potential for cellular uptake as they can get through the cell’s lipid bilayer easier than water-soluble compounds. The free hydroxyl groups also work against a compound in that they are more likely to be metabolized by the liver before hydroxyl-free compounds.”

Pterostilbene uniquely contains two methoxy groups, which increases its lipophilicity, and contains a hydroxyl group that gives it antioxidant potential. “Therefore, even though it may not have as high the antioxidant ‘potential’ that compounds with more hydroxyl groups can have, it is able to get to where it needs to go in the body for its potential to be realized,” Bartos says. “For nonlipophilic compounds, it’s like dressing up for the ball but not having the invitation required to be admitted.”

“The problem is finding antioxidants that localize or even get to the brain,” he adds.

Like pterostilbene, resveratrol has yet to be studied for its effects on the human brain. However, say suppliers, many signs point to the fact that this antioxidant may have benefits for cognitive health.

Herbert D. Woolf, PhD, is president and CEO of Fluxome (Easton, PA), which supplies a form of trans-resveratrol produced using fermentation. This technology produces only the trans-isomer, which Woolf says is the most stable and efficacious form. Besides its antioxidant effects, Woolf says, trans-resveratrol “induces nitric oxide production that relaxes blood vessels, enabling greater blood flow to the brain. Trans-resveratrol has also been shown to improve the synaptic response by regulating the amount of acetylcholine in the synaptic junction, as well as reducing the amount of amyloid plaque formation.”

He says that although there has not yet been a definitive clinical study on trans-resveratrol to demonstrate its effects on cognition, “the collective body of evidence from 1) epidemiologic/cohort studies, 2) animal/basic science studies, 3) human ‘proof-of-concept’ studies, and 4) the few human intervention studies seems to collectively support a key role for trans-resveratrol in maintaining cognition.”

A study in the works may show promise, albeit in an indirect form. Recently, Fluxome announced its resveratrol has been selected for the $3.4 million Long-Term Investigation of Resveratrol on Metabolic Syndrome, Osteoporosis, and Inflammation (LIRMOI) study, which Woolf says will be the longest clinical study to investigate resveratrol to date. “The study’s primary objective is to measure the effectiveness of resveratrol on biomarkers for inflammation, a key underlying cause of cognition loss.”

Pycnogenol’s antioxidant properties have been shown in several studies to counter neuronal oxidation in humans, according to Horphag Research (Geneva), the exclusive supplier of Pycnogenol French maritime pinebark.

The company says that the largest study carried out to date on Pycnogenol (150 mg daily) and cognitive function was a three-month company-funded study performed on 101 senior citizens (60- to 85-years-old) in Australia and published in 2008 in the Journal of Psychopharmacology (Ryan et al., vol. 22, no. 5: 553-562). The double-blind, placebo-controlled study found that the Pycnogenol group displayed improved working memory, including spatial working memory and numeric working memory. The company also notes an additional study, a double-blind, placebo-controlled study published in 2006 that looked at Pycnogenol’s effects on ADHD in children (Trebaticka et al., European Child & Adolescent Psychiatry).

“These studies found a significant reduction of oxidative stress,” says Frank Schonlau, PhD, director of scientific communications for Horphag. He says that nervous tissue is especially rich in polyunsaturated fatty acids (PUFAs), which by nature are very sensitive to oxidative damage. “The study in Australia showed a significant reduction of metabolites developing from oxidized PUFAs. The coincidence that this took place simultaneously after three months’ intake of Pycnogenol is striking.”

Also, he adds, “ADHD is an entirely different pathology, yet here again the improvement of cognitive symptoms coincided with significantly reduced oxidative stress.”

Schonlau adds that the company has completed another significant study on Pycnogenol and cognitive health in healthy students, not yet published. “We have begun to understand that there’s more to the activity of Pycnogenol for neuronal function than antioxidant protection to the oxidation-sensitive membranes of neurons.” He says the results will be made public later this year.

Expanding Markets

If such ingredients can indeed help consumers stay sharp, it makes sense to anticipate future growth in the brain-health market. The drivers-evolving research, a growing population at risk for dementia, and consumers’ desire for prevention at an earlier age-will continue to advance this category.

“Unfortunately, there is no ‘magic pill’ to reverse the effects of severe neurological disorders. Most ingredients on the market today can stabilize cognitive decline, but they cannot boost it back up,” says Chemi Nutra’s Hagerman. “This is why preventative measures are so vital to health.”

“Cognitive health is increasingly being considered and marketed as a long-term nutritional investment for the consumer,” says Cyvex Nutrition’s Phillips.

Younger consumers have become a target market for this industry.

“We are seeing younger consumers who want to maintain their edge as well,” says CapsuleWorks’ Melissa Ritacco Morreale.

“Research suggests that some aspects of cognitive decline begin in healthy, educated adults in their early 20s to 30s,” says David Romeo, managing director for Nutraceuticals International (Elmwood Park, NJ). “Ingredients geared toward improving the functioning of a healthy mind would be beneficial for the elderly and Baby Boomers, but for preventing cognitive decline, it would be best to start supplementing with beneficial ingredients at an early age.”

“Baby Boomers are still a target, but cognitive health is now addressed to all age groups,” he says. “The Baby Boomers will be looking for something to help the degeneration, while a young adult wants to preserve what they have for the future and a teenager desires a product that can help with mental focus.”

As cognitive-health research expands, so to should supportive ingredients for all age groups.