Mark Whitacre Research Review: Selenium's Role in the Quest for Brain Health

Supporting brain health and cognitive function throughout life may well prove to be one of the most important quests in nutrition science. As our aging population expands, the numbers of people who may be affected by reduced cognitive function with age will certainly grow, and with it the consequences to quality of life and public health costs.
The trace mineral selenium (Se) could be essential in addressing these issues. It is now well understood that selenium is essential to a healthy brain. This is evidenced by the fact that severe Se deficiency can result in irreversible brain damage (Burk & Hill, 2009). It is also quite interesting to note that the brain is the last organ to become depleted when there is an Se deficiency as well as being the first organ to become depleted once Se intake becomes adequate (Cardoso et al, 2010).

August-Research-Review-BlogMoreover, there is now strong evidence that selenium is critical for brain health as we age. The causes of age-related cognition fall into several categories (Aaseth et al, 2016) and selenium is involved in most of them. For example, in the neurotransmitter hypothesis, it is noted that there may be a reduction in acetylcholine in early stages of cognitive decline that may be due to excess oxidation, which can be addressed with adequate selenium.
Other theories in declining cognition also involve selenium:

  • The amyloid cascade hypothesis suggests that Se is a transporter of selenoprotein P, which has been shown to inhibit amyloid-β aggregation (Du et al, 2014).
  • The metabolic hypothesis has determined that advance glycation end-products (AGE) and similar substances, such as methylglycoxal, resulting from metabolic syndrome are neurotoxic and react with SH groups—selenium plays a role in protecting these groups.
  • In the tau protein hypothesis, tau transport proteins are altered (hyperphosphorylated) and can clog neural pathways to negatively alter brain function. Se is a potent inhibitor of tau phosphorylation, a critical step in the formation of neurofibrillary tangles. What’s more, Se supplementation in animals not only reduces neural degeneration, it also increases cognition. (van Eersal et al, 2010).
  • The metal theory suggests that selenium is involved with protecting against excessive mineral deposits in the brain from substances like copper and iron (Aaseth et al, 2016).
  • In the peroxidation theory, it is thought that high concentrations of highly unsaturated fatty acids, such as DHA, along with a high metabolic rate may make the brain more susceptible to peroxidation. Both neurons and glial cells are rich in glutathione peroxidase and thioredoxin reductase, two proteins that require Se and are essential to protecting the brain (Cardoso et al, 2015).
  • And finally, in the neuroinflammation theory, Se supplementation not only inhibited glial activation and inflammation, it also increased cognition in transgenic mice with Alzheimer's Disease (Song et al,)

Given selenium's role in many of these neural pathways, researchers are now looking closely at how selenium levels may correlate with cognitive issues and neural disorders, such as Alzheimer's Disease. In a compelling 2010 study, Alzheimer's patients were shown to be deficient in selenium levels (Cardoso et al, 2010). When compared with Alzheimer’s patients, non-Alzheimer’s subjects were found to have 56 percent higher Se in their blood; 81% higher Se in their red blood cells (RBCs) and 32% higher Se in their nails. It is also worth noting that this study found 89% and 96% of AD patients had blood and RBC selenium levels below the recommended level of 60-90µg/l, as compared to 76% to 68% of the control subjects. 

Research now suggests that low plasma selenium may be an issue long before any disorder is found, and is a factor in reduced cognition as people age. One clinical trial has shown that Se levels are linked to cognitive decline. The trial involved 1,166 French subjects, between the ages of 60 and 70, with high cognitive function (Berr et al, 2000). After a four-year follow up, the researchers found that subjects with the lowest plasma Se levels (lowest quartile; <75.8 µg/l) were at a 58% higher risk for cognitive decline (per their Mini-Mental State Exam [MMSE] scores) compared to those with the highest Se levels (µg/l). They also found that cognitive decline could be associated with oxidative stress, as determined by plasma TBARs (Thiobarbituric acid reactant substances), with high TBARs increasing the risk of cognitive decline by 125%.

In a nine-year follow up with these patients, the research team came to two essential conclusions: Those who had the greatest decrease in plasma Se had a high probability of cognitive decline. And amongst those who had an increase in plasma Se—those with the smallest increases had the highest probability of cognitive decline overall. More specifically, the researcher noted that those with the lowest plasma Se levels (the lowest quartile) had a 131% increased risk of experiencing a significant drop in cognition (a 2 pt drop in MMSE scores).
Additional studies seem to concur with these findings. A 2007 study (Gao et al) found that lower nail selenium levels were significantly associated with lower cognitive scores (p<0.0001); and this was after adjustment for gender, age, education, smoking, Body Mass Index, cancer and APOE (the apolipoprotein E genetic risk factor for Alzheimer’s Disease) genotypes.

Trials looking at Alzheimer’s patients are particularly compelling. In one study, patients with very mild Alzheimer’s Disease were found to have significantly lower plasma Se levels compared to healthy, age-matched controls (Olde Rikkert et al, 2014). Another study found subjects with Alzheimer’s to have even lower plasma levels than subjects with mild cognitive impairment (Gonzalez-Dominguez et al, 2014). 

Beyond noting the association between low Se levels and cognitive decline, evidence is also suggesting that selenium may have a protective effect. In a 2016 study, researchers found that Se supplementation can improve cognition. Older subjects (77 years old) with mild cognitive impairment who ingested one Brazil nut a day (~288.75 µg/ Se/day) for six months saw significantly improved cognition. They measured this improvement by noting significantly increasing verbal fluency ~10% in the subjects, while the control group saw a decline  of more than 10% (p=0.007 vs control group). They also noted improvements in constructional praxis (the ability to perform tasks such as drawing and assembling objects) by 20%, as compared to a slight decrease in the control group (p=0.031 vs control group).

In summary, selenium levels are now clearly linked to age-related cognitive decline, so supplementation with a highly-bioavailable selenium yeast, such as SelenoExcell® is a well studied and safe solution to this growing health issue.


  • Aaseth J, Alexander J, Bjorklund G et al. Treatment strategies in Alzheimer's desease: a review with focus on selenium supplementation. Biometals 2016;29:827-39.
  • Akbaraly NT, Arnaud J, Hininger-Favier I, Carriere I et al.  Plasma selenium over time and cognitive decline in the elderly. Epidemiology  2007;18:52-8 .
  • Berr C, Balansard B, Arnaud J et al. Cognitive decline is associated with systemic oxidative stress: the EVA study. J Am Geriatr Soc 2000;48:1285-91.
  • Burk RP, Hill KE. Selenium  P--Expression, Functions and Roles in Mammals. Biochim Biophys Acta. 2009 Nov;1790 (11)1441-1447.
  • Cardoso BR, Apolinario D, Bandiera VDS et al. Effects of Brazil nut consumption on selenium status and cognitive performance in older adults with mild cognitive impairment: a randomized controlled pilot trial. Eur J Nutr  2016;55:107-16.
  • Cardoso BR, Ong TP, Jacob-Filho W et al. Nutritional status of selenium in Alzheimer's disease  patients. Brit J Nutr 2010;103:803-6.
  • Cardoso BR, Roberts BR, Bush Al, Hare DJ. Selenium, selenoproteins and neurodegenerative  diseases. Metallomics 2015;7:1213.
  • Dalla Puppa L. Savaskan NE, Brauer AU er al. The role of selenite on microglial migration. Ann NY Acad Sci 2007;1096:179-83.
  • Du X, Wang C, Zheng Y et al. Inhibitory effect of selenoprotein P on copper induced Aβ 42 aggregation and toxicity. Inorg Chem 2014;53:1672-8.


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 These statements have not been evaluated by the Food and Drug Administration.These products are not intended to diagnose, treat, cure or prevent any disease.


Cypress-Dr-Mark-WhitcareAuthor Dr. Mark Whitacre is the Chief Science Officer at Cypress Systems. Dr. Whitacre has nearly two decades of executive management experience in both Fortune 500 and entrepreneurial companies, including broad international experience. Much of his career has been in the area of biotechnology and microbiol fermentation. Dr. Whitacre earned a Ph.D. in Nutritional Biochemistry from Cornell University where he studied under a world-renowned selenium scientist, Dr. G.F. Combs, Jr.  






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