Dementia Incidence Not Affected by Antioxidant Supplements

After controlling for comorbidities and demographics, there was no significant difference in dementia incidence in the study groups.

Supplementation with the antioxidants vitamin E and selenium have no positive effect on dementia incidence in men, according to a new paper published in JAMA Neurology.1

“Oxidative stress is an important mechanism in brain aging.  Research shows that protein oxidation is linked to the brain’s response to the abnormal proteins seen in Alzheimer disease (amyloid beta plaques in particular) leading to inflammation, DNA repair problems, reduced energy production, and other cellular changes that are identified mechanisms in the Alzheimer brain,” Richard Kryscio, PhD, of the Sanders-Brown Center on Aging at the University of Kentucky in Lexington, told Neurology Advisor.

“Both vitamin E and selenium are antioxidants obtained either through food or supplements. These are believed to reduce oxidative stress throughout the body. In the brain, they may reduce the formation of amyloid beta plaques, reduce brain inflammation, and improve other brain processes,” Dr Kryscio said.  

It is estimated that the number of Americans who develop Alzheimer’s disease (AD) will continue to increase in the setting of no disease-modifying treatments. Therefore, trials are now focusing on identifying ways to prevent cognitive decline.

Dr Kryscio and colleagues reported the results of the Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) trial, which was initially associated with the Selenium and Vitamin E Cancer Prevention Trial (SELECT) that ended in 2009 after a futility analysis. The PREADViSE trial then continued as a cohort study from 2009 to 2015.1

The study included men 60 or older who were randomly assigned to take vitamin E or selenium, both supplements, or a placebo. During the SELECT trial, participants were evaluated at their site with a 2-stage dementia screen. The PREADViSE cohort was also assessed by a 2-stage cognitive evaluation via telephone follow-up.  

The mean age of the participants (N=7338) was 67.5 and more than half (52.2%) reported at least a college education. At baseline, 21.3% of the participants reported a family history of AD and 25.5% were found to carry the APOE ε4 gene.

The overall dementia incidence in the study was 4.4% (325 out of 7338 men). The incidence of dementia was not found to be significantly different in the 4 groups, with an incidence of 3.9% in the vitamin E group, 4.1% in the selenium group, 5.0% in the combination group, and 4.6% in the placebo group. When the results were adjusted based on comorbidities and demographic data, the differences were not significant in the vitamin E group (hazard ratio [HR] 0.88; 95% CI, 0.64-1.20, P =.41), the selenium group (HR 0.83; 95% CI, 0.61-1.13, P =.23), or the combined group (HR 1.00; 95% CI, 0.74-1.35, P =.98).1

Dr Kryscio noted, “There is likely a difference between taking a supplement to boost antioxidant levels in the body and having the levels increased due to an antioxidant rich diet like that found in the Mediterranean diet.”

Steven DeKosky, MD, of the McKnight Brain Institute at the University of Florida in Gainesville, and Lon Schneider, MD, of the Alzheimer’s Disease Research Center at the Keck School of Medicine at the University of Southern California, Los Angeles, discussed the issues with this trial and other dementia prevention trials in an accompanying editorial.2

Drs DeKosky and Schneider noted that a dementia prevention trial requires long-term follow-up and would need to show clinically significant delay of cognitive impairments. Further, the US Food and Drug Administration (FDA) has stated that because of AD biomarker limitations as a substitute for cognitive outcomes, no drug could be marketed based on an ability to have an impact on biomarkers. Therefore, much of the data available for dementia prevention is based on epidemiological and observational studies.

Limitations specific to the PREADViSE trial include suboptimal cognitive testing, incomplete documentation of cognitive tests, and a low incidence of dementia possibly related to the younger age and higher level of education of the participants.

“The PREADViSE trial illustrates many of the difficulties for undertaking prevention trials: uncertainty of medication dose, mechanisms of action, and proof of target engagement; proper selection of a diverse population that can be observed for a realistic period to yield enough cases of dementia to determine success or failure of the intervention; use of appropriate assessment tools and methods of accurate diagnosis; and use of effective ways for maintaining participation and assuring adherence in the study over time,” Drs DeKosky and Schneider wrote.2


  1. Kryscio RJ, Abner EL, Caban-Holt A, et al. Association of antioxidant supplement use and dementia in the prevention of Alzheimer’s disease by vitamin E and selenium trial (PREADViSE) [published online March 20, 2017]. JAMA Neurol.  doi:10.1001/jamaneurol.2016.5778
  2. DeKosky ST, Schneider LS. Preventing dementia many issues and not enough time [published online March 20, 2017]. JAMA Neurol. doi:10.1001/jamaneurol.2017.0045