By Ellen Feldman, MD

Altru Health System, Grand Forks, ND

Dr. Feldman reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • This article presents the results of the largest primary prevention trial in Alzheimer’s disease: the Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE.)
  • The study began as a seven-year randomized clinical trial and continued with a subgroup of participants as a prospective or cohort study for another seven years.
  • All study participants entered as asymptomatic males of at least 60 years of age.
  • There were four arms of the study: vitamin E alone, selenium alone, combination of selenium and vitamin E, and a placebo arm. The incidence of dementia was 4.4 % in all arms.

SYNOPSIS: This large-scale study of asymptomatic elderly men reveals no indication that selenium or vitamin E (taken alone or in combination) prevents development of dementia.

SOURCE: 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). JAMA Neurol 2017;74:567-573.

In 1906, Dr. Alois Alzheimer first described “a peculiar disease.” It has been more than 100 years since Dr. Alzheimer reported distinct microscopic changes in the brain of patients presenting with progressive memory loss, confusion, and other hallmarks of the disease that today bears his name.1 In the intervening period, medical science has come to understand more facets of the etiology and progression of dementia in general and in Alzheimer’s disease (AD) specifically. Unfortunately, efforts to cure this progressively deteriorating condition remain beyond our reach. Although available medications can slow progression, results are inconsistent and do not change the outcome of the disease.2 Preventive measures have demonstrated more success — consequently the incidence of AD in developed nations appears to be on the decline. However, there remains concern of AD prevalence reaching worldwide epidemic numbers by 2050, in part because of longer life spans among the population.3

The etiology of AD is multifactorial and complex, including both genetic and environmental stimuli. Although the medical field has been aware of the characteristic neurofibrillary tangles and amyloid plaques in the brains of AD patients since Dr. Alzheimer’s time, the role of oxidative stress in the development and progression of AD has been investigated only recently.4 As results of studies regarding oxidative stress in AD became more compelling, researchers began developing an interest in intervention with potent antioxidant supplements, such as vitamin E and selenium. At the onset of the Kryscio et al study, selenium, which is suspected to be essential for optimal central nervous system functioning, had mixed results from several randomized trials.5 Vitamin E research was pointing to a role for this agent in slowing the progression of mild cognitive impairment to dementia.6 However, until this current study's publication, very little was understood about the long-term effects of these two supplements in members of the aging asymptomatic population.

Oxidative stress refers to a process when the ability of the body to neutralize free radicals is reduced, often leading to destabilization on a cellular level and potential tissue and organ damage. Free radicals typically are neutralized by antioxidants — a molecule that chemically reacts with and stabilizes a free radical without itself destabilizing.7

The study described here is an offshoot of a larger study that began in 2001 to investigate potential roles of vitamin E and/or selenium in the prevention of prostate cancer. The larger study, known as the Selenium and Vitamin E Cancer Prevention Trial (SELECT), was a double-blind, randomized, clinical study that terminated in 2008, four years earlier than scheduled because of results of a futility analysis and lack of efficacy.8

Beginning in 2002, a subgroup of men 60 years of age were recruited from within the original SELECT participants, eventually reaching an enrollment of 7,540 men. Eligibility for this study, the Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE), included the absence of dementia and the absence of substance abuse at baseline, as well as a negative history of specific neuropsychiatric conditions.

When SELECT ended in 2009, participants were asked to remain on as members of a cohort study for both SELECT and PREADViSE. In this manner, 4,271 men from the original 7,540 PREADViSE participants agreed to stop taking the supplements and participate in annual telephone-conducted, two-tiered memory screens. A protocol including referral to specialists (with medical records requested by the PREADViSE group) or further telephone-conducted screening tests was established to evaluate the presence or absence of AD.

Selected Results

Kryscio et al noted that the results of this study are best viewed in context of the circumstances surrounding the methodology; that is, the number of participants from the randomized, clinical trial was reduced almost in half to 4,271 men and became a strictly observational cohort study after the halt of the active clinical trial in 2009. To put the results in perspective, this group conducted sensitivity analyses and several other statistical studies to verify legitimacy of the final numbers. The mean time of supplement use for the group was 5.4 years. The dose was vitamin E 400 IU daily and selenium 200 micrograms daily. (See Table 1.)

Table 1: Selected Results from Study Participants

 

Vitamin E

Selenium

Combined

Placebo

Development of dementia

71 men

78 men

91 men

85 men

Percentage of total

4.0%

4.2%

5.0%

4.6%

Hazard ratio

0.88 (0.64-1.2)

0.83 (0.61-1.13)

1.00 (0.74-1.35)

1 (reference)

P value hazard ratio

0.41

0.23

0.98

NA

COMMENTARY

This study regarding prevention of AD began as a double-blind, randomized, clinical trial and morphed into an observational cohort study after the original parent study (SELECT), which investigated the effect of antioxidant supplements on prostate cancer, was halted because of both lack of efficacy and the association of vitamin E with increased rates of prostate cancer.8 With the transition to the observational study, participants were instructed to stop supplement use. Thus, in interpreting the results of the study, it is relevant to recognize that while this is the first study regarding the long-term effect of vitamin E and selenium on prevention of AD, the active use of the supplements did not continue throughout the entire study period. Additionally, it is interesting to note that all participants were at least 60 years of age when beginning the supplement use — it very well may be that earlier and lengthier use would show a different effect.

It is also important to note that all arms of the study had a lower rate of dementia development than would be expected in the general population. According to recent estimates, the risk of AD development among U.S. men between the ages of 65 and 75 years is 9.1-10.2% — considerably higher than the 4.4% found in the study under discussion here.9 Kryscio et al mentioned that this lower rate of AD overall may have made it more difficult to detect an effect from the supplements. They speculated that the lower rate could be because of the relatively higher level of education in the men recruited as study participants.

Over the past three decades, evidence has accumulated showing that educational level is associated with lower incidences of AD. The cognitive reserve theory postulates that specific life experiences lend resistance to the neuropathological insults involved in the development and progression of AD, while others have speculated that detecting AD via standard memory and processing screens may be less sensitive in persons with higher intellectual levels at baseline.10 Participants in this study were well-educated, with slightly more than half holding at least a college degree. Standard AD screens were used for disease detection; there were no imaging studies unless a participant was referred for further testing. Given this combination of factors, underdiagnoses should be suspected.

Another factor to note is that the vitamin E supplement used in this study was in the form of alpha-tocopherol. However, there are eight distinct forms of vitamin E, several of which may be beneficial for health.11 Recent studies using the standard alpha-tocopherol vitamin E supplement have noted that use of only this single isomer may inadvertently decrease serum levels of other forms of vitamin E and lead to misinterpretation of the overall effect of this vitamin.12

It is also important to note that the recommended daily allowance (RDA) for selenium for adults is 55 micrograms;13 this study dosed 200 micrograms daily. One of the risks of excessive selenium serum concentration involves central nervous system toxicity. Although the tolerable upper limit of selenium at 400 micrograms daily is well above the dosage used in the study, the study dose may have had subtle adverse effects in a vulnerable older population.13

Despite the methodological limitations of this study — which in addition to those already mentioned include the recruitment of only male participants and the relatively young age at baseline — it may be that antioxidants in supplement form simply are not neuroprotective or useful in prevention of development of AD. A 2013 meta-analysis looking at dietary forms rather than supplement forms of vitamin E found a 20% lower risk of AD with higher dietary intake of vitamin E as well as lower risks with foods rich in vitamin C and beta-carotene.14 It may be that dietary intake of antioxidants is the key and that supplements simply do not offer the same benefits as a healthy, vitamin- and antioxidant-rich meal plan.

The results of this study offer providers an opportunity to remind patients of the importance of maintaining a healthy and varied diet. Although the jury remains out on the use of supplements in the prevention of AD in general, there is no indication that either vitamin E or selenium in supplement form is useful in prevention of AD. There remains clear evidence that dietary intake of antioxidants is helpful in maintenance of health in general and in AD prevention as well.

REFERENCES

  1. Hippius H, Neundorfer G. The discovery of Alzheimers. Dialogues Clin Neurosci 2003;5:101-108.
  2. Cummings J, Aisen PS, DuBois B, et al. Drug development in Alzheimer’s disease: The path to 2025. Alzheimers Res Ther 2016;8:39.
  3. Prince M, Ali GC, Guerchet M, et al. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 2016;8:23.
  4. Aliev G, Obenovich ME, Reddy VP, et al. Antioxidant therapy in Alzheimer’s disease: Theory and practice. Mini Rev Med Chem 2008;8:1395-1406.
  5. Vinceti M, Mandrioli J, Borella P, et al. Selenium neurotoxicity in humans: Bridging laboratory and epidemiologic studies. Toxicol Lett 2014;230:295-303.
  6. Peterson RC, Thomas RG, Grundman M, et al,; Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379-2388.
  7. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008;4:89-96.
  8. Kristal AR, Darke AK, Morris JS, et al. Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 2014;106:djt456.
  9. Alzheimer’s Association. 2012 Alzheimer’s Disease Facts and Figures. Available at: https://www.alz.org/downloads/facts_figures_2012.pdf. Accessed May 15, 2017.
  10. Xu W, Yu JT, Tan MS, Tan L. Cognitive reserve and Alzheimer’s disease. Mol Neurobiol 2015;51:187-208.
  11. Schmölz L, Birringer M, Lorkowski S, Wallert M. Complexity of vitamin E metabolism. World J Biol Chem 2016;7:14-43.
  12. Abdala-Valencia H, Berdnikovs S, Cook-Mills JM. Vitamin E isoforms as modulators of inflammation. Nutrients 2013;5:4347-4363.
  13. National Institutes of Health. Selenium. Available at: https://ods.od.nih.gov/factsheets/Selenium-HealthProfessional/. Accessed June 12, 2017.
  14. Li FJ, Shen L, Ji HF. Dietary intakes of vitamin E, vitamin C, and B-carotene and risk of Alzheimer’s Disease: A meta-analysis. J Alzheimers Dis 2012;31:253-258.