Antioxidant Supplements: No Effect on Dementia Prevention

March 23, 2017

Taking antioxidant supplements vitamin E and selenium for 5 years did not show any effect on the prevention of dementia during a total follow-up of 11 years in a large population of older men in the PREADViSE (Prevention of Alzheimer’s Disease by Vitamin E and Selenium) trial.  

The trial, published online in JAMA Neurology on March 20, was conducted by a team led by Richard J. Kryscio, PhD, Sanders Brown Center on Aging, University of Kentucky, Lexington.            

Dr Kryscio noted that this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.  

"This will make people pause and think twice about the potential of antioxidants as a preventative strategy for Alzheimer's," he told Medscape Medical News. "Although oxidative stress is an established dementia pathway, personally I think this is probably the end of the road for the idea of using antioxidants to prevent dementia."

The trial started in 2002 as part of SELECT (Selenium and Vitamin E Cancer Prevention Trial), which evaluated selenium and vitamin E for the prevention of prostate cancer. It recruited 7540 men (mean age, 67 years) without any symptoms of cognitive impairment at baseline. They were randomly assigned to vitamin E (400 IU daily), selenium (200 μg daily), both agents, or placebo.

SELECT was terminated early in 2009 because of futility and the toxicity of selenium. Patients in the PREADViSE study stopped taking the supplements but continued to be followed for 6 additional years as a cohort study. However, Dr Kryscio explained that when SELECT closed, about half the study sites stopped all activity so those patients were lost to follow-up. "Therefore we only had about half our sample available — 3786 patients — for the full follow-up time."

While taking study supplements, participants were evaluated for dementia by using a two-stage screen. During the cohort study, men were contacted by telephone and assessed with an enhanced two-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment.

Results showed that at the end of the follow-up period, 325 men (4.4%) had developed dementia, but this was not different among the four study groups. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% confidence interval [CI], 0.64 - 1.20) for vitamin E, 0.83 (95% CI, 0.60 - 1.13) for selenium, and 1.00 (95% CI, 0.75 - 1.35) for the combination compared with placebo.

The authors note that data monitoring in SELECT showed that selenium appeared to elevate levels of type 2 diabetes (although this elevated rate subsequently decreased with additional follow-up) and that vitamin E appeared to increase prostate cancer incidence.  

The supplements had no effect on mortality, other cancers, cardiovascular events, nausea, fatigue, or nail changes. Selenium was associated with a significant increase in alopecia and grade 1 and 2 dermatitis.

"The supplemental use of vitamin E and selenium did not forestall dementia and are not recommended as preventive agents," the researchers conclude.

But they add that this conclusion is tempered by the underpowered study, inclusion of only men, a short supplement exposure time, dosage considerations, and methodologic limitations in relying on real-world reporting of incident cases.

Difficulties for Prevention Trials

In an accompanying editorial, Steven T. DeKosky, MD, McKnight Brain Institute, Florida Alzheimer's Disease Research Center, Gainesville, and Lon S. Schneider, MD, Keck School of Medicine of the University of Southern California, Los Angeles, note that the PREADViSE trial joins several other studies that have failed to show any effect of various interventions — including gingko biloba, anti-inflammatory medications, statins, and hormone therapy — on the development of dementia.

They point to several issues that may have contributed to the failure of the PREADVISE trial to show any effect. These include the loss of half of the participants because of the stopping of the parent trial, incomplete records of cognitive assessments in the cohort part of the study, and the low level of dementia cases (which may have been due to the high level of education and the relatively young age of the participants at study entry).

'With the minimum age for entry into the trial set at 60 years, most of the cohort was observed in their 60s, when dementia incidence is still exceedingly low," the editorialists add.

They say that the PREADViSE trial illustrates many of the difficulties for prevention trials. These include 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.

"Finding efficient and cost-saving ways to address these issues in long-term, disease-modifying trials must be major goals for research groups around the world," they conclude.  

In an interview with Medscape Medical News, Dr Kryscio addressed some of the issues raised in the editorial.

"The randomized part of our trial was stopped early because it was piggy-backed onto the prostate cancer study and we lost half our patients for longer-term follow up — so, yes, it is underpowered. But we didn't get anything close to significant effects, so even if we doubled our sample size, I don't think we would have got a positive result.

"The participants in this study were cognitively normal at baseline and I suppose it was quite ambitious to think we may be able to show an effect in this population, but at the time the study started this was what the field was doing. Now it is focusing more on 'secondary prevention' — looking at groups at high risk of developing dementia."

On the age of the participants at baseline, Dr Kryscio pointed out that they recruited men in their 60s and followed them into their 70s. "I think this is quite reasonable — many patients develop Alzheimer's in their 70s, and if you go for an even older population then you start to see lots of different issues, particularly vascular dementia, which can complicate the issue," he said. "Our participants could have been a few years older, I suppose, but I don't think it would have made any difference to the results."

He noted that the trial was based on research from animal models suggesting that oxidation was associated with Alzheimer's disease and that vitamin E could block this process, and also some observational studies indicating that high levels of antioxidants were associated with a lower risk for dementia.

He believes that despite all the limitations of the trial, the results do not suggest a way forward for antioxidant supplements for prevention of dementia.

"Others might think other forms of vitamin E or selenium or other antioxidants may be worth trying, but personally, I doubt they would work."

The study was supported by grants from the National Institute on Aging. The Selenium and Vitamin E Cancer Prevention Trial was supported by grants from the National Cancer Institute. The study authors and editorialists have disclosed no relevant financial relationships.

JAMA Neurol. Published online March 20, 2017. Full text, Editorial

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