The Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial

Richard J. Kryscio, Erin L. Abner, Allison Caban-Holt, et al.

Key Points
Question Can vitamin E or selenium prevent dementia in asymptomatic older men?

Findings The Prevention of Alzheimer’s Disease by Vitamin E and Selenium trial initially enrolled 7540 elderly men who were exposed to the supplements for an average of 5.4 years; a subset of 3786 men agreed to be observed for up to 6 additional years. Dementia incidence (4.4%) did not differ among the 4 study arms.

Meaning Neither supplement is recommended as a preventive agent for dementia.

Abstract
Importance Oxidative stress is an established dementia pathway, but it is unknown if the use of antioxidant supplements can prevent dementia.

Objective To determine if antioxidant supplements (vitamin E or selenium) used alone or in combination can prevent dementia in asymptomatic older men.

Design, Setting, and Participants The Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) trial began as a double-blind randomized clinical trial in May 2002, which transformed into a cohort study from September 2009 to May 2015. The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized clinical trial of the same antioxidant supplements for preventing prostate cancer, which closed in 2009 owing to findings from a futility analysis. The PREADViSE trial recruited 7540 men, of whom 3786 continued into the cohort study. Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites, and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms.

Interventions Participants were randomized to vitamin E, selenium, vitamin E and selenium, or placebo. While taking study supplements, enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen. During the cohort study, men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment.

Main Outcomes and Measures Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information, including a functional assessment screen.

Results The mean (SD) baseline age of the 7540 participants was 67.5 (5.3) years, with 3936 (52.2%) reporting a college education or better, 754 (10.0%) reporting black race, and 505 (6.7%) reporting Hispanic ethnicity. Dementia incidence (325 of 7338 men [4.4%]) was not different among the 4 study arms. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% CI, 0.64-1.20) for vitamin E, 0.83 (0.60-1.13) for selenium, and 1.00 (0.75-1.35) for the combination compared with placebo.

Conclusions and Relevance Neither supplement prevented dementia. To our knowledge, this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.

Introduction
In the United States, an estimated 5 million elderly persons have Alzheimer disease (AD), and the number of people who develop AD is expected to increase substantially by 2050.1 A 2014 review2 of clinical trials from 1984 to 2014 showed a focus on enrolling patients with mild to moderate dementia in many trials, with no real progress on identifying disease-modifying treatments. As a result, there has been a shift in focus to clinical trials emphasizing the prevention of cognitive decline, especially through secondary prevention trials targeting high-risk groups3,4 and large trials that promote lifestyle changes to address modifiable risk factors for AD.5,6 The usual primary end points of these trials are cognitive decline or composites of biomarkers and cognitive measures.7 The gold standard of prevention is disease incidence, but to our knowledge, few current trials have this as their primary end point because of the time required to observe reductions in disease incidence.

Multiple mechanisms associated with disease onset and progression have been described,8 and one key mechanism implicated in AD is oxidative stress,9 which may be modifiable through diet and/or antioxidant supplements.10 Antioxidant use as a potential treatment for cognitive impairment or dementia has been of interest for many years. The use of vitamin E has had mixed results in treatment trials; in patients with moderate dementia treated for 2 years, its use slowed disease progression,11 but more recently, when used in an antioxidant cocktail, its use failed to improve cognition in patients with AD with mild to moderate dementia.12 It also failed as a preventive agent for dementia progression in persons with mild cognitive impairment,13 although early in the trial, its use did somewhat improve cognition. A review14 of controlled trials and case-control studies on the use of selenium in arresting the progression of AD also yielded mixed results. Observational studies correlate cognitive decline with decreased plasma selenium over time.15,16 However, to our knowledge, nothing is known about long-term use of these supplements as preventive agents in asymptomatic individuals.

This article reports the main results of the Prevention of Alzheimer’s Disease by Vitamin E and Selenium (PREADViSE) primary prevention trial. The PREADViSE trial, the largest primary prevention trial in AD to date, began in 2002 as an ancillary trial within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a double-blind randomized clinical prostate cancer prevention trial.17 When SELECT ended prematurely in 2009 owing to results of a futility analysis, the PREADViSE trial continued as a cohort study for a subset of its enrollees.18 Extended follow-up over a 7-year period (blinded) allowed for case ascertainment, yielding a comparison of the study arms for effectiveness in preventing dementia. We present the results of this large primary prevention study of antioxidant supplements as a method to modify oxidative stress, one mechanism in the evolution of AD.9

Results
Table 1 shows that the 3786 participants evaluated with at least 1 memory screen in the cohort study were similar to the complete PREADViSE trial enrollment, except possibly for less education at the college level or higher (52.2% vs 60%), fewer black participants (8.4% vs 10.0%), and fewer Hispanic participants (2.5% vs 6.9%). Table 2 lists participant characteristics at the time of PREADViSE trial enrollment by study arm. Based on the means and percentages, despite randomization occurring at SELECT baseline rather than PREADViSE trial enrollment, there were no perceivable differences between study arms in terms of medical history, APOE ε4 genotype, or initial MIS score.

Incident dementia cases were defined as above. There were 325 of 7540 men (4.3%) with incident dementia in the study, and of these, 121 of 325 men (37.2%) provided medical records (Table 3). Unadjusted cumulative dementia incidence varied among the study arms; there were 71 men (4.0%) in the vitamin E arm, 78 men (4.2%) in the selenium arm, 85 men (4.6%) in the placebo arm, and 91 (5.0%) in the combination arm (Table 3).

To compare the hazard rates for dementia among the 4 study arms, mITT analysis based on a Cox proportional hazards model was fitted to the data. The mITT analysis excluded 201 participants who had only a baseline visit. Hence, the Cox model included 7338 men with at least 1 follow-up visit. None of the active study arms had a significantly lower adjusted hazard rate for incident dementia compared with the placebo arm; the vitamin E arm had an HR of 0.88 (95% CI, 0.64-1.20), while the selenium arm had an HR of 0.83 vs placebo (95% CI, 0.61-1.13) (Table 4). The combined supplements arm was indistinguishable from the placebo arm and had an HR of 1.00 (95% CI, 0.74-1.35) (Figure).

Because this was a truncated RCT (owing to the futility analysis for SELECT), the Cox model was refitted by weighting each man’s survival time to dementia by the length of time that man was exposed (time receiving supplement) multiplied by the estimated proportion of this time that the man was compliant with the assigned treatment (ie, compliance). The weighted analysis showed results similar to the unweighted mITT analysis (Table 4).

Additional sensitivity analyses were conducted. First, the analysis was restricted to the 3786 participants who volunteered for the cohort study and were screened by telephone at least once; here, the number of incident dementia cases was 228. The reported effects were an HR of 0.97 (95% CI, 0.65-1.43) for the vitamin E arm, an HR of 0.92 (95% CI, 0.63-1.34) for the selenium arm, and an HR of 1.18 (95% CI, 0.82-1.68) for both. Second, the analysis used all 7338 participants with at least 1 annual follow-up screen but only classified a participant as having dementia if confirmed by medical records. This reduced the number of events to 121, yielding an HR of 0.80 (95% CI, 0.59-1.62) for vitamin E, an HR of 0.70 (95% CI, 0.41-1.19) for selenium, and an HR of 0.97 (95% CI, 0.60-1.58) for both.

Discussion
The PREADViSE trial was a double-blind RCT conducted as an ancillary study to a cancer prevention trial (SELECT), both of which evolved into observational cohort studies. This trial investigated whether the supplements vitamin E and selenium used alone or in combination would prevent new AD or dementia onset. The results showed that neither vitamin E nor selenium (with a mean [SD] time of supplement use of 5.4 [1.2] years) had a significant preventive effect on incidence. One possible explanation for the negative findings is that the trial met only 75% of its planned accrual; however, the results also show that the effect sizes observed for either supplement are likely much lower than the projected HR of 0.60.19 Nevertheless, to our knowledge, this is the first large-scale primary prevention trial to investigate the association of antioxidant supplements with reducing dementia incidence.

The PREADViSE trial is a member of the first generation of AD prevention trials,27- 30 all of which failed in their primary goal. One common reason for the failure of those trials was the low incidence of AD and dementia observed during follow-up. This was attributed partially to selection bias, since participants had higher levels of education than the general population and perhaps more cognitive reserve. Dementia incidence among PREADViSE trial participants was very low for several additional reasons. Case ascertainment could not use modern diagnostic procedures because those with suspected dementia did not, as a rule, visit dementia specialists for diagnosis. Instead, ascertainment relied on a consensus review of medical records derived from a variety of care professionals. Case ascertainment was also affected by continual staff turnover at study sites in the RCT component of the study, which was associated with a low cognitive screen failure rate (less than 1%). The failure rate increased substantially once centralized follow-up began.18

The rationale for this trial was supported by results from the basic sciences as well as observational and prospective studies in humans suggesting that the use of antioxidants improved cognition and reduced dementia incidence. The studies preceding the trial focused more on the benefits of vitamin E because it was being evaluated in a number of therapeutic trials at that time, including a trial that studied its effect on the progression of mild cognitive impairment to dementia.13 As in the mild cognitive impairment trial, vitamin E had no effect on dementia incidence in the asymptomatic cohort in the PREADViSE trial.

A 2014 review of studies on selenium31 argues that selenium is vital for central nervous system function and that brain selenium levels are maintained at the expense of other tissues. A study16 of 2000 rural Chinese individuals 64 years and older showed that participants in the lowest quintile of nail selenium levels had significantly lower scores on all instruments in the CERAD battery except for animal fluency. It is well known that high levels of selenium are toxic, inducing a severe selenosis by pro-oxidant action and glial activation, leading to neuronal death.31

For the PREADViSE trial, dose decisions were made by a committee in the parent SELECT study.32 The absence of biomarkers for target engagement of the supplements makes it difficult to translate basic science findings into prevention trials in a rigorous manner.

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.17The 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 grades 1 and 2 dermatitis17 (Table 4).

Limitations
Our study had some limitations. The transitioning process cost the study about half of its participants for long-term follow-up; this was unavoidable because the study had to rely on SELECT sites to enroll the participants for the cohort study. Fortunately, Table 1 shows that the major cost was sample size (reduction in person-years of follow-up), as no new large selection biases were introduced. Aside from transitioning to a cohort study from an RCT, the PREADViSE trial had other limitations. Publicity about the negative effect of supplements may have affected the conduct of both the RCT and cohort study. The Selenium and Vitamin E Cancer Prevention Trial reports on the potentially harmful effects of vitamin E (increased prostate cancer) and selenium (potentially increased diabetes), coupled with outside negative reports on vitamin E (ie, increased mortality33) created issues to be addressed.34 Many individuals who failed the screening instruments refused to see clinicians for further testing; recent research suggests that this could be because of the stigma attached to such an event or living alone.35 This complicated case ascertainment. Diagnoses of AD that rely on the choice of cut points on neuropsychological tests have been shown to fail to identify individuals in the initial symptomatic stages of the disease.36 Hence, our methods for case ascertainment could have missed individuals that would have been identified by more rigorous in-clinic examinations. Future trials may benefit from electronic medical records. The reluctance to visit physicians prompted the introduction of the AD8 during the follow-up phase of the study, which could have induced bias because of the inability of participants or informants to distinguish anosognosia from dementia. This is a likely a small bias because examining those with medical records showed a high level of agreement with the AD8, as also evidenced in another study.37 The reliability of telephone assessments vs in-clinic assessments used in the 2 phases of the study was less of an issue owing to high intraclass correlations, which ranged between 0.92 and 0.98.38 In addition, the TICS-m has been shown to be a reliable discriminator between cognitively intact individuals and those with amnestic mild cognitive impairment.39

Conclusions
The supplemental use of vitamin E and selenium did not forestall dementia and are not recommended as preventive agents. 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.

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