24 Mar 2017

Vitamin E and selenium failed to reduce dementia risk in cognitively normal older men. That disappointing conclusion emerged from analysis of the PREADViSE trial (Prevention of Alzheimer’s Disease by Vitamin E and Selenium), as reported March 20 in JAMA Neurology. Piggybacked onto a cancer study, PREADViSE was hamstrung when that trial was halted prematurely, experts agreed. However, the investigators, led by Richard Kryscio at the University of Kentucky in Lexington, salvaged what they could, turning PREADViSE into an observational cohort study. The results emphasize the difficulties of executing primary prevention trials, and call for a deeper biological understanding of how antioxidants affect the brain, commentators said.

Vitamin E.

In an accompanying editorial in JAMA Neurology, Steven DeKosky of the University of Florida in Gainesville and Lon Schneider of the University of Southern California in Los Angeles commended the authors for pursuing the observational study, despite the low odds of success. “It is very unlikely that the PREADViSE trial could have detected a salutary effect from the vitamin E or selenium interventions, if indeed there was one to be had,” they wrote.

Long touted for anti-aging, neuroprotective effects, antioxidants have a mixed record. Animal studies suggested that vitamin E protected neurons from numerous insults, including amyloid toxicity, and a clinical trial found that patients with moderate AD who took the vitamin declined more slowly than controls (see Sano et al., 1997). However, in subsequent trials, people with mild cognitive impairment found no protection, and AD biomarkers were unaffected by antioxidants in people with mild to moderate disease (see Apr 2005 news; Mar 2012 news). Selenium studies also appeared to contradict each other, with some studies hinting at protective effects, while others came up short (for a review see Loef et al., 2011).

Against this murky backdrop, Kryscio and colleagues sought to put antioxidants to the test in cognitively normal people. They took advantage of the SELECT trial that was testing the ability of antioxidants to prevent prostate cancer (see Lippman et al., 2009). With enrollment starting in 2001, participants in this double-blind, randomized controlled trial took daily doses of placebo, 400IU vitamin E, 200μg selenium, or a combination of both antioxidants, which were planned to continue for seven to 12 years, depending on date of enrollment. In 2002, as enrollment for SELECT continued, the researchers started recruiting men over the age of 60 from that trial into PREADViSE. By 2008, they had enrolled 7,540. With the primary outcome measure of dementia incidence, participants who failed a five-minute memory test as part of their annual office visits for SELECT were given the more thorough CERAD test and referred to a clinician for a full medical exam if dementia was suspected. The primary outcome measure for PREADViSE was incident dementia.

In September 2008, a futility analysis threw a wrench into the works. It found that not only were the supplements unlikely to prevent prostate cancer, but that people in the vitamin E group had higher incidence of the disease than those in the placebo group. SELECT’s safety committee halted the trial, leaving PREADViSE participants with no continued treatment or means for regular medical follow-up. By this point, the 7,540 men enrolled in PREADViSE had taken the supplements for an average of 5.5 years (see Kryscio et al., 2013).

Kryscio and colleagues then scrambled to transfer PREADViSE participants from the trial’s 130 sites into an observational study to continue tracking dementia incidence. All told, nearly half of the volunteers dropped out. Four thousand, two hundred and seventy-one agreed to annual cognitive assessments via phone as opposed to the in-person exams they had during the SELECT trial. Of those, 3,786 completed at least one assessment before the observational study ended in 2015. In the absence of in-person clinical assessments, the researchers drew upon multiple sources to make dementia diagnoses. Men who performed poorly on telephone tests were advised to see their local clinician for follow-up, and asked to submit medical records. For those who did not submit medical records, the researchers relied on further phone screening, interviews with family members, or a self-reported prescription of memory-enhancing drugs or dementia diagnosis to ascertain dementia.

Of the 7,540 men originally enrolled in PREADViSE, 4.3 percent developed dementia overall, either during the treatment portion of the study or, for those who continued onto the observational study, during follow-up. There were no statistically significant differences in the incidence of dementia among control and treatment arms. The same was true when the researchers restricted their analysis to the 3,786 men who continued onto the observational study, 6 percent of whom developed dementia overall. Given that there was a wide variation in the length of time each man took supplements—from one to seven years—the researchers also performed a proportional hazard analysis, in which each man’s contribution was weighted based on the amount of time they were treated and also their compliance, as assessed by returned pills. This analysis found no significant differences in dementia risk between the control or study arms of the trial.

Kryscio said the failure to detect any protection against dementia was disappointing, yet not entirely surprising given the many setbacks that struck the study.

Several factors may have prevented the detection of an effect. For one, at 4.3 percent, the overall incidence of dementia in the total cohort was low, limiting the chances of seeing any protection. The relatively young age and high education level in the cohort might explain the incidence, the researchers proposed. The researchers had planned to enroll more than 10,000 men, but only a third of SELECT’s 427 study sites agreed to participate in PREADViSE, which lowered enrollment to 7,540. Furthermore, cognitive assessments were conducted by non-dementia specialists spread out over 130 sites during the treatment portion of the trial, and by telephone interview during the observational follow-up. This lack of consistency, and expertise in some cases, could have precluded accurate diagnoses, the researchers pointed out. Kryscio added that men who performed poorly on cognitive screens often failed to see clinicians for further assessment, perhaps due to the stigma attached to dementia.

Regardless of trial design issues, perhaps antioxidant supplements simply do not provide a sufficient neuroprotective effect, said Ronald Petersen of the Mayo Clinic in Rochester, Minnesota. “Fundamentally, there is just little evidence that vitamin E is going to be therapeutic,” he told Alzforum. “I’d have to think long and hard about designing a new study to look at the role of high-dose vitamin E in prevention or treatment.” He added that while some people may be tempted to take the supplements despite negative trial results, the antioxidants are not without risk. High doses of vitamin E have been implicated in elevated bleeding risks, and high doses of selenium are known to be neurotoxic.

Douglas Galasko of the University of California, San Diego, added that without appropriate biomarkers to understand whether antioxidants enter the brain and engage their targets, it is difficult to say why they come up short in trials. In an earlier antioxidant trial of people with mild cognitive impairment, Galasko addressed this by measuring CSF levels of isoprostane-F2, but he noted that even the choice of that biomarker was based on shaky biological ground, because antioxidants are known to affect multiple signaling pathways. “If we’re going to target AD, it would be useful to come up with more specific mechanisms, targets, and biomarkers, and run exploratory studies along the way before embarking on further, large public health trials,” he said.

Galasko, Petersen, and Kryscio all added that it is possible the antioxidants derived from foods may have beneficial effects that supplements lack. Kryscio added that perhaps future trials should focus on people with antioxidant-poor diets at baseline, or who have low levels of antioxidants in the blood.—Jessica Shugart