Earlier testing of Alzheimer's drugs urged
Would require telling people about risk factors before symptoms are evident
In the fight against Alzheimer's disease dementia, researchers have long targeted beta-amyloid plaques, accumulated protein fragments in the brain that are a hallmark of the disease. The plaques are believed to contribute to the cognitive impairment associated with Alzheimer's disease.
Over the past decade, a number of trials of anti-amyloid therapies have proven unsuccessful. But researcher Reisa Sperling argues that these trials may be targeting the wrong population – people who already show signs of cognitive decline and are receiving the treatment too late.
Sperling, MD, MMSc, director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital in Boston, says she and other researchers are planning trials with older patients who have evidence of amyloid accumulation but don't show signs of cognitive decline.
She makes a case for this line of research in a commentary in a recent issue of the journal Science Translational Medicine.
The proposed trials carry with them new ethical challenges for both researchers and IRBs.
Finding subjects will require screening for amyloid accumulation, probably through positron emission tomography (PET) imaging. One concern is what to tell subjects who are found to have these accumulations – Sperling says nearly one-third of everyone over age 70 shows evidence of amyloid buildup.
"Right now, for a given individual, we don't know whether amyloid means they will ever develop Alzheimer's dementia, or whether it's amyloid plus something else that's predictive," she says. "I feel strongly that ethically, we have to convey that uncertainty."
There are two types of investigations that researchers want to conduct. One type consists of natural history studies of both amyloid-positive and amyloid-negative individuals, to try to understand the progression of Alzheimer's disease. The other would be trials of anti-amyloid therapies which previously have been used in study populations who had more advanced stages of the disease.
These therapies may carry some risks to subjects. Development of semagacestat, believed to be a promising candidate against beta amyloid, was halted in 2010 by Eli Lilly and Co. after Phase III trials showed evidence of worsening cognition in subjects, as well as an increased risk of skin cancer.
Sperling says there are a small number of drugs for which there is adequate safety data to move forward with a three-year trial.
"Even though they have significant risks, we're getting a handle on what those risks are, to the point where I feel like from an IRB perspective, we can say here's what we have seen in people who have amyloid and dementia," Sperling says. "It is very likely that we'll see the same set of side effects in people who have amyloid and don't yet have dementia."
And she says that subjects who have no cognitive impairment are in a better position to make decisions about participation than patients with mild dementia, who often must have a study partner who can serve as a surrogate consenter as their disease progresses.
"These are normal people who likely will join this trial because they have seen their family members suffer with this," Sperling says. "They know, unfortunately, what this disease can be. And we will have to say there's significant risk. But again I think that's ethical, if people can make their own decision about this when they don't have cognitive impairment, which might really impact their ability to weigh the risk-benefit."
The key, she says, is ensuring subjects understand what scientists do and do not know about amyloid and Alzheimer's. She says that while researchers have experience conveying this uncertainty to people who already show signs of Alzheimer's disease dementia, it will be trickier to educate people who have amyloid accumulation but no signs of impairment.
"We have to be very upfront, to say, 'We don't know whether having amyloid in the brain means you will develop Alzheimer's disease dementia or not,'" Sperling says. "What we can say is 'We want you to have this screening process to see if you would be eligible to take a medication to lower a protein, that, if we find it in your brain, we think may be an important risk factor.'"
As part of these studies, Sperling says researchers plan to survey subjects about what finding out their amyloid status means to them.
Sperling says she does not see IRB approval as a significant obstacle to getting these trials off the ground. More difficult, she says, will be crafting the partnerships necessary to carry them out — between public funding, industry and philanthropists.
But she says IRBs in general need to keep in mind the serious nature of Alzheimer's disease when weighing risks and benefits in a proposed study.
"We accept huge risks in cancer (research)," Sperling says. "But for a long time in Alzheimer's disease, we were unwilling to do that. People used to think, oh, Alzheimer's disease, that's just old and forgetful. But for many people, Alzheimer's disease is more devastating than cancer.
"I think from an IRB perspective, we need to really think about what level of risk we might be willing to tolerate and realize how devastating this disease is."
Reference
Sperling RA, Jack CR Jr., Aisen PS. Testing the Right Target and Right Drug at the Right Stage. Sci Transl Med. 2011 Nov 30; 3(111):111cm33.
In the fight against Alzheimer's disease dementia, researchers have long targeted beta-amyloid plaques, accumulated protein fragments in the brain that are a hallmark of the disease. The plaques are believed to contribute to the cognitive impairment associated with Alzheimer's disease.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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