A large clinical trial aimed at screening and early treatment for Alzheimer’s disease holds the potential to be groundbreaking—if enough volunteers can be recruited to get it off the ground. By September, organizers want to begin screening thousands of potential candidates aged 65 and older at dozens of participating sites across the United States, Canada, and Australia.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (“A4” for short), is led by a 2010-13 BrightFocus grantee Reisa Sperling, MD, a neurology professor at Harvard Medical School. A4 is the first clinical trial aimed at preventing memory loss by identifying and treating beta amyloid plaque buildup before subjects are “symptomatic,” meaning before they begin to lose cognitive function.
Support for the trial comes from the National Institute on Aging (NIA) and Ely Lilly & Co., whose drug, solanezumab, is being investigated to see if it can prevent Alzheimer’s symptoms by “flushing out” excess beta amyloid protein in the brain before it causes irreversible damage. Plaque, or clumps of beta amyloid found in the fatty membrane surrounding nerve cells, tend to build up in the brain as people age and can be associated with Alzheimer’s disease, although not in all cases.
Solanezumab, the drug being studied, is an investigational (ie, not yet approved) monoclonal antibody developed specifically as a “neuroprotector” to fight Alzheimer’s disease. Monoclonal antibodies are derived from live immune cells that have been bioengineered to bond to specific substances in the body. The generic drug names for monoclonal antibodies always end in “mab.” Solanezumab was designed to bind to beta amyloid protein that forms plaque.
Results from two earlier trials with solanezumab, Expedition 1 and Expedition 2, were disappointing. It showed minimal effect in their overall study groups, consisting of patients with mild to moderate Alzheimer’s symptoms. However, results were more encouraging in subgroups of patients with only mild Alzheimer’s-related dementia. This led to the A4 trial design, with a narrower focus on patients with evidence of early plaque and no other Alzheimer’s symptoms.
An estimated one in three individuals over age 65 has plaque build-up, but postmortem studies have shown that only about two-thirds of individuals with plaque buildup exhibit Alzheimer’s symptoms. Understanding what causes plaque to become “neurotoxic” in the remaining two-thirds of individuals is a major conundrum in the field. There is near unanimity around the idea that treatment to forestall such change must begin early, in “pre-symptomatic stages, before neurons begin dying and cognitive function is lost.
To Participate, Several Screening Tests Required
At least 1,000 subjects are called for in A4’s trial design. To qualify, volunteers aged 65 to 85 will be imaged for beta amyloid plaque as well as tested for normal health and cognitive function. They’ll also receive screening to ensure they’re psychologically prepared to receive the news that they have amyloid buildup.
Once the trial begins, half the 1,000 or more enrollees will receive a placebo and half will receive a daily dose of solanezumab over a period of 39 months. Then, if solanezumab is shown to be effective, all participants will be given the choice to be treated with the drug at the end of the trial.
Only an estimated one third of screened volunteers are expected to qualify, which is why recruiting large numbers of volunteers is so important. So far, only 500 people have expressed interest nationally and 50 are in the screening process, according to the Washington Post—and that’s fewer than 1/60th of the volunteers needed. Many people do not want to know if that have—or are likely to get—Alzheimer’s disease. Facing up to that diagnosis can require a great deal of courage at a time of life when most people are already coping with limitations and changes to their health, independence, lifestyle, and other things they once took for granted. Even with very limited treatment options available to treat Alzheimer’s, however, most experts agree that patients who fare best are those who have their disease diagnosed early.
Another recruiting challenge is that unlike many trials, this one is looking to recruit at least one-fifth or more of its participants from underrepresented groups such as African Americans and Latinos, who typically make up only five percent of clinical trials. Not only are such groups understudied, but also generally undertreated. Churches and universities with large minority populations are being asked to help spread the word.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study, described below, is being led by 2010-13 BrightFocus grantee Reisa Sperling, MD, a neurologist who directs the Center for Alzheimer's Research and Treatment at Harvard’s Brigham and Women’s Hospital, Boston, MA. Her BrightFocus project complements this large-scale clinical trial by attempting to detect very early cognition changes associated with beta amyloid buildup in the brain. To demonstrate that, Dr. Sperling has conducted brain “stress testing” in humans by administering a very low dose of medicine that causes short-term memory problems and confusion, then used neuroimaging techniques to examine the same individuals’ brain function while having them participate in tests of memory formation. The hypothesis is that older individuals with beta amyloid plaques identified through brain imaging will be more vulnerable to the effects of the stress test on memory performance and brain activity. While awaiting final results, so far this “cholinergic vulnerability” hypothesis (referring to the brain’s ability to send messages using a biochemical, acetylcholine, which acts as a neurotransmitter) appears to be borne out.
This content was last updated on: Tuesday, June 30, 2015
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