Twenty-three years ago, Helene DeCoste's mother died of Alzheimer's disease, and three years ago, her older sister was diagnosed with the disease at age 70. Today, DeCoste, a 67-year-old retired teacher, is enrolled in her first-ever clinical trial—the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease, or A4 study—in the hope that it will help in the fight against Alzheimer's disease.

DeCoste first heard about the A4 study on the radio while driving back from her sister's house after a long day cleaning up the accumulated clutter that her sister had been unable to clear out. "I walked in and there were just stacks and stacks of unopened mail on her counters, and when I opened the closet in her room I found 10 more big garbage bags full of mail." As her sister's symptoms worsened, the family decided to move her to an in-patient senior center.

DeCoste decided then, just six months after turning 65, to make an appointment with A4 researchers at a test center in Boston. Three months later, she was given her first intravenous infusion; she did not know whether she had received a sham drug or solanezumab, an antibody being investigated by the pharmaceutical company Eli Lilly as a potential therapy for Alzheimer's disease. Now, she's an enthusiastic advocate for participating in clinical trials. "I really want to encourage others to participate. This is a unique opportunity to help ourselves and future generations," she says. "In the past I never even considered being part of a clinical trial, but I'm really happy that I have. I'm just a little cog in the wheel, but the more people who join, the better the chance that we might one day beat this terrible disease."

Preventative Treatment 

Solanezumab binds to amyloid-beta, a peptide of 36 to 43 amino acids that is derived from a larger protein known as amyloid precursor protein (APP). Clumps of the amyloid-beta peptide form the plaque in the brains of those with Alzheimer's disease. Solanezumab was first tested in a phase 3 trial completed in 2014 in people with mild to moderate disease and found to be safe and well-tolerated. However, it failed to produce any clinical benefit: There was no difference between treated and untreated patients on standard memory and cognition tests, nor was there less accumulation of amyloid in the brain after positron emission tomography (PET) scans.

When investigators looked more closely at the data, however, they found that the drug appeared to slow cognitive decline by as much as 34 percent in participants who had only mild symptomatic Alzheimer's disease. This led them to consider the possibility that treating individuals early in the course of the illness might be more successful, much like blood-thinning statins are used to prevent cardiovascular disease.

This thinking resulted in the A4 study, which is testing solanezumab in people between the ages of 65 and 85 who have no memory loss or cognitive problems. It is estimated that up to one in three cognitively normal people over the age of 65 have some amyloid plaques in their brains, so being able to slow or halt additional buildup could be beneficial in reducing the anticipated surge in symptomatic Alzheimer's disease as the population ages.

"If the drug can work 10 years before any symptoms appear, it could help many at-risk people. This is why it is so important for healthy seniors to volunteer," says research leader Reisa Sperling, MD, professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital, in Boston.

Study Parameters 

Participants who want to join the A4 trial initially undergo brain imaging to scan for current levels of the amyloid-beta protein. Only those who have elevated levels are eligible. After their amyloid imaging results are disclosed to them, those who are eligible and agree to enroll in the A4 study are divided into two groups of 500 volunteers each: one group is given the active drug intravenously and the other group is given an inactive placebo. No one in either group is aware of what treatment (active or inactive) he or she is getting. Participants receive an infusion of the antibody once a month for 80 weeks. They must also visit the A4 site for cognitive assessments. The aim of the study is to demonstrate that those on active treatment maintain cognitive status better than those on placebo. At the end of the 80 weeks, all participants (including those who had been on placebo) can continue in the study on solanezumab (the active drug) for another 104 weeks.

More Volunteers Needed

Thus far, approximately half of the 1,000 volunteers needed have enrolled, says Dr. Sperling. Some have joined because they are concerned about their memory and others simply because they want to help.

"Participation is not terribly cumbersome or time-consuming," Dr. Sperling says. Volunteers can enroll at one of 56 research sites across the country, or in Canada or Australia. And solanezumab has repeatedly demonstrated a good safety profile overall, she emphasizes. To date, a small number of patients reported mild side effects such as lethargy, a rash, dizziness, and chest pressure, she says.

DeCoste, who was one of the first volunteers at the Boston site, has had only positive experiences. "Everyone I've met, both other volunteers and those working at the trial site, are wonderful," she says. "When I go to the site it always feels like I'm coming home. I can't find anything negative to say—it's a very social group."

"We will need to see if our data are sufficient for the agency [US Food and Drug Administration] to approve additional trials, so it is very important that patients come forward to participate in the research, especially those with normal cognition," Dr. Sperling says.

Future Studies

Another trial, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study, is a companion to the A4 trial, thanks to an $8 million research grant from the Alzheimer's Association—the largest ever awarded by the group. The four-year study will follow 500 participants who screened for the A4 study but did not have elevated levels of amyloid-beta; participants will undergo the same cognitive and clinical testing as those in the A4 study. The goal is to identify other brain changes that may cause cognitive decline, such as increased levels of tau protein, another hallmark of Alzheimer's disease that forms microscopic clumps in the brains of affected people.

The A4 trial should be completed by 2019, after which Dr. Sperling hopes to conduct another study, A5, with people between the ages of 60 and 85 who have elevated amyloid-beta demonstrated by PET scans but are still cognitively normal. Those participants will be given oral doses of a beta-secretase (BACE) inhibitor drug that decreases the generation of amyloid-beta protein from APP. Other prevention trials are being planned.

"It's possible that if we can successfully reduce accumulation of amyloid-beta or tau, it could revolutionize early detection and prevention," says Dr. Sperling. The hope is that these trials will add to the current understanding of how early amyloid-beta and tau start to accumulate, how this might be delayed or prevented, and how to identify people, who have no memory problems, for early screening, she says.

"Much of our work and that of other groups is being supported collectively by funds from the government [the National Institute on Aging is a sponsor], private philanthropic organizations, and major pharmaceutical companies collaborating together. The old competitive model [of drug company] funding has not helped anyone, so this is a major change," she says, adding that all data from these studies will be available online for other research teams.

Positive Prognosis 

Researchers involved in the trial at other sites are equally optimistic. At the Mayo Clinic, for example, 400 individuals have already been screened. "Some of our participants have been involved for two years, and side effects have been minimal, so I would say things are going really well," says David S. Knopman, MD, FAAN, professor of neurology at the Mayo Clinic in Rochester, MN, who served on the data safety monitoring board for the phase 3 solanezumab trials in people with mild to moderate Alzheimer's disease.

Depending on the results, the studies "could provide a huge benefit for millions of individuals. This field has never had any therapeutic breakthroughs." Positive findings would also confirm the theory that amyloid-beta accumulates and brain changes occur long before any cognitive symptoms appear, he says.

Jeffrey Cummings, MD, FAAN, professor of neurology and chair of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, NV, another site for the trial, agrees. "Amyloid-beta accumulates very quickly in the brain, and if the new study works, we may be able to interrupt it in patients without cognitive signs of the disease," he says.

Many Alzheimer's disease researchers are watching the trials with interest, including Douglas Scharre, MD, a professor of clinical neurology and psychiatry and director of the Center for Cognitive and Memory Disorders at Ohio State University Wexner Medical Center, in Columbus.

If the new trial in asymptomatic people is successful, it might yield important information about the disease, says Dr. Scharre, who was involved in earlier studies of solanezumab in patients with symptomatic disease but is not part of the A4 study group.

"The A4 trial involves older individuals without memory or cognitive problems, so it is likely researchers will be able to measure significant biomarker [indicator of a disease in blood, other body fluids, or tissue] progression. If so, they might be able to predict when a patient may progress from asymptomatic stages to mild cognitive impairment or Alzheimer's disease dementia."

Because the study is assessing changes in cognitive tests, he added, it may also help determine if change over time in a "cognitive biomarker" by itself could be used to identify individuals at risk for pre-symptomatic Alzheimer's disease. "And if any significant alterations in the rate of change in these biomarkers are observed in the group receiving the drug," he says, "that would provide some evidence that these specific treatments may work."

For more information, including site locations and a video by current A4 participants, visit a4study.org or call 844-247-8839. The National Institute on Aging also has information at nia.nih.gov.

Protein Problem

Tau and amyloid-beta are two proteins implicated in Alzheimer's disease. Here's how they affect the brain and contribute to cell dysfunction and death.

Alzheimer's disease occurs in the brain when two normal brain proteins—amyloid-beta and tau—lose their usual structure and become misfolded. The brain's apparent inability to deal with this misfolding results in the loss of brain cells and the consequent loss of function of those cells. The most vulnerable cells are those responsible for memory and thinking abilities, which gradually but relentlessly decline.

The amyloid-beta protein is normally in a solution in the brain. Under abnormal conditions, the protein sticks together in misfolded forms, which are deposited in the brain tissue as amyloid or senile plaques. The presence of these plaques sets off a cascade of responses that result in cell dysfunction and death.

The tau protein helps maintain the normal structure of brain cells. In Alzheimer's disease, the protein becomes misfolded into twisted fibers inside brain cells called neurofibrillary tangles, which interfere with normal cell structure and function and also lead to cell death.

Experts continue to investigate whether amyloid-beta and tau work together or independently to cause the devastating symptoms of the disease.