What’s Next for Alzheimer’s Disease: Clinical Trials Show the Promise of Intervening Early

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Researchers at the Brigham are developing and advancing treatment options for Alzheimer’s disease by intervening early to prevent the symptoms of the disease, taking aim at new targets, and building on the legacy of the Department of Neurology’s top researchers. This story is part of a series on what’s next in Alzheimer’s disease research.

According to the Alzheimer’s Association, 6.7 million Americans are living with Alzheimer’s disease. Researchers at the Brigham are working on multiple studies to test new treatment options for patients—both those who have symptoms and those who are currently symptom free but may be at risk.

In July of 2023, the Food and Drug Administration approved the anti-amyloid medication lecanemab for the treatment of early Alzheimer’s disease, a major milestone for patients, researchers and clinicians. In the same month, results from a Phase 3 clinical trial of donanemab were presented, demonstrating that this second anti-amyloid medication decreased rates of cognitive decline in participants with early symptomatic Alzheimer’s disease. Together, these successes reflect a new chapter for Alzheimer’s disease treatments and open the door for new kinds of research to make meaningful treatment options available for patients. Investigators at the Brigham are at the forefront of research in this area. In new and ongoing trials, researchers are testing whether intervening even before symptoms begin can slow disease progress or prevent the symptoms of Alzheimer’s disease from ever occurring.

“It’s really exciting to think about different ways that promising drugs are acting in the brain and the potential for using them together to alter the processes that lead to symptoms of Alzheimer’s disease,” said Seth Gale, MD, a neurologist at the Brigham.

Building on the Bedrock of Biological Research

The plan to target amyloid would not be possible if it weren’t for the decades of work by researchers like Dennis Selkoe, MD, a neurologist at Brigham and Women’s Hospital. Selkoe hypothesized in the early 1990s that amyloid buildup is a key factor in Alzheimer’s disease. In 1991 he published an article titled “Molecular Pathology of Alzheimer’s disease” in Neuron. The next year, a colleague in London published a similar study. Both papers stated amyloid was behind the events that lead to Alzheimer’s disease.

“One of the most striking discoveries I’ve made with my colleagues is that the amyloid protein is made throughout life by everyone,” Selkoe said. “If you have certain factors that allow excess buildup of the amyloid beta protein in late years, you are on the road to Alzheimer’s.”

In 1999, Selkoe’s team discovered the gene that makes the amyloid beta protein is presenilin, and that mutations in this gene cause early-onset, familial forms of Alzheimer’s. This work explained how mutations that cause Alzheimer’s operate to increase lifelong production of amyloid beta protein.

Now, Selkoe’s colleagues, including Reisa Sperling, MD, are leading clinical trials of therapies that target amyloid beta. He is thrilled to witness the translation of biological discoveries into potential preventive treatment.

“Reisa stands out as arguably the world leader in translating that fundamental biology and designing trials for the prevention of Alzheimer’s,” Selkoe said.

Staying AHEAD of Symptoms

Research suggests as many as 20 years before the symptoms of Alzheimer’s disease begin, detectable changes, such as amyloid buildup, are happening in the brain. Intervening more than a decade before symptoms occur could prevent the further buildup of amyloid plaques and subsequent memory problems.

One promising trial in which the Brigham is taking a leadership role is the AHEAD study, an international trial in which people at risk for memory problems are treated with the antibody medication lecanemab before symptoms of Alzheimer’s disease begin. Lecanemab, which was recently approved by the FDA for patients who already have symptoms of mild cognitive impairment, works by clearing away the beta-amyloid that builds up in the brain, slowing the rate of cognitive and functional decline. The AHEAD 3-45 Study has two sister trials, with an “A3” trial that is enrolling people with intermediate levels of amyloid as young as age 55. The Brigham is one of 75 AHEAD trial sites in North America, and 100 sites worldwide.

The study, which is funded by the National Institutes of Health (NIH) in partnership with the pharmaceutical company Eisai, is led by internationally recognized Alzheimer’s disease research experts. Sperling is one of the researchers who designed the AHEAD Study and serves as the global lead investigator.

“Lecanemab is approved for ‘early AD’, but mild cognitive impairment and mild dementia is not early in my world,” Sperling said. “We have treatments we can give to people at relatively mild stages of symptoms, which is a tremendous breakthrough, but we know the disease process has already been going on for at least a decade by the time people have those mild symptoms.”

Participants in the AHEAD study have visits either every two weeks or once a month for the first two years after enrollment. All have visits once a month thereafter for a total of about 4 years. Those visits are a part of the process by which people receive infusions of the medication and are monitored for side effects, including infrequent cases of inflammation in the brain that can occur with amyloid-clearing antibodies.

Gale, who is site principal investigator at the Brigham for the AHEAD study, said that in prior studies with lecanemab, about 3% of cases of inflammation cause symptoms, with the vast majority being mild and resolving over time or with stopping the medication if needed. Patients who had these side effects were also typically farther along in the disease process than those in the AHEAD study, and thus researchers suspect they may see even fewer cases of inflammation-related symptoms than they did before. MRIs are completed regularly in all patients taking anti-amyloid medications as additional measures of screening and safety.

“Overall, the goals of the AHEAD Study are to help determine if intervening when memory is still normal can prevent or slow the onset of symptoms,” Gale said, “and to see if giving a medication early can improve the underlying biology of the disease. We hope to enroll individuals around the world, from many populations, races, ethnicities, and with various sociodemographic factors, to help answer these questions.”

Early Detection, Early Intervention

The AHEAD study and the approval of lecanemab come on the coattails of results of a prior trial related to AHEAD which was called the A4 Study. Collectively, these studies are known as “prevention trials.”

In March, results from the A4 Study were released. While the medication tested in that trial, solanezumab, did not slow memory loss, the trial’s design brought to light new ways of identifying patients years before symptoms appeared. It also suggested researchers needed to be more aggressive with reduction of amyloid—something lecanemab has been shown to do in all studies so far.

Building on research conducted at Mass General Brigham in the Harvard Aging Brain Study, the A4 trial demonstrated that clinically normal individuals showed evidence of subtle abnormalities in brain function. Sperling and her colleagues, Dorene Rentz, PsyD, of Mass General, and Kathryn Papp, PhD, of BWH, created a new test for memory of names and faces to detect very early memory changes. A4 also showed that PET scans can detect the other hallmark pathology of Alzheimer’s disease, tau tangles, using a brain imaging technology called Tau-PET, largely based on work by Keith Johnson, MD, of MGH, in the Harvard Aging Brain Study.

Researchers have also developed pen and paper tests and smartphone-based tests that can detect early stages of cognitive decline and are exploring brain imaging, blood tests, and spinal fluid tests to try and identify a potential buildup of amyloid long before symptoms start.

Sperling wants to focus next on an “A2” trial. Her idea is to enroll people who are not yet amyloid positive on a PET scan but have very early changes detectable on a blood test. Participants would then receive an anti-amyloid antibody or active amyloid vaccine to prevent amyloid from accumulating before there is substantial buildup.

While A2 is still in the very early planning stages, the foundation is being laid through the APEX study. APEX is enrolling patients who were screened for the AHEAD study but were not enrolled based on different factors. Researchers will follow patients’ blood tests in the APEX study every year over time to detect these very early brain changes and use the results to measure outcomes in the A2 trial. Researchers believe this timeline of changes in the blood tests could help them predict who will become amyloid positive and thus have significant risk for Alzheimer’s disease on future PET scans.

“Our goal is to not only bend the curve of decline for individuals but to help stave off the public health emergency of Alzheimer’s disease,” Sperling said.