AAs more than 7,500 clinicians and researchers gather in Philadelphia for the Alzheimer’s Association’s international conference, a deep divide is emerging over the new treatments for the disease that bring them together each year. That divide is over when to prescribe one of the new drugs to treat Alzheimer’s disease. Lecanemab (Leqembi) was approved by the U.S. Food and Drug Administration (FDA) in 2023 but received a negative recommendation last week from the European Medicines Agency’s Committee for Human Medicinal Products. Donanemab (Kisunla) was approved by the FDA in July.
Both of these factors have critical health and financial implications that will affect Alzheimer’s treatment, but can also affect the diagnosis patients receive, depending on where their neurologist stands.
At the heart of this divide is a pernicious brain protein called beta-amyloid. In Alzheimer’s disease, deposits of this protein, called plaques, disrupt brain function, affecting memory and cognition.
We are physicians who specialize in the research and treatment of Alzheimer’s disease. To better understand how our field views the new treatment landscape that has generated headlines, advances, and serious debate in just the last two years, we surveyed 268 neurologists from the United States and Europe on June 14, 2024, via an online platform in collaboration with Sermo, a physician social network.
The results reveal stark divergences: 59% of U.S. neurologists approve of amyloid-targeting therapies (like the two that have been approved), but 41% remain skeptical because of past failures and side effects. And only 5% of neurologists consider changes in biomarkers (such as imaging or blood tests that measure reduction in amyloid plaques) as a measure of clinical benefit.
More than 47 million Americans have silent amyloid accumulation, meaning they have high levels of amyloid plaques without memory loss or cognitive impairment. Neurologists call this preclinical Alzheimer’s disease.
With the advent of amyloid-clearing monoclonal antibodies like donanemab and lecanemab, and others in development, Alzheimer’s therapies are expected to become a $30 billion industry over the next decade, potentially ushering in a whole new way of thinking about and treating dementia.
Our survey of neurologists, however, reveals significant divisions within the medical community. These divisions are influenced by geography, different theories about Alzheimer’s disease, and concerns about serious side effects, such as brain hemorrhages, associated with these new drugs.
No matter where people live, they have an incredible chance of finding a neurologist willing to prescribe an amyloid-targeting treatment for preclinical Alzheimer’s disease—which would be an off-label use, meaning a use other than what the FDA has approved it for.
Our survey showed that just over half of neurologists in the United States and Europe are willing to diagnose Alzheimer’s disease based on blood biomarkers even before symptoms appear and to prescribe new drugs like Leqembi or Kisunla without needing FDA approval for this use. The other half remain skeptical, likely because of past failures of amyloid-targeting drugs in clinical trials or a reluctance to replace clinical assessments with biomarkers.
This division highlights the urgent need for robust evidence demonstrating the reliability of beta-amyloid biomarkers in the diagnosis and treatment of Alzheimer’s disease.
Place of residence affects the likelihood of finding a physician willing to prescribe anti-amyloid treatment. Although these anti-amyloid drugs are not commercially available in Europe, 83% of European neurologists consider these new treatments to be standard care, while only 59% of their American counterparts do so, reflecting strong regional contrasts in perception and probably practice.
Nearly half of U.S. neurologists remain skeptical, in part because they want to see stronger evidence that the drugs work. Notably, 95% of neurologists overall do not consider biomarker changes as a measure of clinical benefit—they value cognitive and functional benefits and reduction in hippocampal volume (a memory center in the brain) over plaque reduction. This skepticism is reflected in the slow adoption rate of anti-amyloid therapies in the United States. Of the several million Americans with early-onset Alzheimer’s who are potentially eligible for this therapy, we estimate from registries that only about 10,000 have been prescribed Leqembi since its FDA approval in July 2023 and Medicare coverage began.
In our survey, 71% of neurologists were particularly concerned about the risk of serious side effects such as brain swelling and microbleeds (called amyloid-related imaging abnormalities or ARIAs), further complicating the decision to prescribe these new treatments. Notably, 8% of U.S. neurologists believed the risks were so dangerous that they would never use these treatments. Twenty-eight percent were also very concerned about the greater loss of brain volume associated with amyloid-targeting antibodies.
This professional division directly influences patient care, where the choice of treatment can differ considerably depending on a physician’s position on new therapies.
Anyone who knows one of the 45 million people worldwide with Alzheimer’s disease would likely do anything to help stabilize their symptoms or slow their cognitive decline as the disease progresses. This ongoing debate over treatment underscores the need for conclusive research to validate biomarker findings and potentially work toward harmonizing treatment approaches to ensure consistent and effective patient care.
To improve patient care and unify the field of neurology, informed decisions must be based on comprehensive data. We urge companies that develop and market anti-amyloid therapies to fully disclose their clinical trial databases so that physicians and researchers can better understand the potential risks and benefits of these drugs.
For example, there is little evidence that reduction in amyloid plaques directly correlates with outcomes. Yet treatment guidelines for donanemab suggest stopping treatment once plaque levels normalize. Open access to these datasets would allow dementia specialists to confirm the validity of this biomarker-based treatment endpoint.
Drug companies and researchers funded by the National Institutes of Health may be reluctant to share their data for fear of misuse, but the benefits of transparency outweigh those concerns. Pervasive distrust of commercial motives, fueled by a divisive political climate, could be mitigated by greater openness. Although 60% of Americans believe prescription drugs have improved their lives, more than 80% believe drug companies prioritize profits over patients, underscoring the need for transparency to improve public perception.
Reducing inequities in Alzheimer’s treatment is critical to avoiding the inconsistent practices and care that prevent many eligible people from accessing potentially life-changing medicines. By making more clinical trial data available, pharmaceutical companies can help rebuild public trust and enable healthcare providers to fill knowledge gaps that lead to disparities in treatment recommendations.
The European Medicines Agency refused to approve Leqembi because the small clinical effects seen with the drug were “not large enough to outweigh the risks” of brain swelling and bleeding severe enough in some patients to require hospitalization.
We – and many of our colleagues – will wait and see whether the strong enthusiasm of European neurologists, as expressed in this survey, will be enough to reverse the position of the European Medicines Agency, or whether more results and safety data, as we are requesting, will be needed.
Murali Doraiswamy, MD, is professor of psychiatry and geriatrics at Duke University School of Medicine and a member of the Duke Institute for Brain Sciences. Lon S. Schneider, MD, is professor of psychiatry, neurology and gerontology at the University of Southern California and the Della Martin Chair in psychiatry and neuroscience at USC. The authors thank Sermo for funding the international survey of neurologists. Both authors have served as advisors to government agencies, pharmaceutical companies, and advocacy groups in this field; but this survey was not funded by any company.