Anyone who has witnessed the physical, emotional, and mental toll Alzheimer’s exacts on its victims and their caretakers will surely applaud last week’s decision by the FDA to approve a new drug whose makers say will slow the cognitive decline of patients in the early stages of the disease. It’s this sense of desperation that allows folks to overlook sketchy evidence of the drug’s efficacy, its documented side effects, and its exorbitant cost.
The decision, which came after 10 of the 11 members of the agency’s independent advisory committee voted against approval, will make Aduhelm available to eligible patients contingent on its manufacturer, Biogen, agreeing to conduct further trials. But, as advisory committee member G. Caleb Alexander, MD, tells the New York Times, it’s now too late to thoroughly evaluate the drug’s benefits and liabilities.
“Once the product is approved, the cat’s out of the bag, the horse is out of the barn,” says Alexander, an internist and epidemiologist at Johns Hopkins Bloomberg School of Medicine. “There’s no way to recover the opportunity to understand whether or not the product really works in the post-approval setting.”
Three advisory committee members — Joel Perlmutter, MD, of Washington University; David Knopman, MD, of the Mayo Clinic; and Aaron Kesselheim, MD, of Harvard University — resigned as a result of the decision. In a letter to FDA Commissioner Janet Woodcock, Kesselheim called the move “probably the worst drug approval decision in recent U.S. history.”
Critics and supporters agree that the drug reduces amyloid plaque in the brain, considered a biomarker of Alzheimer’s, but decades of earlier research have demonstrated that amyloid reduction does not necessarily ease the symptoms of the illness. And two of Biogen’s Phase 3 trials revealed contradictory results: one reporting a slight slowing of cognitive decline; the other showing no benefit. Meanwhile, the drug’s side effects — brain swelling and bleeding among 40 percent of those taking high doses — raised some understandable fears.
“There’s so little evidence for effectiveness,” notes Lon Schneider, MD, director of the California Alzheimer’s Disease Center at the University of Southern California. “I don’t know what caught the FDA’s fancy here.”
Still, the controversy surrounding the FDA’s decision is unlikely to dampen consumer enthusiasm over the first new Alzheimer’s drug in nearly two decades.
“I had this conversation with a real patient who was very interested in it,” says Knopman. “I presented the data to the patient and her husband, and they didn’t hear a word I said about my concerns. All they heard was there might be a benefit.”
Though I am reflexively skeptical of pharmaceutical promises, I hope the FDA’s confidence in Aduhelm proves to be warranted. Years ago, I watched helplessly as my father-in-law descended into dementia, losing first his short-term memory, then becoming unable to retrieve the war stories that so riveted his grandkids, and ultimately finding himself unable to communicate at all. He was at least able to get a diagnosis, which too often evades people from BIPOC communities. And this disparity, some experts predict, will only be exacerbated with the introduction of Biogen’s newest product.
As Usha Lee McFarling writes in STAT, Black people are twice as likely and Latinx people 1.5 times as likely as white people to develop dementia. But physicians are far less likely to diagnose them with the disease, blocking their timely access to the specialists needed to treat the condition.
“The emergence of any new drug could really widen healthcare disparities that already exist,” Allan Levey, MD, a neurology professor at Emory University School of Medicine, tells McFarling. “COVID provided examples of exactly the same issues we could face here — disparities in detection, testing, and treatment.”
In March, the Alzheimer’s Association released a report noting that 66 percent of Black Americans believed racial barriers prevented them from accessing appropriate treatment for the disease, a view shared by about 40 percent of Latinx and Native Americans. For Daisy Duarte and her mother, Sonia Cardona, those barriers were very real.
Cardona began to display short-term memory loss in her 50s, and despite worsening symptoms and a family history of dementia, five years passed before she was diagnosed. “They kept telling her she was depressed, depressed, depressed,” Duarte recalls.
After a stint in a mental hospital during which the retired teacher’s aide lost the ability to speak English, Cardona was told she was suffering from a terminal illness: Creutzfeldt-Jakob disease (CJD). “The doctor just said it was a rare disease and no one lives more than nine months,” says Duarte. “He didn’t give me any more information, not a pamphlet, nothing. He told me to Google it.”
Diagnostic disparities are not just a product of unsympathetic physicians. Clinical trials for potential Alzheimer’s drugs are notoriously tilted toward white patients. Fewer than 10 percent of the participants in Biogen’s Aduhelm trials, for instance, were Black, Latinx, or Native American. And, as John Morris, MD, puts it, “If we only study white people, we’re only going to learn about Alzheimer’s in white people.”
Recent research by Morris, director of the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University, suggests that Alzheimer’s biomarkers may differ by race. Tau may accumulate more slowly in the brains of Black people, for instance, delaying a timely diagnosis.
Those findings have sparked some controversy, primarily because drug manufacturers have recruited so few BIPOC volunteers for their Alzheimer’s trials. “We don’t know these differences exist and the reason we don’t know is we have an inequitable system,” says Columbia University neurology professor Jennifer Manly, PhD, who studies Alzheimer’s predictors in Black and Latinx communities.
Three months after her CJD diagnosis, Cardona and Duarte traveled from their home in Chicago to St. Louis to see a neurologist at Washington University. He told them Cardona did not have the terminal disease, but her MRI clearly showed indications of Alzheimer’s. She had inherited a gene mutation (PSEN1) that predicts with some certainty the development of the disease.
None of this surprised Duarte. “Seventy-five percent of my mom’s family has it,” she says. “I took care of my uncle that had it. We would visit my grandmother in Puerto Rico who had it.”
Unlike her mom and others in her family who descended into dementia with few treatment options, Duarte, 45, was offered the chance to participate in a clinical trial of a plaque-reducing drug developed by Roche. She agreed immediately.
Genetic tests confirmed that she also carries the gene mutation, and she now gets an infusion of the drug every 28 days — at no cost to her. It gives her hope that she’ll avoid the fate of her mom, who succumbed to Alzheimer’s in January at the age of 65.
Meanwhile, drug manufacturers need to do a better job recruiting Latinx volunteers, Duarte argues. “If more Spanish people were in clinical trials, I think I would have been reached, I think my mom would’ve been reached,” she says. “I never knew there were clinical trials. I never knew anything.”