Lecanemab (Leqembi), a new Alzheimer’s drug, received accelerated approval from the FDA this year. However, experts express concern over its efficacy as well as the fact that most patients may not even be eligible for it.
MDs also wonder if the “amyloid hypothesis,” upon which the drug and others like it is based, is entirely accurate.
More than 55 million people worldwide live with dementia, with Alzheimer’s disease making up 60-70% of those cases—causing cognitive decline and eventual brain changes that affect physical function. The many challenges of Alzheimer’s can cause grief trauma, and be overwhelming for both patients and their caregivers, underscoring the urgent need for effective, accessible treatment.
Both efficacy and accessibility are under question regarding recent Alzheimer’s treatments, like Lecanemab—which secured accelerated approval from the The Food and Drug Administration (FDA) earlier this year and traditional approval in July.
Lecanemab (Leqembi) is an antibody intravenous (IV) infusion drug that targets and lowers beta-amyloid from the brain in patients with early Alzheimer's disease, mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease, or patients with elevated beta-amyloid in the brain.
A new article in JAMA explores how the drug became the first ever anti–amyloid-β monoclonal antibody (mAbs) ever to get traditional approval (and Medicare coverage) from the FDA. As the author writes, that regulatory pathway is “reserved for drugs to treat serious conditions for which there is an unmet medical need. Such drugs must affect a surrogate endpoint—in this case, brain amyloid levels—that is ‘reasonably likely’ to benefit patients clinically.” 
Medicare will pay for anti–amyloid-β mAbs, but for drugs like these—which receive accelerated approval—costs will only be covered for beneficiaries in randomized trials. In traditional approval circumstances, however, Medicare will pay for the treatment (sans clinical trial) if a clinician sends their patient’s information to a data registry.
Lecanemab comes with a hefty monetary and logistical price tag. It costs an estimated $26,500, requires regular infusions and multiple MRIs, and poses health threats. One study found that only 8% of 237 patients were even eligible for it based on trial inclusion criteria, for example. More so, its efficacy is uncertain.
In a phase 3 trial for Lecanemab, progression was delayed at 18 months by about five months. The study authors summarized, “In persons with early Alzheimer’s disease, Lecanemab reduced brain amyloid levels and was associated with moderately less decline on clinical measures of cognition and function than placebo at 18 months but was associated with adverse events. Longer trials are warranted to determine the efficacy and safety of Lecanemab in early Alzheimer’s disease.”
In contrast, Dr. Merrill refers to Donepezil, which is designed to treat symptoms of Alzheimer's disease. “Donepezil [offers] symptomatic improvement and less worsening. And it’s a once-a-day pill. It might cause a laxative effect or a slow heart rate, but you don’t need serial brain scans and infusions, and it doesn’t cost thousands,” he says. “So, unfortunately, these new drugs have caused confusions in patients, family members, healthcare workers, and even thought leaders.”
Other recent Alzheimer’s drugs have also been questioned, like aducanumab, which was given accelerated approval in 2021. In fact, David Knopman, MD, a neurologist on the FDA advisory committee for aducanumab, resigned when it was approved—calling the process a “sham” and citing a lack of evidence that the drug even works.
David Merrill, MD, PhD, geriatric psychiatrist and director of the Pacific Neuroscience Institute’s Pacific Brain Health Center in Santa Monica, CA, says he understands the uproar regarding these types of drugs.
“It’s easier to gain approval now. In years and decades past, benefits would outweigh risk or harm. But we saw with these drugs that that’s not the case, and [advisory] members were resigning in protest. The primary trials failed primary endpoints…There’s less worsening [of the disease] to a statistical but not clinical significance.” Dr. Merrill also says that, for now, his clinic isn’t set up to offer Lecanemab.
Heather Sandison, ND, a neurocognitive medicine expert, says there are real (though rare) risks associated with drugs like mAbs—like bleeding or brain swelling. More so, she says, “Although women are two-thirds of Alzheimer's patients, these medications work less well on women than men.”
The JAMA article also says some experts question what’s referred to as the popular ‘amyloid hypothesis.’ Sandison explains, “The amyloid hypothesis has postulated that misfolded proteins cause the decline in memory and cognition Alzheimer's patients experience.” 
However, she adds, amyloids may not tell the whole story: “Many scientists now agree that inflammation, infections, toxins, sleep deprivation, and many other factors may trigger the misfolding of proteins in the brain's attempt to protect itself. If that is the case, going after amyloid plaques is attacking the symptom rather than the cause and is unlikely to lead to an improvement in cognition,” Sandison says.
Dr. Merrill echoes her sentiments. “There’s an idea that amyloid is created in the brain due to health stressors, like vascular disease, diabetes, or toxins, and that it’s produced by the body and might actually be providing a service. The amyloid might even be part of the body’s response to resolve an issue. So removing the body’s response to a health stressor might be akin to removing a bandaid,” he says. He thinks identifying the amyloid as the enemy simply may be naive: “The biology of the brain is not that simple.”
Dr. Merrill says treating patients with Alzheimer’s requires a team approach. “Neurologists may need the help of general medical or specialist medical providers (like endocrinologists, cardiologists, and toxicologists),” he says, citing the fact that multiple risk factors play into Alzheimer’s, including things like smoking, pollution, exercise, and nutrition.
In the end, Dr. Merrill says desperation is driving the market. “Patients and families are desperate. They’re desperate for hope. The field has invested decades of time and money in testing the amyloid hypothesis, and that’s enough to justify giving the option of offering this to patients…But it’s controversial, certainly,” he says.
“I expect real hope will come for families affected by Alzheimer's when these mAb medications are used with other lifestyle modifications, precision based medicine, and prevention strategies aimed at reducing or eliminating known risk factors for dementia and Alzheimer's,” Sandison says.