In 1906, a German pathologist of no renown autopsied the brain of a woman in her fifties who had been exhibiting behaviors more typical of the elderly: she was disoriented, hallucinatory, aphasic, and, in other ways, had lost the ability to form or retrieve memories. What he found, using a stain that had recently become available, were clumps of plaques stuck to the outside of her neurons and a welter of tangles strangling them from the inside. Four years later, that pathology became the accepted diagnostic signature of a disease that now bears that doctor’s name. It is estimated that six million people in the United States, and thirty-five million people worldwide, currently suffer from Alzheimer’s disease. That number is expected to rise significantly, with a new case of dementia occurring every minute, because, in the nearly hundred and twenty years since Alois Alzheimer’s finding, no one has figured out how to slow the progression of the disease, let alone prevent it or reverse its damage.
In September, the Japanese pharmaceutical company Eisai announced that a monoclonal antibody it had been developing for nearly two decades appeared to give people with early manifestations of the disease around three more years in that liminal state, compared with those who had been given a placebo. This was a projection based on a clinical trial with nearly nine hundred participants; after eighteen months, those receiving treatment exhibited a twenty-seven per cent slower rate of cognitive decline. Although that is both a small effect and a notional number—some people did better, while others did worse—perhaps more important, trial participants receiving the antibody scored better on self-reported measures of quality of life, as did their caregivers. Eisai’s Chairman and C.E.O. of its U.S. division, Ivan Cheung, was quick to point out that the antibody, known as lecanemab, was “not a cure,” but the trial results were heralded as a significant breakthrough. “I finally have something I may be able to offer to patients,” Dr. Scott Small, the director of the Alzheimer’s Disease Research Center at Columbia University, told me.
The plaques that Alzheimer observed in 1906 were made of a protein called amyloid-beta precursor that begins innocently enough, hanging out inside neurons. For reasons that are still being studied, some of that protein begins to break into fragments that then stick together and form the plaques that colonize an Alzheimer’s brain. The tangles are made from a different protein called tau, and there is a chicken-and-egg debate among researchers whether tau tangles are caused by amyloid clumping or an independent pathology, but research has shown that people who develop amyloid plaques are much more likely to develop tau tangles as well. The presence of amyloid clusters in an Alzheimer’s brain has led to an assumption that, in its broadest strokes, is known as the amyloid hypothesis: if Alzheimer’s brains are full of amyloid, and the amyloid is killing neurons, then it stands to reason that amyloid plaques cause Alzheimer’s disease.
The amyloid hypothesis has driven a great deal of Alzheimer’s drug development throughout the past few decades, with scientists looking for compounds that attack and vanquish the amyloid plaques or stop them from forming in the first place. But the results of that research have been underwhelming. It turned out that not everyone who develops amyloid plaques in their brains is cognitively impaired, and, prior to last fall, around two hundred other anti-amyloid clinical trials were a bust. Even the compounds that cleared amyloid did not affect cognition. Jason Karlawish, a professor of medicine at the University of Pennsylvania and the co-director of the Penn Memory Center, told me, “I can find reasonable scientists who make the argument that this disease is driven by amyloid. I can find reasonable scientists who will make the argument that amyloid is perhaps a back-seat actor. And I can find scientists who sort of occupy a middle position and say [that] it has a role, but it is not determinative of the disease process.”
Eisai’s trial results came at an especially fraught moment in the debate over the validity of the amyloid hypothesis. A few months earlier, it was discovered that a key paper advancing the hypothesis, published in Nature, in 2006, contained images that were doctored and data that was fudged. (An article in Science described it as looking “like key parts of the experimental evidence in these papers is nothing more than cut-and-paste jobs assembled to show the desired result.”) That data and those images were then used by other unsuspecting scientists as they sought and failed to counteract agents of the disease. “You can cheat to get a paper. You can cheat to get a degree. You can cheat to get a grant. You can’t cheat to cure a disease,” Matthew Schrag, the Vanderbilt neuroscientist who discovered the deceit, said at the time. “Biology doesn’t care.” By some accounts, that deception set the field back by decades, but later assessments were more circumspect, because the research in question addressed only one kind of amyloid—there are many—and not the most likely amyloid target.
Still, it was a discouraging mess that occurred nearly in tandem with another. In March 2019, the pharmaceutical company Biogen announced that trials of its much awaited anti-amyloid antibody—another tongue-twisting compound called aducanumab—had failed to show any cognitive benefit despite clearing amyloid plaques. Then, upon further data analysis, the company reversed that finding, claiming that it had observed a slight statistical effect in one of its two trials. The company submitted the treatment, which would cost fifty-six thousand dollars a year, for F.D.A. approval. One stock analyst, looking at the results of the Biogen trial, wrote a note to his clients declaring it “the final nail in the coffin” for the amyloid hypothesis. Yet despite aducanumab’s limited effect, the F.D.A. approved the treatment—despite the objections of its own experts—as part of an accelerated approval process in the first week of 2021. The Centers for Medicare and Medicaid Services said that it would not pay for it, and doctors, including Karlawish, announced that they would not prescribe it.
Later, an eighteen-month congressional investigation found irregularities in the relationship between Biogen and the F.D.A. that enabled the company to get the drug approved despite limited evidence of its efficacy. Internal documents obtained by the lawmakers also showed that Biogen priced the treatment so exorbitantly because it wanted aducanumab to be “one of the top pharmaceutical launches of all time.” The investigation’s report revealed that Biogen was planning on spending twice the amount of money on marketing the drug than it had on developing the treatment in order to counter the narrative that aducanumab, which it had renamed Aduhelm, was not worth its high cost. Eventually, Biogen halved the price, but there was little uptake. Biogen’s stock tanked, dragging the amyloid hypothesis with it.
In a stroke of good luck, though, years before the aducanumab debacle, Biogen had signed a partnership deal with Eisai, which included an agreement to fund half the cost of the Japanese company’s lecanemab-antibody trial and, if the trial were successful, half the cost of bringing the drug to market. It was a somewhat controversial arrangement because Biogen was already spending tens of millions on its own antibody trial. But Biogen’s antibody aimed at clearing plaques congregating along the walls of blood vessels; Eisai’s went after soluble amyloid as it circulated in the blood. A report on the medical Web site Stat News described the difference between Eisai’s and Biogen’s approaches with an apt metaphor: if amyloid were snow, then Eisai was targeting snowflakes where Biogen had been targeting snowbanks. “The argument that won at the end of the day was twofold,” Steven Holtzman, Biogen’s executive vice-president for corporate development at the time, told me. “One, on general principle, just because they were both monoclonal antibodies didn’t mean they were equal. They each had different characteristics, and you can’t assume that one is going to be as good as the other. The second was that there are different species of amyloid, and the Biogen and Eisai molecules targeted different species. So you had an a-priori reason for saying [that] just because they’re both going for amyloid doesn’t mean they’re going to have the same potential effect on cognition.”
Those different targets may explain why Eisai’s trial was more successful than Biogen’s, but other factors were at work, too. Eisai’s trial only enrolled participants in the earliest stages of the disease. They all also had to have evidence of amyloid plaques in their brains. And the company used a particular kind of statistical analysis throughout its Phase II trial to determine which dose was having an effect on which kinds of patients, and it continually adapted the parameters of the study to reflect those results. When it was time for the larger Phase III trial, which enrolled close to two thousand participants, the researchers knew who should get the drug, at what strength, and for how long. Reisa Sperling, a professor of neurology at Harvard Medical School and the director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, told me, “That’s the way Phase II and Phase III should work: you learn in Phase II and then design a Phase III that will really test the hypothesis that the Phase II suggested.” The results of Eisai’s trials have revived Biogen’s stock and, with it, the amyloid hypothesis.