For Alzheimer’s Scientists, the Amyloid Debate Has No Easy Answers

Watching the Alzheimer's research world from the outside has felt like a car ride without a seatbelt. The FDA overruled its advisory committee to approve the sale of Aduhelm, a new Alzheimer's drug. The drug was designed to clear the brain plaques associated with the disease. The drug did remove amyloid, but it didn't improve cognitive function, so the committee didn't recommend it.

The FDA gave Aduhelm accelerated approval after determining that amyloid clearance was sufficient. Three members of the advisory committee resigned after the decision was controversial.

In order to explain why the FDA approved a drug without evidence that it reduced symptoms, journalists across the country had to break down the amyloid hypothesis. Many scientists have believed for a long time that Alzheimer's disease is caused by clumps of misfolded amyloid alpha. The amyloid camp has maintained a hegemonic hold on the field, forcing out alternative theories despite the failures of amyloid-targeting drugs. Science highlighted allegations against a researcher accused of serious and systematic dishonesty, reinforcing concerns that the amyloid hypothesis was a scam.

Preliminary results from the Phase 3 trial of lecanemab were released in September. Lecanemab was developed by the same companies that created Aduhelm. The drug slowed cognitive decline in almost 2,000 people with early-stage Alzheimer's. Everyone got worse over the course of the trial, but those who got the drug experienced less decline than those who didn't. Patients on lecanemab saw half a point less of a decline on a standardized cognitive scale after 18 months.

Lecanemab seemed to have proved the amyloid hypothesis when it cleared amyloid from people's brains. The story in the research world has been mostly black and white. Alzheimer's scientists are excited that something may have worked after many failed drugs. The implications of the trial are complicated because of the amyloid hypothesis.

People think amyloid is important. Eleanor says that she doesn't think anyone is saying that amyloid is unimportant. She wants to know if it is enough to justify a drug approval with little other evidence of benefit and enough to dominate the search for a cure for Alzheimer's.