Schaeffer, a 59-year-old costume historian in North Berwick, Maine, has no symptoms of Alzheimer’s. But in 2021 her family history led her to apply to join a clinical trial testing a drug on people at risk for developing them. To participate, volunteers couldn’t have cognitive impairment. But they needed to test positive for a biomarker that put them at higher risk for mental decline ― deposits of a sticky toxic protein in the brain called beta-amyloid that is a hallmark of the disease.
Schaeffer underwent a PET scan of her brain and tested positive for amyloid. Finding out that she was eligible for the study ”was both the best and the worst day,” she said.
Since February 2022, Schaeffer has driven about 160 miles round trip every other week to Brigham and Women’s Hospital, where researchers are testing an intravenous drug they hope will prevent the onset of symptoms, or at least delay them. It is one of about 100 clinical trial sites around the world involved in the study, which will ultimately recruit 1,400 volunteers between the ages of 55 and 80.
The drug in question, Leqembi, was developed by Cambridge-based Biogen and its Japanese business partner Eisai. In a landmark decision on July 6, the Food and Drug Administration approved it for people already showing early symptoms of Alzheimer’s, a scourge that afflicts more than 6 million Americans. With a price tag of $26,500 a year per patient, Leqembi was the first medicine proven to slow the rate of cognitive decline for people with mild Alzheimer’s symptoms. It is believed to do that by removing amyloid plaques from the brain.
The approval buoyed families affected by Alzheimer’s and the doctors who treat them. Nonetheless, Leqembi’s slowing of the disease for those with early symptoms was relatively modest ― 27 percent over a separate 18-month study the companies conducted ― and the treatment didn’t come without potentially dangerous side effects.
Schaeffer is enrolled in a different study to determine whether Leqembi will produce more dramatic benefits to people who have yet to show signs of cognitive decline and memory loss. Those signs may not show up for 10 to 20 years after the formation of deposits of amyloid and other toxic proteins in the brain, experts say.
“I often use the cholesterol analogy,” said Dr. Reisa Sperling, a neurologist at Harvard Medical School and Brigham and principal investigator in the study funded by Eisai and the National Institute on Aging. “If you give somebody a statin drug when they’re in the ICU, it does nothing. But when you give statins before people have a heart attack or a stroke, it really changes the morbidity and mortality. Alzheimer’s disease is very similar. If we can go after this underlying process early enough, we can one day prevent dementia.”
To qualify for the four-year prevention study, called AHEAD, Schaeffer had to undergo a series of cognitive tests to make sure she was unimpaired. The tasks included counting backward by 7 from 100, listening to a story and recounting as many details as possible, and recalling pictures of household objects that she reviewed in a binder. She was relieved to learn she had no cognitive impairment but was understandably dismayed to later test positive for amyloid.
So far, she has received nearly 50 intravenous infusions in her arm at the hospital’s Center for Alzheimer Research and Treatment. Each infusion takes about an hour. She passes the time by playing video games on her cellphone, including Sudoku. She plans to receive the infusions in Boston for another 2½ years.
Neither she nor trial investigators know whether Schaeffer is getting Leqembi or a placebo of saline solution. But she suspects she’s getting the drug because she had a mild allergic reaction after her first infusion. Regardless, Schaeffer said her motivation for volunteering wasn’t necessarily to help herself.
“Whether or not I personally benefit from it is beside the point,” said Schaeffer, who showed framed photos of relatives who died of Alzheimer’s to a Globe photographer during a recent infusion. “Having watched people I love go through this, knowing what it’s like for them to vanish. . . .” Her voice trailed off. “I do best in difficult situations when I have the feeling that I’m doing something,” she said.
Researchers plan to administer PET scans halfway into the four years of infusions and then again after the trial ends, to see if participants’ amyloid deposits grew, Sperling said. Investigators also give periodic cognitive tests and check with trial participants and their relatives or friends to see if they notice any mental decline, such as difficulty following news stories or handling finances, Sperling said.
Volunteers in the prevention study began receiving infusions in late 2020, Sperling said. The trial, which is still enrolling participants, is scheduled to be completed by 2027.
If Leqembi does prevent the onset of symptoms after four years, it remains to be seen whether recipients would need to stay on the drug, Sperling said. However, investigators are lowering the dosage midway through the study.
It’s not the only large clinical trial testing an amyloid-clearing drug in people without symptoms of Alzheimer’s.
About two years ago, the pharmaceutical giant Eli Lilly began recruiting volunteers for a study of a similar experimental medicine called donanemab. That amyloid-clearing drug generated even more impressive results than Leqembi in a recently published study of patients with early Alzheimer’s symptoms; donanemab slowed the rate of cognitive decline by about 35 percent. Based on that data, donanemab is widely expected to win FDA approval this year for people with mild impairment.
Like Eisai’s prevention study, Lilly is separately testing donanemab on volunteers who have no symptoms but are at risk for developing them because of evidence of amyloid deposits. Ultimately, the trial is expected to enroll 3,300 volunteers at dozens of sites in the United States and Japan.
Kris Tualla, a 69-year-old author of historical romance novels who lives in suburban Phoenix, needed little convincing to volunteer for Lilly’s study, called TRAILBLAZER, at the nearby Banner Alzheimer’s Institute.
Her paternal grandmother and her father both had dementia, and her father’s brother was diagnosed with Alzheimer’s when he was only 60.
“The idea of losing me, losing my mind, has probably been the one thing that I’ve worried about in my life,” she said. “My prayer for probably the last 10 years is ‘please, God, don’t take my mind.’ ”
So far Tualla has received four donanemab infusions. Unlike the Leqembi infusions, which are administered every other week, donanemab infusions are monthly, and trial participants only get nine. Tualla doesn’t know whether she is getting the drug or a placebo, either, but thinks she might be getting donanemab because she felt dizzy after the first two doses.
As in the case of the Leqembi trial, volunteers who randomly received the placebo will later be offered the drug if it proves safe and effective.
While the history of Alzheimer’s drug trials is littered with high-profile failures, Dawn Brooks, Lilly’s global development leader for the disease, said providing donanemab to high-risk people before symptoms appear makes sense.
She noted that Lilly’s study of 1,736 patients published in July in the Journal of the American Medical Association found that donanemab slowed the progression of early Alzheimer’s most in patients who started receiving the drug when they had less of another protein called tau that forms tangles in the brain.
“We saw the strongest efficacy in the less advanced patients,” she said. “This is all about slowing down and, ideally, preventing the onset of what we know is a debilitating and often fatal disease.”
Dr. Paul Aisen, a physician who directs the Alzheimer’s Therapeutic Research Institute at the Keck School of Medicine at the University of Southern California, agreed.
“We used to say that Alzheimer’s lasts about seven years from the onset of dementia to death,” said Aisen, who is helping to run the Leqembi trial with Sperling. “But that’s the tail end of what we now consider to be a 25-year process starting with the accumulation of amyloid.”
“It’s intuitively clear that the earlier you start [treatment] the better,” he said. “Why not attack the pathology when the brain is functioning normally?”
Jonathan Saltzman can be reached at firstname.lastname@example.org.