Despite a 99 percent failure rate and a recent setback, Alzheimer's researchers are plowing ahead with hundreds of experiments - and a boost in federal money - to try to crack a deadly disease that has flummoxed them for decades.
A law passed by Congress in December and signed by President Barack Obama sets aside $3 billion over 10 years to fund research of brain diseases and precision medicine, a shot in the arm for Alzheimer's research. The law, called the 21st Century Cures Act, also includes prize money to encourage Alzheimer's experiments.
But billions of dollars have so far made little progress in decoding the memory-robbing disease, which affects five million Americans. Alzheimer's is the nation's sixth-leading cause of death. Decades of research have not produced a single drug that alters its course.
December began with a major setback: Eli Lilly shared disappointing results of a late-stage clinical trial of its experimental drug solanezumab, which failed to significantly slow Alzheimer's progress.
But scientists are not giving up on the main hypothesis behind Eli Lilly's trial: that Alzheimer's can be defeated by using drugs to attack amyloid plaques that build up in the brain. Some scientists believe these cause the disease.
Many observers hold out hope for another anti-amyloid drug, Biogen's aducanumab, which in an early trial improved cognitive decline in a small number of patients.
Other potentially groundbreaking research aims to intervene even before symptoms emerge. Using PET scans, scientists can identify amyloid plaques building up years before Alzheimer's develops. One study, for instance, is testing solanezumab in adults who are accumulating amyloid plaques but showing no signs of Alzheimer's, such as memory loss or cognitive decline.
Other scientists are targeting what they believe is the true culprit, tau, the disease's other primary marker, a protein that creates what are called "tangles" in the brain.
The experiments continue against a bleak backdrop: No new Alzheimer's therapies have won federal approval since 2003, and Alzheimer's clinical trials have had a 99 percent failure rate. Only five drugs have been approved by the Food and Drug Administration to treat Alzheimer's, and those merely alleviate symptoms, such as memory loss and confusion; they don't prevent, slow or reverse the disease.
"The history of clinical trials results has been a history of disappointment," said Keith Fargo, director of scientific programs and outreach at the Alzheimer's Association.
Still, 77 Alzheimer's drugs are being investigated or developed, according to the trade group PhRMA. And other experiments seek to repurpose drugs approved for other conditions, such as diabetes or cancer, to see whether they can help Alzheimer's patients - and cut several years from the drug development process.
Non-pharmaceutical solutions are also being explored. Observational studies have shown that people who exercise more and have healthier diets seem to get the disease later in life. Researchers are conducting trials to measure the effects of exercise and diet. One trial underway at Wake Forest University, dubbed EXERT, is testing the effects of high-intensity aerobic exercise on adults with mild cognitive impairment by enrolling them in exercise programs at a YMCA.
Even before passage of the 21st Century Cures Act, public funding for Alzheimer's research was rising. The National Institutes of Health allocated almost $1 billion to the disease in fiscal 2016 - a $350 million increase over the previous year, according to Laurie Ryan, chief of NIH's Dementias of Aging Branch. There are 468 open clinical trials related to Alzheimer's - and more than 100 more in progress - listed in the government's ClinicalTrials.gov database.
Meanwhile, Alzheimer's advocates still grapple with a basic question: Is the rate of Alzheimer's going down? A study in JAMA in November found that even as scientists have made no progress in changing the course of Alzheimer's, overall dementia rates, which include Alzheimer's and other dementias, appear to be dramatically declining. The paper cast doubt over a major talking point of the Alzheimer's lobby: that as baby boomers age, the number of Americans living with Alzheimer's will explode from the current five million to 14 million in 2050. The study also suggested that lifestyle changes may make a difference.
While some heralded that as good news, others played down the finding.
Even if dementia rates drop, Alzheimer's remains a major killer, and the number of afflicted people will probably still rise, because the U.S. population is aging so rapidly, Fargo predicted. He also questioned the study's methods, which relied largely on telephone interviews.
"It's not time to let our foot up off the gas," Fargo said.
Eli Lilly's closely watched trial, dubbed Expedition 3, was the latest potential breakthrough to fall flat. In 2,100 people with mild dementia, solanezumab failed to show significant results compared with a placebo.
Some critics said the failure casts doubt on the hypothesis that Alzheimer's is triggered by the buildup of amyloid plaques.
But Eli Lilly spokeswoman Nicole Hebert said more work is needed to test the hypothesis, because the trial explored just one method of removing amyloid on one subgroup of people. She said the company is pursuing seven other lines of attack.
"Rumors of the death of the amyloid hypothesis have been around for many years, and they're probably premature," Fargo agreed.
Fargo noted that brain imaging has shown that amyloid plaques start to build up 15 to 20 years before signs of dementia appear. So to really test the amyloid hypothesis, he said, scientists may have to intervene earlier than they did in Expedition 3.
Despite the latest failure, Fargo said, "there's still more optimism in Alzheimer's research right now than there has been for 10 years."
The answer to Alzheimer's, Ryan said, is not going to be one "magic bullet," but an array of solutions tailored to different patients.
Will scientists ever find a cure?
Ron Petersen, director of the Alzheimer's Disease Research Center at Mayo Clinic, isn't betting on it. But there's still "a lot going on to be hopeful about," he said.