December 7, 2020
By Adam Piore
Dr. Eric Reiman can't reveal the identity of the 73-year-old woman from a rugged mountain town outside Medellin, Colombia, who arrived at Boston's Logan Airport a couple of years ago for tests at Harvard Medical School. But he will say this: Finding her may well be among the most surprising developments to emerge from a nearly three-decade-long study of Colombians cursed with a gene that usually dooms its victims to full-blown Alzheimer's disease by the age of 50.
The Colombian woman is just the latest piece of evidence to emerge suggesting that the causes of Alzheimer's disease are far more complex and heterogeneous than previously understood. Despite a brain scan that revealed more amyloid-beta plaque deposition than many of her doctors had ever seen, her cognitive abilities were only mildly impaired. Which is why, even as the list of failed treatments continues to grow, many in the field have found cause for renewed optimism.
This hope is fed by an explosion in technological innovations in gene sequencing, data analysis and molecular biology, which are allowing scientists to study the progression of the disease earlier and in far more detail than previously possible. It's also fed by money: the National Institutes of Health is expected to spend $2.8 billion on Alzheimer's research in 2020—a six-fold increase since 2011, when Congress passed legislation directing the NIH to come up with an aggressive and coordinated plan to accelerate research with the ambitious goal of coming up with a way to prevent and effectively treat Alzheimer's by 2025.
That ambition reflects a growing urgency on the part of an aging public, their doctors and public health officials. By the year 2050, the number of Americans with the disease will double to 14 million, with a projected cost in treatment and care that, by some estimates, will top $2 trillion—10 percent of the present U.S. GDP. Scientists are racing to diffuse a ticking demographic time bomb. Although the field seems unlikely to meet the 2025 deadline, what researchers have learned in the past few years has given them a far more detailed and nuanced understanding of the disease. And it is raising hopes that we are finally getting closer to cracking Alzheimer's disease.
What made the Colombian woman special was not just what doctors discovered when they first scanned her brain to measure the buildup of amyloid-beta, the sticky plaques long suspected of playing a key role in the devastating cognitive decline seen in advanced Alzheimer's disease. She had the highest levels they'd ever recorded. What made the woman so special was that—despite those plaques—she seemed almost normal for her age.
"Nobody's at higher risk for Alzheimer's than she would have been," says Reiman, a neuroscientist at the Banner Alzheimer's Institute in Phoenix, who has spent the last three decades studying the loosely related, 6,000-person family cohort she belongs to in Colombia. "But she developed mild cognitive impairment about three decades after the average age in her family. And she still hasn't developed Alzheimer's dementia."
The Colombian woman's case is a potent testament to both the tantalizing promise—and the enormous frustration—that have come to characterize the pursuit of drugs to treat Alzheimer's disease. In two decades, the pharmaceutical industry has spent $600 billion in pursuit of drugs, focusing with almost single-minded intensity on compounds designed to safely reduce or prevent the buildup of deadly plaques that are one of its primary hallmarks.
Attacking plaque is precisely the point of the new Alzheimer's drug aducanumab, made by the drug maker Biogen, which was being tested in two separate clinical trials. High-ranking officials at the U.S. Food and Drug Administration have supported the drug and recently called preliminary trial results "highly persuasive." But in early November, a panel of independent experts, convened by the FDA to review data from ongoing trials, contradicted this assessment. They cited conflicting data—one trial showed a mild therapeutic effect, another trial showed none—and a lack of efficacy. "The totality of the data does not seem to provide sufficient evidence" of effectiveness, declared one of the FDA's own statisticians in a report. An FDA advisor, Dr. David Knopman of Mayo Clinic, called for a new clinical trial. "Contrary to the hope that aducanumab will help Alzheimer patients," he wrote in a report, "the evidence shows it will offer improvement to none, it will harm some of those exposed, and it will consume enormous resources."
Even if the FDA were to contravene its own experts and approve aducanumab in March, the drug appears unlikely to live up to the early promise of the class of drugs that stave off Alzheimer's by interfering with the accumulation of plaque in the brain. With aducanumab, Biogen's approach reflects the dominance of a theory called the "amyloid cascade hypothesis," which argues that amyloid-beta plaques are the first step in the condition—the kindling that eventually ignites into the fire that causes the massive cell death and memory and thinking problems that make Alzheimer's such a devastating disease. But that theory has been losing steam for years, as the case of the Colombian woman suggests.
From the beginning, there was good reason to suspect the thick plaques that characterize the disease might also be their cause. In 1901, a 50-year-old woman named Auguste Dieter was placed under the care of Dr. Alois Alzheimer at the Frankfurt Psychiatric Hospital with an inexplicable set of symptoms, which included memory loss, disorientation, hallucinations, aphasia and delusions. "I have lost myself," she lamented shortly before her passing in 1906, according to Alzheimer's meticulous notes.
In an autopsy, Alzheimer noted the buildup of dark clumps of plaques formed by protein fragments known as amyloid-beta, along with the other two symptoms that are now considered the primary physical hallmarks of the disease that bears his name: the tangles of stringy protein molecules known as tau that clog up the space between brain cells and disrupt normal cell function, and massive cerebral atrophy caused by the death of the gray matter we rely upon to think, feel and live.
Still, the modern age of Alzheimer's research wouldn't begin until decades later, when Robert Katzman, a prominent UCSD neurologist, penned an 1978 editorial arguing that the obscure condition known as "Alzheimer disease"—a term previously reserved for those developing dementia before age 65—was actually the primary cause of what was then known only as senility. By that measure, Katzman argued, Alzheimer's disease ranked as the fourth or fifth most common cause of death in the United States and thus constituted a vastly overlooked public health challenge. In the years that followed, the first patient interest groups began to mobilize and the newly established National Institute of Aging began pouring resources into research.
Then came the discovery and study of families carrying rare mutations, like those seen in the mountains outside Medellin, Colombia, that caused them to develop the symptoms of full-blown Alzheimer's disease far earlier than elsewhere. Using the genetic tools available at the time, researchers throughout the 1990s homed in on specific mutations that appeared to be present only in family members who had developed early-onset Alzheimer's—mutations that were entirely absent in close relatives spared by the disease. Virtually all the genetic typos seemed to appear on genes that could be directly linked to the buildup of the amyloid-beta plaques in the brain.
These discoveries were among the most compelling evidence for the amyloid hypothesis, which by the early 2000s had become the dominant model used to explain how and why Alzheimer's disease progresses. And with the advent of brain scanning technologies that allowed clinicians for the first time to measure the plaques in the brains of living people, it suddenly seemed possible to track this accumulation in real time.
The implications were clear: if scientists could develop a drug capable of countering the accumulation of plaques, we could halt the progression of Alzheimer's, and the heartbreaking cognitive decline that came with it, in its tracks. "I was a student at the time—and they were heady times," recalls Scott Small, a neurologist who directs the Alzheimer's Disease Research Center at Columbia University. "We thought we had it figured it all out."
Unfortunately, things have not proven that simple. Between 1998 and 2017, there were 146 unsuccessful attempts to develop medicines to treat and potentially prevent Alzheimer's, according to a 2018 report put out by the Pharmaceutical Research and Manufacturers of America (PhRMA), the vast majority focused on the amyloid hypothesis. (The last Alzheimer's medication to receive FDA approval was Namenda in 2003, a drug that aims to temporarily boost cognitive performance by boosting the chemical messengers in the brain known as neurotransmitters).
The list of disappointing drugs that promised to cure or slow the progression of the disease is long. There was, for instance, Pfizer and Johnson & Johnson's bapineuzumab, a monoclonal antibody designed to bind to amyloid-beta. In 2012, the study's principal investor at Harvard declared human trials had produced "absolutely no evidence at all of a clinical benefit of treatment on either of the primary measures, one cognitive and one functional" in 1,100 patients with mild to moderate symptoms of the disease. Another widely anticipated drug, semagacestat, was halted after some recipients developed skin cancer and their cognition declined. In 2016, Eli Lilly & Co's solanezumab, "did nothing to improve cognition" in the phase 3, placebo-controlled trial of 2,129 patients with mild Alzheimer's disease who took the medication for more than a year.
The latest shining hope has been aducanumab, a drug whose on-again, off-again journey toward approval seems to encapsulate the infuriating ambiguity of the present moment. In 2016, the drug, developed by Biogen and Eisai, made the cover of Nature Magazine after researchers announced it had slowed cognitive decline and reduced plaques in the brains of a small group of study participants. In 2018, massive phase 3 trials kicked off in clinics around the globe, slated to finish in 2021. In March 2019, Biogen announced that a preliminary look at the results, known as a "futility analysis," had shown the medicine wasn't working as it should on the more than 3,000 hopeful early stage Alzheimer's patients participating in the study. They shut the trial down two years early and declared it a failure.