Doctored E-Book

Charles Piller

• Herausgeber: Icon Books
• Kategorie: Ratgeber
• Sprache: Englisch

Seitenzahl: 532

Veröffentlichungsjahr: 2025

Beschreibung

For readers of Empire of Pain and Dopesick, an arresting deep dive into how Alzheimer's disease treatment has been set back by corrupt researchers, negligent regulators, and the profit motives of Big Pharma. Nearly seven million Americans live with Alzheimer's disease, a tragedy that is already projected to grow into a $1 trillion crisis by 2050. While families suffer and promises of pharmaceutical breakthroughs keep coming up short, investigative journalist Charles Piller's Doctored shows that we've quite likely been walking the wrong path to finding a cure all along - led astray by a cabal of self-interested researchers, government accomplices, and corporate greed. Piller begins with a whistleblower - Vanderbilt professor Matthew Schrag - whose work exposed a massive scandal. Schrag found that a University of Minnesota lab led by a precocious young scientist and a renowned director delivered apparently falsified data at the heart of the leading hypothesis about the disease. Piller's revelations of Schrag's findings stunned the field and the public. From there, based on years of investigative reporting, Doctored exposes a vast network of deceit and its players, all the way up to the FDA. Piller uncovers evidence that hundreds of important Alzheimer's research papers are based on false data. In the process, he reveals how even against a flood of money and influence, a determined cadre of scientific renegades have fought back to challenge the field's institutional powers in service to science and the tens of thousands of patients who have been drawn into trials to test dubious drugs. It is a shocking tale with huge ramifications not only for Alzheimer's disease, but for scientific research, funding, and oversight at large.

Leseprobe

ALSO BY CHARLES PILLER

Gene Wars: Military Control Over the New Genetic Technologies (with Keith R. Yamamoto)

The Fail-Safe Society: Community Defiance and the End of American Technological Optimism

 

 

Published in the UK in 2025 by

Icon Books Ltd, Omnibus Business Centre,

39–41 North Road, London N7 9DP

email: [email protected]

www.iconbooks.com

ISBN: 9781837732593

eBOOK: 9781837732609

Copyright © 2025 Charles Piller

The author has asserted his moral rights.

Every effort has been made to contact the copyright holders of the material reproduced in this book. If any have been inadvertently overlooked, the publisher will be pleased to make acknowledgement on future editions if notified.

No part of this book may be reproduced in any form, or by any means, without prior permission in writing from the publisher.

Interior design by Jill Putorti

Printed and bound in the UK

For Surry, Nate, Sandra, and Maya

Contents

Prologue

Chapter 1: A Vanishing Mind

Chapter 2: “Magic Hands”

Chapter 3: “Everything Is Figureoutable”

Chapter 4: The French Connection

Chapter 5: Prodigy Meets Genius

Chapter 6: One Hundred Years of Solitude

Chapter 7: Drug of Choice

Chapter 8: Image Problem

Chapter 9: Doctored

Chapter 10: “Biology Doesn’t Care”

Chapter 11: Trust but Verify

Chapter 12: The “Amyloid Mafia”

Chapter 13: Blots on a Field

Chapter 14: Federal Failures

Chapter 15: Scholarly Deceptions

Chapter 16: Ivory Tower Deceits

Chapter 17: Shock and Duty

Chapter 18: Slow-Motion Meltdown

Chapter 19: Survival Mode

Chapter 20: Brain Games

Chapter 21: Impact on Alzheimer’s

Chapter 22: Innovation and Hope

Epilogue

A Note on Reporting

Acknowledgments

Notes

Prologue

2021–2022

In December 2021, I fell into one of the biggest and most disturbing stories of my career. A credible whistleblower with strong credentials in dementia research tipped me to a major case of apparent misconduct in his field. He produced convincing evidence that lab studies at the heart of the dominant hypothesis for the cause of Alzheimer’s disease might have been based on bogus data. My investigative story for Science magazine in July 2022 exposed those findings and their far-reaching significance, drawing global media attention. But I didn’t suspect it would begin a yearslong, high-stakes journey into hidden, sordid corners of science and medicine.

Just a couple months later, two giant drug companies announced what many described as one of the most dramatic developments in the history of Alzheimer’s. For decades scientists had struggled fruitlessly to offer hope to millions of patients who suffer the gradual, debilitating decline in their ability to think and remember loved ones, or enjoy self-aware lives. Finally, a major test seemed to prove that a new medication could alter the course of the disease.

That drug, Leqembi, strips away from brain tissues the sticky plaques and other toxic compounds that comprise a substance called “amyloidbeta.” In so doing—said its makers, experts in their pay, and cheerleading journalists—Leqembi definitively validated the “amyloid hypothesis,” the long-debated notion that Alzheimer’s is caused by the buildup accumulation of amyloid in the brain. If true, its removal would lead to a cure.

Understandable excitement—hope against hope—greeted Leqembi. Alzheimer’s afflicts nearly seven million Americans, about one in every nine over the age of sixty-five, making it the fifth leading cause of death among the elderly. Up to 360,000 adults in the prime of life—including people as young as thirty—suffer from early onset Alzheimer’s. Comparable figures in the United Kingdom, Europe, and the rest of the world have made the leading cause of dementia a global scourge. And dementia totals will more than double by 2050.

In the United States alone, more than eleven million family members care for fathers and mothers and grandparents who have fallen prey to the cruel disease that begins by gradually stealing a person’s mastery of everyday life, then cherished memories, and finally the sense of self that makes each of us human. Alzheimer’s families face incalculable emotional costs—including lost dreams of retirement and pleasures with loving partners. For many, the disease also means financial impoverishment. Family caregivers in the United States provided a staggering $350 billion in care to Alzheimer’s patients in 2023—nearly matching the amount paid for dementia care by all other sources, including Medicare.

Unfortunately, the Leqembi “breakthrough” amounted to just this: Alzheimer’s patients lost their ability to remember, think clearly, and live normal lives only slightly less rapidly than others taking a bogus treatment. The drug offers so modest a benefit that doctors and patients might not perceive any effect whatsoever.

It was the latest example of the exaggeration, hype, and sheer fakery and fraud that has characterized Alzheimer’s research for decades. By then I realized that I could tell the full story of how the hunt to cure the insidious and chilling illness went awry. I had to show why billions of dollars in spending by governments, pharma companies, and philanthropies had done little for desperate patients.

For decades, proponents of the dominant amyloid hypothesis have sidelined, starved for resources, and even bullied rebels behind other promising notions of how to treat Alzheimer’s. If Leqembi and look-alikes with similarly lackluster results hold sway in drug development and dominate mindshare among patients and doctors, a genuine Alzheimer’s cure might become even more remote.

Many patients take a leap of faith in such drugs as a hedge against creeping fear. Big pharma companies, among others, bet their bottom lines on that basic instinct. Alzheimer’s research has offered endless opportunities for advancement and riches to corporate shysters and ruthlessly ambitious scientists who cut corners or engage in brazen deception.

I set out to unmask decades of arrogance, greed, fabulism, and error that have emptied research coffers and littered the drug development landscape with failure after failure.

My reporting followed the path of a junior professor who faced great personal risks to challenge his field’s institutional powers. He uncovered hidden and fabricated data instrumental to keeping the amyloid hypothesis supreme at the expense of other possible solutions. As I dug deeper, a scientific underworld of deceit and lies rose into view. I gradually saw an opportunity to help reshape how scientists, doctors, and patients understand one of the most terrible human afflictions—and add realistic hope in the process.

The story begins where it must, with a deeply determined patient struggling with dementia. He dared to hope that he could be one of the first people living with Alzheimer’s to find a transformative treatment.

Chapter 1

A Vanishing Mind

Tabernacle Township, New Jersey 2020–2022

“I have to handle things differently.”

—STEPHEN PRICE, RETIRED CONSTRUCTION CONTRACTOR WHO LIVES WITH ALZHEIMER’S

Stephen Price and his son, Matt, had driven for an hour from the family home in Tabernacle Township, New Jersey, to a medical strip mall in Toms River, on the Jersey Shore, to begin the experimental drug simufilam. It was May 3, 2021. Cassava Sciences, a Texas biopharma company, developed simufilam to treat or cure Alzheimer’s disease, the debilitating, ultimately deadly illness that afflicts tens of millions of people worldwide. Stephen was enrolling in a clinical trial—a human experiment to examine the drug’s safety and effectiveness.

For experimental drugs that show promise in lab studies, the Food and Drug Administration (FDA) requires such trials to enforce rigorous standards for administering drugs and measuring their effects, and close monitoring to ensure that patients get help and treatment if they show unforeseen or worrisome side effects. Stephen had enrolled in a “phase 2” trial—a test of safety and possible benefits. It had followed a small, phase 1 safety trial meant to ensure that simufilam was not obviously toxic. Later, large phase 3 trials would test whether simufilam helped volunteers regain some of their memories and ability to cope with daily life—or at least slowed their gradual decline. If the results looked strong, the FDA might permit doctors to prescribe simufilam. Drug regulators in the European Union, the United Kingdom, and many other nations follow a similar, time-honored, apparently careful approach.

Matt was Stephen’s “study partner”—necessary to help his dad, already impaired from the disease, negotiate the somewhat-complex process. Stephen, then seventy-three, had been diagnosed more than six years earlier. Simufilam, they hoped, would stop his memory, ability to concentrate, and mastery of daily life from continuing to ebb away.

In December 2022, trim-framed with neatly cropped gray hair, the seventy-four-year-old Stephen cut a handsome pose. He towered over Toni, his wife and high school sweetheart. They looked the picture of a quiet, middle-class retirement. Stephen had owned and operated a tiny construction firm for thirty years, mostly digging foundations for new homes and businesses. Toni had taught English to teens with behavioral challenges, then grew lavender on their land in the rural exurbs east of Philadelphia—sixty-seven acres of woods and fields. Their comfortable, two-story home rests at the end of a half-mile gravel drive. For most of his life, Stephen was a man who kept his own counsel. On that day, he spoke openly about his experience with Alzheimer’s.

Gazing steadily from blue eyes behind heavy, black-framed glasses, Stephen spoke with a direct friendliness, albeit a bit guarded at times. He sometimes became confused about small matters or lost his train of thought. To hold up his end of a conversation, he favored short replies. He paused to find an elusive word or anecdote, smiling apologetically to fill the gaps.

Asked when he and Toni first met, Stephen looked upward for a few moments, pondering. “Before we entered high school,” he said.

“No, no . . .” she interjected, gently.

“When you were doing the baton thing in the parades,” Stephen replied, turning to his wife.

She replied softly, “Okay”—acquiescing to his version with a hint of polite frustration. Caring for someone with Alzheimer’s calls for infinite patience.

“I have to handle things differently,” Stephen said. “And it took a long time for my wife and Matt to catch up or get at the same speed I am on. I have to do things one thing at a time. And if I get interrupted—when, like, I’m putting my meds together, something like that—I have to go back to the beginning again and start all over. It’s hard for other people to understand that. You know, it’s, it’s a very different world,” he said, smiling again, this time sheepishly. Toni looked stressed.

Stephen wore a plaid flannel shirt over a white T-shirt. He looked ready to head out to dig a new foundation, as he chatted about career and business. “It was a smaller company where everybody knew everybody,” Stephen said, gesturing with his arm, as if encircling his crew, who he said enjoyed each other’s companionship in hard but satisfying work. “It was just a nice way to have a, have a business,” he added.

Nowadays, despite his decline, Stephen regularly and fondly checks his remaining equipment that hasn’t yet been sold off. An old front-end loader dominates a barn-sized warehouse down the drive from their home. He meanders around, scanning and moving small tools—more comforting ritual than inventory check. Matt and Toni installed video security inside. Not to safeguard the property. They don’t want to worry about Stephen’s well-being in case he becomes confused during a nostalgic visit.

Stephen has participated in various drug trials in his journey as a patient and research volunteer in the search for an Alzheimer’s cure. He wants to feel like part of the solution to the great and terrible Alzheimer’s mystery—to help scientists explore new treatments for patients who will follow. Two of those might be his own children. That’s because Stephen carries two copies of a gene known as APOE4—a risk factor for coming down with Alzheimer’s and passing it to the next generation. Matt remembers his dad saying “What can I do for society? What can I do for my family? And what can I do for myself?”

Matt likes to say that he knows “just enough about clinical trials to be dangerous.” That’s unduly modest. His sophistication about what to look for in a trial would put many physicians to shame. A Harvard-trained epidemiologist and global-health specialist, he knows how to assess a trial’s structure and approach. I asked his father whether Matt showed this taste for studious diligence as a kid, foreshadowing his luminous scholarly achievements.

“He was very self-motivated,” Stephen replied, with a self-effacing grin. “I don’t know where it came from,” he added, showing that he could still crack a small family joke.

Near the beginning of the simufilam trial Stephen was battling what he described as “some issues.” He suffered from an often overlooked but common Alzheimer’s symptom: depression. It traces back to the cruelty of the illness. As dementia first encroaches, many people sharply— painfully—witness their own gradual decline with conscious alarm. In the early stages, they can see their sense of self and intimacy with loved ones slowly wane. Medications usually provide meager benefits at best. And Stephen knew that Alzheimer’s might kill him.

Antidepressants didn’t help much. So, in 2020 Matt helped him join a clinical trial to see whether the mind-altering drug psilocybin could do better. Stephen and Toni had never used drugs recreationally. Consuming the mushroom-derived chemical—safely within the comfortable, closely supervised confines of Johns Hopkins University—was a novel experience.

The effects proved profound. “It kind of got my head on straight. I wish I could go back there again,” Stephen said. (He thought the trial lasted two or three years—perhaps a reflection of how favorably he remembered it. Including therapy and follow-up, it ran less than a year.)

“At the time, Dad reported that it was among the most meaningful experiences he’s had in his life. During the session it was traumatic, but he came to view it as a positive experience,” Matt recalled. The psilocybin alleviated some distressing feelings from his childhood, and helped Stephen express his deep compassion for Toni—who had faced her own health problems at the time. Matt described his views of Stephen’s experience: “Eye-opening. I was surprised by how much it seemed to help him accept his illness for a period of at least a few months.”

In that “open-label” trial, investigators and participants knew that all volunteers received psilocybin, rather than some getting a placebo— a dummy treatment, like the classic sugar pill. Such small, early experiments aim to gather initial readings on side effects or benefits. They rarely convince the FDA to approve a drug for marketing. For that, the agency normally requires randomized, controlled, and double-blinded trials, in which volunteers are divided into groups that get either the drug or a placebo. (Treatments for late-stage cancers, for example, in which it would be unethical to give a dying person a placebo, can be an exception.) Expectations by investigators or participants can change outcomes, sometimes profoundly, independent of getting the study drug or a placebo. So neither volunteers nor investigators know who gets the real treatment. Double-blinding reduces the risk of bias, intentional or not. Guarding against that thumb on the scale can be essential to finding out if a treatment really works.

LIMITED OPTIONS

Then thirty-seven, Matt had been trying to get his father into a trial for a drug that, unlike psilocybin, was designed to be “disease modifying.” Rather than calming symptoms, the goal would be to slow, stop, or reverse cognitive decline—or for people who have no symptoms, prevent them—by attacking Alzheimer’s biochemical cause. When he first heard about simufilam, it sounded exciting. In principle, the drug repairs a brain protein, filamin A—one of the many proteins that accelerate chemical reactions and form key structures in cells. Filamin A, according to Cassava, can block sticky brain deposits, or “plaques” of another protein— amyloid-beta, widely seen as a hallmark of the disease. The amyloid hypothesis holds that two types of amyloid proteins—plaques that form between nerve cells, and toxic forms of amyloid that can dissolve into the cerebrospinal fluid that surrounds brain tissues—spark a biochemical chain of events that ends with Alzheimer’s devastating impairment. According to Cassava, simufilam also affects the brain in other ways that might cure the disease, such as reducing amyloid’s toxic downstream effects.

If simufilam could improve cognition, Stephen might regain the capacity to navigate everyday activities and enjoy life more. Perhaps he could recapture the person he and his family saw slipping away, Stephen, Toni, and Matt thought. If the company was right, simufilam might be their best hope.

Matt read Cassava’s scientific explanations and research underpinning the trial and talked them over with a friend—a physician and PhD scientist trained at Harvard and the Massachusetts Institute of Technology. Doubts immediately emerged. The logic of Cassava’s approach—far from the mainstream and not robustly validated by independent researchers— “seemed weird and bit thin,” Matt said.

Matt had looked for other trials of potential disease-modifying drugs. Those only accepted volunteers who suffered from mild cognitive impairment, an early stage of Alzheimer’s. Investigators for such trials by major pharmaceutical companies rejected Stephen. In cognitive tests, his Alzheimer’s seemed too advanced—in the “moderate” range of impairment.

So they circled back to simufilam. Despite Matt’s misgivings, the trial offered appealing qualities: Many experimental treatments require uncomfortable and potentially dangerous intravenous infusions in a clinic. Simufilam is a pill Stephen could take at home. Most important, Cassava didn’t share the qualms of other companies about accepting people with moderate impairment.

Matt worried about the rigor of the trial. Some experts saw Cassava’s screening criteria to qualify patients for the trial as suspect. For example, it relied on a test called the Mini-Mental State Examination (MMSE), widely considered imprecise and easily susceptible to coaching. “It seems unthinkable that the diagnosis of a devastating illness such as Alzheimer’s disease would hinge on the results of a rough-and-ready 5 minute test,” as two neurologists wrote in a 2016 analysis, calling for the test’s retirement. Individuals who scored in the MMSE’s “normal” range—no apparent dementia—could still be included in the simufilam trial if a scan showed shrinkage in the hippocampus, the part of the brain responsible for emotion and memory. Alzheimer’s notoriously causes brain atrophy, but so do other conditions that cause dementia.

The broad range of likely patients in the trial—people with mild or moderate Alzheimer’s, and others with no symptoms of dementia—could make the results of the experiment impossible to accurately compare to conventional studies.

Still, the relatively lax criteria offered a distinct advantage: Stephen got in. Matt recalled driving home from Toms River that day in 2021 after his dad took that first dose. “We were encouraging each other. We were saying, ‘We’re not sure if this is going to work out. But even if it doesn’t we’re doing the best that we can to fight.’ ” Matt paused, gathering his thoughts. “We were kind of rehearsing that narrative. Dad was optimistic.”

The trial used a hybrid format—open-label for the first twelve months, double-blinded for the next six, then another six months of open-label. So for at least eighteen months of the twenty-four-month trial, participants would know they were getting the study drug, rather than possibly a placebo. Such an approach makes it much easier to recruit people who see themselves living on borrowed time, but harder to interpret the results.

By December 2022, Stephen had lost track of those details, though he remained hopeful. “I think I’m on the drug now, but I don’t know that I have the full effect of the drug. Because I’d like to be a little bit more ‘with it’ than I am presently,” he said.

Tests of drugs to treat conditions like cancer use objective biomedical measures—for example, a tumor shrinks or grows—that can show definitively if a drug is helping or failing. Fading memory or a waning ability to manage routine tasks can’t be measured biologically. That requires nuanced, often-subjective tools. Scientists use memory tests, along with questionnaires about the experience of home life, to probe trial participants and gather the assessments of loved ones and clinicians. They try to map the contours of thought to find some ground truth about whether a drug might be working.

Cassava hired private contract-research sites—typical in large trials recruiting volunteers across the nation, or even internationally—to test participants on tasks including memory quizzes, copying shapes like diamonds and boxes, and completing simple tasks. For example, they told Stephen to place a pencil on a card, then move it to a different location on the desk. They used the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Although widely accepted, bias can still infect the scoring, results, and interpretation of the test. Scientists who study Alzheimer’s regard it as a poor substitute for other assessments. Statistician Suzanne Hendrix of Pentara Corp., an expert in such testing and a reviewer for Cassava’s findings, had coauthored an article that described the unreliability of ADAS-Cog. She debunked the idea that it is an accurate test for patients with mild Alzheimer’s. It was more accurate for those who suffer from a moderate case of the disease, Hendrix wrote. In other words, if ADAS-Cog was useful, it might work better for patients like Stephen Price.

To people living with Alzheimer’s and their loved ones, efforts to find a cure can seem like an impenetrable black box of scientific complexity. But Matt had the expertise to crack the box open. As the trial progressed, he began to study simufilam and its maker. What he learned renewed his earlier doubts, then left him frankly concerned. Over the next two years, Matt began to see his father’s experience as a sign of how clinical research might succumb to expediency—and why big ideas to cure a disease are not always what they seem.

When he compared his dad’s experience, and his own as a study partner, against the disclosure documents, Matt came to view certain aspects of the trial as ethically problematic. For example, at the outset, a clinician sampled Stephen’s cerebrospinal fluid, which bathes the brain and spinal cord. Cassava needed it to look for signs of Alzheimer’s biomarkers. If Stephen did not show certain biomarker levels, he would not qualify for the trial. Investigators used a standard lumbar puncture or “spinal tap.” They inserted a needle between two vertebrae, into Stephen’s spinal column, to collect the precious fluid. The procedure is routine, but hardly risk free. In rare cases it causes paralysis or even death. Yet Cassava listed none of the serious side effects on the consent forms Stephen signed.

The forms also said any trial participant could obtain their own spinal-tap results. Matt and Stephen wanted to see the levels of amyloids and other proteins in that fluid—in part to get a reading on the possible trajectory of Stephen’s symptoms. But several requests went nowhere, as Matt began to wonder if the samples were ever actually tested.

Cassava might have been leery about handing over the data because their testing program had apparently violated a New York State lab licensing and inspection requirement meant to safeguard clinical trial participants. Spinal fluid and other samples for Stephen’s trial would have been tested by Cassava’s close collaborator Hoau-Yan Wang, a City University of New York (CUNY) neuropharmacologist. The state requires all labs that test such samples to be certified and inspected, but no lab at CUNY was on the certified list. That might have been why Cassava abruptly changed the trial protocol in June 2021: It would test spinal fluid for twenty-five patients only. Most likely, Stephen’s fluid wasn’t tested. Cassava said it could not reply about a contractor’s licensure, and Wang did not respond to questions about lab certification.

It seemed a foreboding misstep, given the experience of another ambitious medical company, Theranos. Infamously, that Silicon Valley startup claimed to build a device that could conduct a multitude of tests on a single drop of blood—an advance that could revolutionize laboratory efficiency and render the discomfort of blood draws from a vein nearly obsolete. But a key step in the firm’s ultimate exposure as an elaborate deception came when one of its employees contacted the same New York regulators who apparently called Cassava’s bluff and they learned that Theranos’s testing evidently violated the same state rules.

Matt also questioned how the final data would be interpreted. The six-month, double-blinded interlude, sandwiched between two open- label periods, allowed Cassava to say it used the gold-standard approach, in part. But the blinded interval in this multipart trial was regarded by many scientists as too short to demonstrate a clear effect or provide statistical reliability.

Matt again reached out to his friend, an expert in a nerve-cell receptor called TLR4. Such receptors can perceive the presence of toxins and affect inflammation that can harm brain cells. Cassava says TLR4 plays a central role in how simufilam works. Matt’s friend reviewed some test-tube and mouse experiments that the company said supported the idea that the drug was promising, partly due to its impact on TLR4. The papers were key to Cassava’s justification that simufilam was ready to test in people. The linkages looked “very tenuous,” the friend concluded.

But Matt didn’t want his skepticism, however justified, to wipe out his family’s hopes. From his own work in global health, Matt knew that aggressive trials with drugs that posed a relatively low risk for even a small chance of a stunning reward could be worth trying. Although the ledger didn’t favor simufilam, he thought it might still be worth the benefit of the doubt.

“WHAT’S POSSIBLE IS SHRINKING”

Before the trial, Stephen could remember words and places and times, draw shapes, and follow simple instructions with ease. By December 2022, about eighteen months into the trial, he had trouble remembering words like “apple” and “chair” moments after being asked to read them aloud. He couldn’t fold a letter and place it into an envelope or recall the word “harmonica” when shown the instrument. He couldn’t name Toms River, where his trial clinic was located, or remember the year or day of the week. Asked for the current month, he answered correctly—only to forget that fact seconds later.

In a March 2023 examination, Stephen was shown an example of a circle and asked to draw his own version. He produced a crude facsimile, like the artwork of a toddler. For a diamond, he drew an indecipherable squiggle.

“On the ride back, he just mentioned offhand that he is acutely aware of his own deficits, like when he’s asked to draw shapes,” Matt said. “Most of his days he kind of stays within the universe of things he feels he can do most of the time. Being subjected to a series of tests, I think it’s a real downer for him—not like the beginning of the study. He does have insight that he’s not getting better.”

Still, certain hints of normalcy give Matt and Toni hope. Tai Chi, the slow, controlled martial art, has become a calming routine. Sometimes he reads news articles. “With some difficulty and hesitation, he comments on them in ways that reflect some retention,” Matt said. Although Stephen hasn’t driven on the road in many years and needs help putting on a seat belt, he sometimes drives his old pickup truck to collect leaves around their property.

“Yet afterwards, he will not know how to take off his own boots,” Matt added, pausing to gather his thoughts. “At dinner, he sometimes looks at the fork, thinking about which end to hold. We’re trying to support his independence as much as possible, while coming to the broader realization that what’s possible for him is shrinking.”

For Stephen, Alzheimer’s was winning. Simufilam was failing.

As the family’s struggle unfolded, an obscure researcher hundreds of miles away was preparing to send shudders through the Alzheimer’s research world and well beyond.

Chapter 2

“Magic Hands”

Big Timber, Montana; Cambridge, Massachusetts; Atlanta; Austin; New York City 1965–2021

“I mean, this is wild. It’s zombie science!”

—ROGER NICOLL, NEUROLOGIST, UNIVERSITY OF CALIFORNIA SAN FRANCISCO

One word captures Lindsay Burns: exceptional. From her beginnings in the remote western ranchlands of tiny Big Timber, Montana—midway between Yellowstone National Park and the Crazy Mountains—to the heights of academia and Olympic stardom, she worked phenomenally hard and aimed high. In everything she touched, the muscular, poised, sandy-haired athlete and scholar with a brilliant, toothy smile seemed destined for greatness.

She would lead research behind simufilam, an effort to turn the experimental Alzheimer’s drug from Cassava Sciences into the most important medicine in the history of dementia.

Born in 1965, Burns spent her formative years on the family spread, with its one thousand head of cattle. The founding patriarch of the western branch of the Burns family was Lindsay’s great-grandfather, Horatio Hutchinson Burns. He migrated out west and by 1884, at twenty-four, owned a cattle and sheep ranching operation in Northern Wyoming.

Horatio’s son, Robert Horatio Burns, became a cow puncher at thirteen, among his proudest achievements. It was a generational signal that the family—which prospered on the vast Wyoming range—fully embraced the cowboy culture. But Horatio still dispatched Robert, fresh off his coming-of-age adventures, to a polar-opposite world: New Hampshire’s elite Phillips Exeter Academy, a preeminent college-prep boarding school. Robert went on to Harvard, where he earned a degree in economics in 1927. So began the family heritage of merging east coast erudition with love for the vast, open west.

After college, Robert returned to work with his father amid Wyoming’s windswept expanses. Then in 1951 the family moved operations two hundred miles northwest to the spectacular vistas of Big Timber, buying a ranch on rugged acres near meandering Swamp Creek, north of the tiny town center. Nestled in the foothills, four thousand feet up, with views of the snow-peaked “Crazies,” even Hollywood found irresistible romance in that scenic land. Robert Redford shot his acclaimed dramas The Horse Whisperer and A River Runs Through It in and around Big Timber. Robert Burns built deep civic connections to his chosen community—joining the Masons, Shriners, Elks, the local Farm Bureau, and the Montana Wool Growers.

But in that isolated land—peopled by individualists and sometimes-restive skeptics of authority—he took an ominous political turn, according to a declassified Federal Bureau of Investigation report from 1964. It described Robert as affiliated with the Minutemen, a right-wing extremist group. They stockpiled weapons to fight an anticipated communist takeover of the United States.

“BURNS SHOULD BE CONSIDERED ARMED AND POSSIBLY DANGEROUS,” the memo blared in scare-caps. “Burns is obtaining an old model Lewis machine gun.” The World War I–era weapon could fire five hundred to six hundred rounds per minute. It added: “Also he desires to obtain some cheap shotguns that could have the barrels sawed off to twenty inches for use by their group.”

The FBI believed Burns was distributing “None Dare Call It Treason,” an anti-Soviet screed that sold millions of copies. The book praised staunch anticommunist Barry Goldwater and red-baited moderate candidates. It was credited as a key factor in Goldwater’s 1964 Republican nomination for president. “None Dare” promoted the conspiracy theory that the US State Department was riddled with communists, and blamed Soviet and homegrown communist infiltration for tearing apart bonds between churches, civic groups, schools, and their communities. Sweet Grass County—home to Big Timber—voted solidly for Goldwater in the general election, giving him the second-highest margin of any Montana county.

Despite Robert Burns’s alleged radicalism, he was never arrested and lived out his life peacefully as a successful rancher. His son, Lindsay’s father Horatio “Rasch” Winspear Burns, was born in 1931 in Sheridan, Wyoming, a relative metropolis with its population of about nine thousand. On Rasch’s fourth birthday, his mother died, a tragedy that seemed to cement his inheritance of Robert’s steadfast self-reliance.

In 1945, at age fourteen, Rasch followed his father’s example, stepping onto a transcontinental train to attend a different boarding school— Milton Academy in Massachusetts, also among the nation’s most prestigious. After surviving “a severe case of culture shock,” he continued on to Harvard to take a degree in economics as his father had done. He added a passion that would prove central to his daughter Lindsay’s future—rowing crew.

After his Ivy League education, Rasch rejected graduate school and turned down job offers from Ford Motor Company and NASA. Again, the allure of the distant Burns ranch and the life of an outdoorsman proved impossible to resist. In early 1953 he rejoined his father, who by then was in Big Timber. Like Robert, Rasch built deep connections to the local community, becoming senior deacon of the Masonic lodge, a representative on various ranching organizations, and vice president of the local rifle club.

An avid hunter, he traveled to Point Hope, Alaska, just across the Bering Strait from Siberia, to shoot a polar bear. It was among several bear-hunting trips, including two to Russia. In 30 degrees below zero weather, he traveled via ski-plane searching for polar bears, peering down from one hundred feet above the icy terrain. After a heart-stopping landing, Rasch shot a nearly ten foot tall, “cunning and crafty” bear from about 185 yards, scoring three direct hits. The hunter and his guide skinned the animal, giving what they considered the “questionably edible” meat to the native Alaskans. The pelt was tanned for the Burns home in Big Timber.

ATHLETIC STRATOSPHERE

Rasch and Sheila Ellen Shepherd married in 1961 and raised their own family of high achievers. Lindsay and her brother, Cameron, emerged from a rich stew of civic engagement, love of the land, guns and hunting, and plenty of athletic competitions. From the start, the siblings showed keen competitive drives, particularly Lindsay. Among the first of dozens of mentions about her exploits in the local paper, the Big Timber Pioneer, was a victory at age seven in the local sack races.

Lindsay’s young life was filled with joyful, rural Americana, including membership in the local 4-H club. At age ten, she and her family made and sold candy suckers at the local Christmas bazaar; their effort earned a charming feature photo in the Pioneer.

In a first hint of her research ambitions, during grammar school Lindsay and a friend surveyed the number of trees in town—a formidable project. “There’s a lot of ‘timber’ in Big Timber,” an article in the Pioneer duly noted. “And if you don’t believe it, just ask Christy Drivdahl and Lindsay Burns.” The girls counted a sampling of trees and houses, then extrapolated their findings to come up with 10,560 trees—about seven times as many trees as people—“not counting bushes.” The precocious grasp of something approximating scientific methodology hinted at her future professional endeavors.

The fourth-generation rancher often herded cattle on horseback and traversed family fields cutting hay on a giant mower. But when she reached age fourteen, following the family tradition, Rasch dispatched his daughter to boarding school. She followed in his footsteps to Milton, whose alumni include Ted Kennedy, Robert F. Kennedy Sr., T. S. Eliot, the legendary World War II general Douglas MacArthur, and Illinois governor and billionaire JB Pritzker.

The school’s rarefied environment set the academically minded young woman on a glide path to Harvard in 1983, where she excelled in psychobiology, and—again, like her father—rowing, a sport in which she would soon eclipse him. Weighing no more than 130 pounds, Burns rowed primarily as a lightweight. The term thoroughly mischaracterized her in every other way, especially her unbridled determination and sheer competitive drive.

As a freshman, she cracked a rib, a painful stress fracture common to rowers, but tried to ignore it. “I rowed on it until it was ugly,” she said. The same year, she flipped her boat in the “icy March waters” of the Charles River in Boston. Burns called it “a lesson on hypothermia, not to mention some details about boats and gravity.” She loved the sport so much that she insisted on practicing on weekends. Harvard’s stately Weld Boathouse was closed, so Lindsay scaled its brickwork like Spider-Woman to enter through a second floor window to get to her boat. (Administrators later nailed the window shut.)

The hard work paid off. Rising steadily through the ranks, Burns traveled to Copenhagen in 1987 for the world championships. She outfitted her team of four with lucky rattlesnake earrings—easy to find in southern Montana. They edged out competitors from West Germany and China. It would be the first major triumph of an illustrious career that took her to Tasmania, Vienna, Prague, and Tampere, Finland.

Burns continued rowing as a PhD student in neuropsychology at the University of Cambridge in England—another of the world’s greatest and most selective institutions of higher learning. Afterward, she returned to Boston to train as a postdoctoral fellow at the Harvard-affiliated McLean psychiatric hospital. Her work involved the successful transplantation of fetal pig cells to rats in an effort to replenish cells killed by neurological disorders. It signified her growing fascination with dementia research.

Burns extended her rowing career to a thirteenth year to compete in the 1996 Atlanta Olympics—which added a lightweight division—in the double sculls, where one rower sits behind another. Before a wildly cheering American crowd, she and Teresa Zarzeczny were narrowly edged out by the German team. The silver medal still provided a glittering capstone to an illustrious athletic career. The exhilarating global recognition paled beside the party in her honor where it mattered most. Big Timber’s “Lindsay Burns Day” that August featured speeches by local dignitaries and a potluck feed for all of Sweet Grass County. “Don’t miss out on this chance of a lifetime! Come celebrate with Lindsay Burns!” the announcement in the local paper trumpeted.

SCIENTIFIC AMBITIONS

Grounded in rough-hewn Western self-confidence, imbued with Ivy League privilege, and armed with the success of world-class accomplishment at a young age, Burns seemed equal to any new challenge. Her next was drug development.

After bouncing around a couple of biotechs, in 2002 she joined the tiny pharma company Pain Therapeutics. Its big idea, amid the raging opioid-addiction epidemic, was an “abuse-deterrent, extended-release gel formulation of oxycodone.” The encapsulated, sticky goo was meant to address a daunting problem: Addicts crushed and snorted or smoked oxy, or dissolved it and shot it up, turning a painkiller designed to work over several hours into an instant, fleeting high. The company named its drug “Remoxy”—described as a narcissistic mash-up of CEO Remi Barbier’s first name and oxycodone. Remoxy “can serve a meaningful social purpose and, potentially, may save lives during the worst drug crisis in American history,” the company boasted in a press release.

Barbier, a finance guy who had spent his career in the drug development business, previously had worked for Exelixis and ArQule, cancer medicine companies. The dark-haired, well-groomed CEO often showed a touch of informality reflected in his open-collar, jeans-clad pose in occasional features about his company in business magazines. Barbier subsidized work on Remoxy with investments from potential partners and investors, supplemented by federal grants. Pain Therapeutics amassed a sizeable research and development war chest.

Burns had trained under illustrious neuroscientist Trevor Robbins at the University of Cambridge, but her work was not notable among his protégés. According to Neurotree, a website that chronicles the influence of leading scholars, forty-three of Robbins’s students went on to esteemed positions in the field. Burns didn’t make the cut. Yet she joined Pain Therapeutics as vice president for neuroscience. Burns and Barbier began a romance. They wed in June 2005 and lived in the Bay Area, where the company was headquartered. Later they bought a luxury home in Austin, Texas, where Pain Therapeutics relocated executive offices in 2011.

Burns formed half of the brain trust behind Remoxy’s development. The other half was Hoau-Yan Wang, a graying but boyish-looking professor at the City University of New York (CUNY) who favors large rectangular glasses. Wang, now in his midsixties, had long conducted basic research on the brain’s dopamine receptors, which play a key role in memory, learning, emotions, and the neural reward system. He was particularly interested in how the habitual use of recreational drugs or painkillers—including cocaine and opioids—promoted deeper addiction by flattening the response of dopamine receptors and sparking demands for more drugs to get the same high. Pain Therapeutics had no labs. Wang conducted much of its bench science at CUNY.

Wang has his own equally driven but less brand-name success story. He emigrated from his native Taiwan in the early 1980s to complete a master’s degree at St. John’s University, then earned his PhD degree in pharmacology at the Medical College of Pennsylvania, which later became part of Drexel University. His collaboration with Burns began in the mid-2000s, when he endured a grueling daily commute between his home in Philadelphia and his new job teaching and running a small lab at CUNY. The cost of the commute weighed on his finances. “New York real estate is very expensive, and my wife and kids are happy in Philadelphia,” he said at the time. When Amtrak raised the price of its monthly pass to more than one thousand dollars, Wang took a slower transit route to save money, he said. “Otherwise, we might as well send my paycheck straight to Amtrak by direct deposit.”

Pain Therapeutics apparently noticed Wang because his basic research examined drug development targets for pain relief, which fit the company’s opioid focus. When he became its research collaborator and scientific advisor, Wang’s long-standing interest in filamin A—the brain protein that he later concluded holds the key to Alzheimer’s disease—also became Burns’s central focus. Filamin A provides cellular scaffolding that affects the brain’s opioid receptors. In one of their earliest joint scholarly papers, published in 2008, Wang and Burns said their data established filamin A as a key target to both improve opioid pain relief, yet “prevent opioid tolerance and dependence.” The company viewed the protein as vital to lift its prospects in a crowded marketplace.

It was the start of a rich research collaboration by Burns and Wang, who ultimately shared inventor credit on fourteen patents related to filamin A. In each case, they assigned Pain Therapeutics the rights to use the intellectual property.

The company worked for more than fifteen years to move Remoxy through the drug approval pipeline. The Food and Drug Administration (FDA) rejected its application for marketing over and over. Shareholders accused Pain Therapeutics of failing to report the agency’s concerns about the drug—including its chemistry and manufacturing—leading to an abrupt drop in the company’s share price. Without admitting wrongdoing, Barbier and his company settled the case for up to $8.5 million. It would not be the last time they faced a shareholder revolt.

Remoxy didn’t work as described, the FDA concluded. Barbier called the move a “horrible travesty,” and blamed a convoluted and sometimes-confusing regulatory maze for the failure. With alliterative flourish, the company cited “math errors, material mistakes, or misrepresentations” in the FDA’s review. Its “lack of transparency, clarity, or helpfulness” stifled innovation, sending more than $100 million down the drain, company officials said in February 2019. “We can’t work with shambolic regulations,” they added. The bitter turn of phrase would later be deployed against his company to caustic effect.

THE NEW BIG IDEA

Barbier had always been one of Pain Therapeutics’s largest individual shareholders, and Burns also received blocks of stock and options—the right to buy shares later at a preset price. Over the years their ownership had been reduced by stock sales that earned the pair many millions of dollars; they still held about 5 percent of the company. But Pain Therapeutics never won federal approval for its drug. With Remoxy moribund, the company looked to be circling the drain. On paper, Pain Therapeutics was worth just $19 million, compared to $470 million a decade earlier. The Barbier-Burns family stake shrank in value to less than a paltry $1 million.

Barbier needed a new big idea fast. Wang and Burns supplied it. Filamin A might not lead to a tamperproof opioid, but it offered a tantalizing prospect for something that could be even more important, and breathtakingly lucrative: a remedy for Alzheimer’s disease.

The duo had been erecting the scientific scaffolding for the company’s new organizing principle just as another bold scientific venture was beginning to unravel under intense scrutiny. In 2015, then-billionaire Elizabeth Holmes, CEO of the once-revolutionary lab-test company Theranos, made a comment that seemed apt for Pain Therapeutics, “When you have that passion, you will get back up when you get knocked down. And you will get knocked down over and over and over again, and you win by getting back up . . . that’s what winning is about.” A few years later, she was infamously exposed as a fraud. As Burns commented about Holmes on LinkedIn at the time: “She has a lot more explaining to do.” Those words would later haunt Burns herself.

Many experts believe that Alzheimer’s dementia can be traced to harm caused by certain hallmark proteins: One of those, “tau,” resides inside neurons, the brain cells central to cognition. Tau deposits are called “tangles”—after their convoluted shape, like a mass of knotted string. The second protein, amyloid-beta, creates sticky “plaques,” amorphous deposits that occupy spaces between the cells, as well as a soluble, toxic form that can kill neurons, according to many scientists.

Wang and Burns offered a novel hypothesis: Alzheimer’s occurs due to a misfolded form of filamin A, twisted into an abnormal shape. Instead of performing its normal scaffolding role, misfolded filamin A causes inflammation and promotes the formation of tau and amyloid-beta proteins, according to the two scientists. Burns and Wang developed an experimental drug—code-named PTI-125—that they said returns filamin A to a benign shape and reverses those terrible effects—the promotion of tau and amyloid-beta proteins—produced by its misfolded evil twin. They said the drug, which could be developed in pill form to treat Alzheimer’s, also lessens resistance to insulin, which regulates blood sugar and has been tied to the formation of amyloid plaques by some scientists. In short, unlike most other Alzheimer’s drugs, PTI-125 purportedly offers a grab bag of “mechanisms of action”—the scientific term for how the drug affects the body biochemically. It adopted several ideas advocated as central to Alzheimer’s by factions in the competitive world of drug discovery. For Wang, it must have been an enormous source of pride. His grandmother and both of his parents-in-law were living with Alzheimer’s.

Pain Therapeutics pivoted hard and fast. Barbier transformed the company’s core mission and changed its name to the stylishly enigmatic Cassava Sciences, “to better reflect a new strategic focus on drug development for neurodegenerative diseases, such as Alzheimer’s.” The name was pulled from the street in the tony Austin neighborhood where Barbier and Burns made their home, according to some observers. It seemed an odd choice. Cassava root is widely touted in online forums and nutritional- supplement ads as a brain-health remedy, including claims that it counters Alzheimer’s symptoms—without a shred of credible evidence. Ironically, some varieties of cassava naturally contain the poison cyanide. If improperly prepared, ingesting the root causes cognitive decline. Nor did it boost the company’s credibility when, a few months later in a corporate presentation, it represented the chemical structure of the hallucinogen LSD as that of PTI-125. For good measure, the LSD diagram apparently came from Wikipedia.

Soon after, Cassava developed a pill form of PTI-125 and adopted the chemical name sumifilam in August 2020. “A very famous author once asked, what’s in a name?” said Barbier, riffing on Shakespeare’s Romeo and Juliet. “With apologies to that author, that which we call sumifilam by any other name would still elicit palpable excitement for an absolutely new type of drug therapy for Alzheimer’s disease.” His comments resembled self-parody three months later, when it came out that sumifilam was already in use for another drug. Barbier transposed two vowels to rename his drug simufilam.

ZOMBIE SCIENCE

Despite the embarrassing snafus, if Burns and Wang were correct, associating the new Alzheimer’s remedy with historically great literature might seem warranted. It could rank as a premier discovery in medical history.

The scientists had established simufilam’s plausibility for tests in people based partly on research on human brain samples conducted in Wang’s CUNY lab. His techniques evoked a different literary masterpiece: Mary Shelley’s Frankenstein.

Wang claimed to have effectively revivified long-dead brain tissue. The samples had been frozen at super-cold temperatures, in some cases ostensibly for years. He partly thawed, then chopped the donated tissue, and said it could transmit chemical signals between nerve cells. Wang dosed the still-subzero tissue with simufilam to test the experimental chemical’s possibly beneficial effects. The technique, he and Burns wrote in scholarly papers, lent support to the overall idea that simufilam can counter the causes of Alzheimer’s. The work’s frigid novelty generated substantial interest in the idea that insulin resistance—akin to diabetes of the brain—plays a leading role. (Insulin, a hormone, regulates how the body processes sugar. People become diabetic when the body makes too little insulin or cells stop responding to it correctly.) A paper to that effect by Wang, Burns, and colleagues, published in the respected Journal of Clinical Investigation, has been cited by other scholars more than 1,800 times. After it appeared, NIH funding for insulin-related Alzheimer’s work rose sharply.

The findings also raised eyebrows. How did an obscure lab at a university not known for cutting-edge neuroscience research make so momentous a discovery involving novel biochemical findings from postmortem brains, when no one had previously done so?

“It’s hard for me to imagine how you could get any life from that tissue,” said brain-slice expert Roger Nicoll of the University of California San Francisco. “I mean, this is wild. It’s zombie science!”

Wang, with or without Burns, cited precedents for the extraordinary work—a standard element of any scientific paper, particularly one meant to establish credibility for an unusual technique. But the footnotes were self-referential, tracing back to earlier work by Wang himself.

The CUNY researcher seemed to have “magic hands”—a term scientists sometimes use to describe a preternatural talent to achieve hoped-for, problem-free results, time after time, experiment after experiment. A laboratory savant, Wang succeeded in work considered outlandish if not impossible by other experimentalists. Such a maven can become a fixer of sorts for other researchers, including top-tier professors who lack the patience for tedious, protracted lab work. Yet when ambitious collaborators get what they want, skepticism can be the first casualty. They’d rather conclude that the lab expert knows what he’s doing.

Wang attracted elite coauthors from leading universities. They included Julie Schneider and David Bennett of Rush University— overseer of a major bank of donated brain samples—and Steven Arnold of Harvard. He even signed on the late John Trojanowski, a University of Pennsylvania scientist who was one of the most prolific and influential Alzheimer’s scholars.

Such coauthors on the “zombie” papers conferred substantial credibility. Arnold, along with Burns’s mentor Robbins and Robbins’s neuroscientist spouse, Barbara Sahakian, and Jeffrey Cummings from the University of Nevada—another prominent Alzheimer’s researcher— joined Cassava’s paid scientific advisory board. Such boards effectively vouch for a company’s work. Given that Cassava had no record of commercial success after two decades of operations, it reassured funders, regulators, and investors. The famous names helped Cassava gain $20 million in grants for simufilam and other work by Wang or Burns from the premier federal funder, the National Institutes of Health (NIH). Their simufilam collaborators (including Arnold) gained tens of millions more for related studies. NIH would ultimately underwrite clinical trials necessary to gain eventual FDA approval. Cassava was suddenly on its way to testing simufilam not in frozen tissue, but where it really counts: in the brains of living Alz heimer’s patients.

MISTAKES WERE MADE

The new strategy slowly lifted the company’s battered share price—until it reported results from an early clinical trial of simufilam involving sixty-four participants. It was a bust. In May 2020, Cassava announced that the drug failed to reduce levels of tau or other targeted biomarkers associated with Alzheimer’s. “Today’s top-line results disappoint and are not consistent with previous clinical experience for reasons that are unclear,” said Barbier. The company’s stock lost three-quarters of its value overnight.

But a few months later, after a fresh analysis, Barbier had better news. Tau and other Alzheimer’s biomarkers actually had improved sharply, he reported. Barbier blamed the earlier disappointing results on unspecified “mistakes” by a lab contractor. “It’s hard for anyone to fess up to exactly what happened and when and who did what,” Barbier said in a call with investors. “We did our forensic inquiries, we clearly see mistakes . . . we really rely exclusively on the second bioanalysis from this study.”

Then he announced a more stunning development: Patients taking simufilam showed memory improvements after just a month— extraordinary for any Alzheimer’s trial. “Filamin-binding molecules are new to Alzheimer’s research and may represent an important advance if these data can be replicated in larger studies,” crowed Cummings, the Cassava advisor, in a press release. He was identified by his academic credentials, with no mention of his role as paid consultant. “I am pleased to see early evidence of disease-modifying effects in patients,” Cummings said. “The data appear to represent a step forward toward urgently needed treatments for Alzheimer’s disease.”

Cassava’s share price rebounded instantly and sharply. And the good times kept rolling. In early February 2021, the company made public triumphant results for the same fifty patients after they had taken simufilam for six months. Their performance on cognitive tests showed that Alzheimer’s-related measures—including memory, anxiety, and delusions—improved even more, this time by 10 percent.

For Wang, Barbier, and Burns, it wasn’t just frozen brain tissue coming back to life. It looked like the kind of scientific resurrection that leads to Nobel Prizes, as some company boosters began suggesting on social media soon after. Less than two weeks later, Cassava announced that it had raised $200 million from investors in a public stock offering at a whopping $49 a share—several times the trading price only weeks earlier. “With solid science, the right people in place, cash in the bank and a clinical roadmap that makes sense, I think Cassava Sciences is positioned to becoming a premier organization to serve patients with Alzheimer’s disease,” Barbier said proudly, when announcing Cassava’s stellar financial condition in March 2021.

The company unveiled more impressive data, described as unprecedented, in July. Simufilam improved cognitive test scores in two out of every three patients after nine months, and most others suffered only modest declines in cognition. “Cassava Sciences believes today’s data is the first report of significant cognitive improvements at nine months that also track with robust improvements in biomarkers in patients with Alzheimer’s,” the company’s press release noted.

Some leading scientists openly scoffed at the Cassava announcement. “Uninterpretable,” said Lon Schneider, a physician and neuroscientist at the University of Southern California Alzheimer’s research center. “Overblown, inappropriate, and naïve,” said Rob Howard, an Alzheimer’s researcher at University College London. “It’s the sort of presentation that one might expect an undergraduate to make.”

Those scientists and others cited basic concerns that would apply to any clinical trial for a new drug. The Cassava experiment’s sample size at nine months was just fifty participants. So tiny a group offers exceedingly weak statistical power—a measure of how confident scientists can be that the findings were not due to chance alone. And the experiment used an open-label design; both experimenters and patients knew that they were getting simufilam pills, rather than a placebo. This made it vulnerable to bias compared to a double-blind, controlled design—particularly with results based on cognitive tests that rely on the subjective impressions of patients and their ever-hopeful caregivers and clinicians.

In an interview in 2021, Barbier was asked if later trials would include a placebo group. He provided a revealing and chilling reply: “It’s an evil necessity.”

Online boosters led a buying frenzy among small-time investors in the volatile stock. Cassava’s market valuation rocketed into the stratosphere, topping $5.4 billion—280 times its value less than two years earlier. On paper, the Barbier and Burns family was suddenly worth $147 million.

They had reinvented the company and rescued it from failure and obscurity. “These clinical data . . . suggest highly encouraging and durable treatment effects for people living with Alzheimer’s disease,” Bar-bier said. To Cassava’s true believers, simufilam was the long-awaited, ever-elusive pill to effectively treat or even cure one of the most terrifying diseases.

The jubilation didn’t last long. On August 18, 2021, weeks after the company’s stock reached an all-time high, two neuroscientists—Geoffrey Pitt of Weill Cornell Medical College and David Bredt, a former executive at drugmakers Eli Lilly and Johnson & Johnson—submitted a lengthy “citizen petition,” in which individuals or a consumer group can ask the FDA to address concerns about an experimental drug—for simufilam. Their attorney provided evidence that dozens of scientific studies underlying simufilam’s development contained manipulated scientific images. In short, they asserted, the work looked like it had been doctored.

The allegations called into question fundamental claims about simufilam and how it might affect Alzheimer’s, if at all. Some of the research by Wang, Burns, and key collaborators, according to the petition, appeared to be “fraudulent.”

The public announcements hit Wang hard. He “collapsed from stress and exhaustion, and due to the significant emotional trauma, he voluntarily admitted himself to Bryn Mawr Hospital for treatment,” his wife later said in an affidavit.

Burns normally let Barbier announce good news and blast critics. This time Burns couldn’t resist lashing out in her LinkedIn feed: “Cassava Sciences hit by false allegations,” she said after the FDA filing, adding a thinly veiled legal threat. “Hit job by a law firm that admits it represents short sellers, makes its case in the Court of Public Opinion (as opposed to a Court of Law). Unreal.” She had a point. Pitt and Bredt were also “shorting” the company’s stock and would profit if Cassava shares fell. But documents provided by the neuroscientists—whatever their motives— were compelling and generated enormous uncertainty about simufilam.

The petition validated and extended growing doubts Matt Price had about the drug that his family was hoping against hope would help his dad, Stephen, gain a few better years. But like so many family members who lacked good options to help a loved one, he couldn’t give up. Matt advised Stephen to stay in the trial. He continued taking simufilam twice daily. “I remembered a meme from the ’90s TV show The X Files of this poster that says, ‘I want to believe’ beneath a little alien saucer,” Matt said. “I wanted to believe that simufilam wasn’t all a fraud.”

The FDA petition’s key findings were not only by Pitt and Bredt. Their lawyer hired a physician and neuroscientist who had the specialized knowledge and skill for the job.

Like Burns, the scientist emerged out of the remote rural west— a Washington State farming town with fewer than two thousand residents— about the size of Big Timber, Montana, five hundred miles east on Interstate 90. Like Burns, he was brilliant and ambitious. But he followed a more humble path into neuroscience—homeschooling, followed by undergraduate training in a less-august university by relatively obscure professors. He became an expert in the dominant amyloid hypothesis of Alzheimer’s, which for decades has marked amyloid-beta proteins as the chief culprit.

During the course of his young career—he was thirty-six when the FDA petition was filed—the scientist had completed thousands of scientific images displaying proteins. In the process, he developed a seasoned eye for detecting digital manipulation with common software programs. Such images can easily be changed to better reflect researchers’ hypotheses—sometimes leading to grants, influence, patents, and even riches. But doctored images, he knew, could also poison the scientific record—sending scientists down costly dead ends. They could even risk patients’ lives.

The simufilam matter and the FDA petition formed the genesis of what would become an epic scientific journey. The young scientist would uncover a scandal that soon eclipsed the Cassava intrigues. His anonymous sleuthing would cast unprecedented doubt on the amyloid hypothesis. His work would lead to the discrediting of leading figures in Alzheimer’s research. It would raise grave concerns about the trustworthiness of the scholarly press he found has been routinely publishing suspect or faked papers. And in the process, the researcher would mount a formidable challenge to billions of dollars in spending by the federal government and giant pharma companies.

The softspoken, nonchalantly rumpled junior professor at Vanderbilt University would become the most important whistleblower in the history of Alzheimer’s.