Dr. Alberto Espay, a University of Cincinnati neurologist, is at the center of a national and international debate that could change the course of the nation’s Alzheimer’s research and pave the way for safer and more effective drugs for treating the disease.
Espay’s groundbreaking research was triggered by a study touted as proof of the effectiveness of a new Alzheimer’s drug published in the prestigious New England Journal of Medicine in late November 2023. A clinical trial had found a slower decline among early Alzheimer’s patients treated with a monoclonal antibody called lecanemab, which reduced the tell-tale sticky plaques in the brain long associated with the disease.
For the nearly 7 million Americans and their families faced with the devastating effects of Alzheimer’s, the possibility of a few more years or even months of companionship with their loved ones was welcome news.
But what made Espay skeptical of the study was that 51 previous clinical trials of similar plaque-reducing drugs had failed to show any positive impact on patients, despite having reduced the presence of plaques in their brains. In fact, placebo performed better than anti-plaque drugs in five times as many trials. Worse still for patients, the new class of drugs presented life-threatening side effects, like bleeding and fluid accumulation in the brain.
For more than 30 years, Espay argues, the National Institute on Aging and Big Pharma have invested tens of billions of dollars in a dangerous hypothesis that they’ve never proven but can’t let go of — the ability of plaque-destroying medications to slow the decline in Alzheimer’s patients.
The tell-tale “amyloid plaques” and tangled nerve fibers found in the brains of Alzheimer’s patients were first discovered by German neuropathologist and namesake Alois Alzheimer in 1907 during a post-mortem of patient Auguste Deter. Prior to her death, the middle-aged woman had shown all the classic symptoms of the disease — memory loss, confusion, erratic behavior. Not until 1984 were the plaques identified as the non-functioning clumps that accumulate in the brain from the destruction of a vital neural protein called amyloid beta 42.
The theory that the buildup of amyloid plaques was the cause of Alzheimer’s got a decisive boost in the ’90s when non-invasive methods, such as PET scans and MRIs, were introduced to measure the amount of plaque in the brain. Armed with a “biomarker” for the disease that could be detected in living patients, doctors and drug companies believed they could measure the effectiveness of their medications by looking at how much of the plaque was removed from the brain. If clinical trials failed to show improvement in patients, it wasn’t because the theory was wrong but rather that the trials were poorly designed or executed, or because not enough plaques were removed.
Contradicting this belief, however, is an undeniable fact — most people with amyloid plaques will never develop dementia as they age. Even at age 100, more than half of centenarians with plaque buildup in their brains showed no signs of dementia in a New England study that began in 1994.
So how was this latest trial of the anti-plaque drug lecanemab any different?
Espay decided to look at the article’s supplementary materials — the how-the-sausage-is-made details behind every study that are seldom published within the article itself. What he found confirmed his suspicion — the new drug not only eliminated amyloid plaques from the brain, but it also increased levels of the healthy amyloid beta protein crucial to normal brain functioning. (The principal author of the lecanemab study, Dr. Charles van Dyck of the Yale School of Medicine, did not return an email asking for comment.)
“Quite a few of us are walking around with plenty of amyloid plaques in the brain and are doing just fine,” Espay says. “But not a single individual with dementia has normal or high levels of amyloid beta 42.” There’s no mystery why, he argues. Amyloid beta 42 is found in the brains of nearly all animals and has survived mutations over millions of years because of the protection it offers the brain.
Espay and his colleagues at UC soon went to work on their own study, analyzing data from 26,000 individuals enrolled in 24 clinical trials testing the effectiveness of anti-plaque drugs in Alzheimer’s patients. In addition to plaque reduction, the clinical trials also assessed levels of the amyloid beta 42 protein before and after treatment. What the UC study found was that higher levels of amyloid beta after treatment were associated with slower cognitive decline. In the few trials where anti-plaque treatment seemed to have benefited patients, the medication also increased the amount of healthy amyloid beta in the brain.
Published in the leading neurology journal Brain in September of 2024, the UC study may offer a safer and perhaps more effective way to treat Alzheimer’s patients by using medications that raise amyloid beta — that is, if this new approach is accepted by the predominant players in the Alzheimer’s research industry. Changing the dominant paradigm in Alzheimer’s research won’t be easy, Espay says. “We love to do research to confirm our ideas. We become enamored with our ideas; we marry them. And it’s hard after you marry an idea to divorce it.”
In recent months, however, the industry’s decades-long faith in anti-plaque theory has been shaken by a new book questioning the data of hundreds of supporting studies. In Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s, investigative journalist Charles Piller asked a team of medical and imaging experts to examine the papers of 46 of the nation’s leading Alzheimer’s researchers.
The experts identified nearly 600 suspect papers, most of them lending support to the treatment of Alzheimer’s patients with anti-plaque drugs. Cited some 80,000 times in the scientific literature, the papers have distorted the field’s knowledge base and reinforced its dangerous conformity, Piller argues. “It’s easier to publish dubious science that aligns with conventional wisdom,” he wrote in a recent New York Times op-ed piece.
As the number of aging Americans increases, so too does the devastating presence of Alzheimer’s, robbing victims of their memories, their dignity and eventually their lives, and robbing their families of meaningful interaction with their loved ones. Women in America who reach the age of 45 have a 1 in 5 lifetime risk of developing Alzheimer’s, while men after age 45 have a 1 in 10 chance, according to the Alzheimer’s Association.
With so many Americans and their families desperate for a way to slow the cognitive decline of Alzheimer’s, perhaps it was only a matter of time before the FDA caved to the pressure. On June 7, 2021, pharmaceutical co-owners Biogen and Eisai announced the FDA approval of “Aduhelm, the first and only Alzheimer’s disease treatment to address a defining pathology of the disease by reducing amyloid beta plaques in the brain.”
Despite the advertising hype, Aduhelm (aducanumab) was soon engulfed in controversy over the evidence for its effectiveness, the laxness of the FDA’s accelerated approval process and the drug’s daunting cost — $56,000 a year, a price tag that threatened to bankrupt Medicare. Six months later, after few doctors would prescribe the drug and even fewer insurers would pay for it, Biogen took Aduhelm off the market.
Over the next three years, the FDA approved two more anti-plaque drugs that showed marginal effectiveness in slowing the decline in early Alzheimer’s patients — lecanemab (Leqembi), again developed by Eisai and Biogen, and donanemab (Kisunla), developed by Lilly. Both are monoclonal antibodies that Espay argues are marginally successful because they increase levels of healthy amyloid beta protein rather than removing amyloid clumps alone. Ironically, the drugs lessen the full benefit of the healthy protein through the toxic action of removing the plaques, he says.
After the FDA approvals of Leqembi and Kisunla, “the thought then was that the amyloid (plaque) hypothesis was right all along,” Espay says. “We just needed to persevere and we’re so happy we persevered because we finally got what we knew all along was there — or should have found earlier if the trials had been better.”
The seemingly endless repetition of negative clinical outcomes for anti-plaque drugs was always blamed on the design of the trials and their execution, never on the theory itself, Espay says. “So, the dose was too high or too low. Or the sensitivity of the measurements wasn’t adequate enough. Or to use the favorite (excuse) — the patient population was too advanced.”
Researchers who have resisted Espay’s analysis include some of his own highly respected mentors. “To be honest, most of the well-known professors were in the field 20 years ago,” Espay says. “They’re the ones who wish to preserve their legacy. It’s unfortunate because no idea is ever perfect, and we should be quicker at rejecting false ideas.”
The dominance of the anti-plaque theory has made it tougher to get funding for alternative treatments that upset the conventional wisdom. Espay says several FDA-approved medications for other conditions could be repurposed for elevating the healthy amyloid beta protein in Alzheimer’s patients, but he can’t secure the federal grants or attract the private investment to start expensive clinical trials. “Funding doesn’t come easily when you are asking to test a therapy that makes no sense under the current paradigm,” Espay told about 20 physicians attending a grand rounds lecture at UC Medical Center in March.
At age 54, Espay — the gentle, soft-spoken father of five — isn’t someone who relishes his role as a scientific gadfly. He was born in Santiago, Chile, but grew up in Venezuela from age 4 after his father was exiled by Chilean dictator Augusto Pinochet. He completed medical school in Venezuela, then his residency at Indiana University, followed by a neurology fellowship at the University of Toronto.
Espay was planning on returning to IU to practice neurology but found the university’s new administrators were more interested in clinical practice than research. In 2005, he came to the University of Cincinnati, where he was encouraged to do both. Espay has published over 300 research articles and eight books. In his introduction to Espay’s grand rounds, his department colleague and protege, Dr. Abhimanyu Mahajan, told the audience that Espay’s “work demonstrates a passion for deconstructing unproven and partially proven hypotheses and investigating scientific gaps and controversies.” He then added less formally, “He has taught me everything I know, but not everything he knows.”
Other promising Alzheimer’s therapies have also been choked by the iron grip of anti-plaque theory. Dr. Mary Newport, a Cincinnati neonatologist whose husband, Steve, was diagnosed with early Alzheimer’s at age 54, says he regained and maintained years of cognitive health with a ketogenic diet extremely low in carbohydrates and supplemented by a daily intake of coconut oil, a drink rich in fats that can be converted to ketones. Within two months of the new regimen, Newport says, he improved from moderate to mild dementia, enough so that he qualified for a clinical trial of an anti-plaque medication in 2010. Lured by the hype for the trials at the time, she quickly enrolled her husband.
But after six weeks of taking the new drug, he began suffering serious side effects — hair loss, fever blisters, wounds that wouldn’t heal — as well as a return of his Alzheimer’s symptoms. Newport withdrew him from the trial and continued with the ketogenic therapy and, in 10 months, he was reading again.
“I had a doctor’s appointment and he was in the waiting room (with copies of the) magazine Scientific American,” she says. “A few hours later, he told me that he had read the story in Scientific American about Albert Einstein and told me some of the details about it. I mean, for somebody with Alzheimer’s, he couldn’t even finish a sentence before he started coconut oil.” Meanwhile, Newport says, the anti-plaque drug trial was discontinued because the medication was making patients worse.
Newport adopted the ketogenic therapy for her husband first developed in the ’90s by Dr. Richard L. Veech of the National Institutes of Health. Veech died in 2020 after decades of studying the health benefits of ketones. “He just couldn’t get a grant, even from the NIH, which he worked for, to do a clinical trial of his (therapy). He just couldn’t convince the people at the top that this was something that could work.”
Both Espay and Newport agree with the growing consensus in the research community that Alzheimer’s disease, like cancer, very likely has multiple causes — genetic, age-related, environmental and perhaps viral as well — and will need a panoply of treatments to subdue.
The heated debate over the anti-plaque treatment of Alzheimer’s is a step in that direction, Espay says. “I want to believe that we’re at that point in which there has been a crisis generated. And crises are good because crises allow us to rethink what we’re doing.”
But change will come more quickly if pressure is applied from patients and their families outside the industry, Espay says. “We don’t need more money or more patients participating in research inspired by the same hypothesis created thirty years ago. We need better ideas, and the ability to reject false ideas more quickly.”
This article appears in Aug 6-19, 2025.