First Opinion is STAT’s platform for interesting, illuminating, and provocative articles about the life sciences writ large, written by biotech insiders, health care workers, researchers, and others.
To encourage robust, good-faith discussion about issues raised in First Opinion essays, STAT publishes selected Letters to the Editor received in response to them. You can submit a Letter to the Editor here, or find the submission form at the end of any First Opinion essay.
The story
“How the ‘amyloid mafia’ took over Alzheimer’s research,” by Charles Piller
The response
Dennis Selkoe has already responded to this article. He was too kind. Piller describes the benefits of Leqembi as “minute” and “minimal.” My wife has been on lecanemab since August 2023. She remains an active and happy 59-year-old. Lecanemab has given us more years together. That’s not “minute” nor “minimal” to me. Piller allows that there are “tragic, rare cases of younger people featured in the media.” Two hundred thousand Americans develop Alzheimer’s before age 65. Maybe the media should ignore them. Piller is critical of the financial motives of the drug companies. Yet, he uses patent sensationalism to promote his book, with monikers of “amyloid mafia,” “cabal,” and “Church of the Holy Amyloid.” The hypocrisy is profound.
— Fred Haberle
The response
Finally an essay on the unbelievable “religious” like fervor surrounding the amyloid myth! As I read the article, what struck me was the use of the word “science” mentioned so many times by the “scientists” who had become so enamored with this hypothesis, that they believed it despite the overwhelming data that rejected it. The data, of course, is the number of amyloid-targeted trials that have been carried out over the years (at enormous cost) that have failed! Many of them demonstrating some effect on the amyloid buildup, with no demonstrable clinical benefit for the patient. The primary outcome must be the clinical improvement of the patient, both by validated instruments over specific timeframes compared with placebo controls as well as patient-reported outcomes between the groups in the trials. Observing and measuring biomarkers has a role, but this must be secondary to the clinical improvement of the patient.
— Brian Levy, InflammX Therapeutics
The response
Charles Piller, through exhaustive efforts and dogged adherence to reproducible facts, lays bare a disturbing although decades-old feature of Alzheimer’s disease research, which is the promotion and in some cases fabrication of data to fit a pre-ordained narrative. In doing so, Piller highlights a systematic crisis in a much broader sense, which is the abandonment of scientific principles. According to scientific philosophy, it is not up to journalists or so-called sleuths to question scientific theory. It is up to the scientists themselves. Instead, modern Alzheimer’s disease research has cultivated advocates for a cause. Letter-writing campaigns from the highest levels of academia, opinion articles in scientific journals and mainstream outlets, and group posturing in a manner of cheerleaders on social media are all 180 degrees out of phase with the scientific mode of inquiry. Yet each of these are embedded in the fabric of modern Alzheimer’s disease research.
The thoughtful, science-minded consumer has no choice but to wonder whether the data being presented to them are part of a broader strategy driven by secondary gain, that is both superficially unassailable and an impediment to progress. Piller, in effect, is doing the work of scientists. He is challenging orthodoxy and providing transparency to a public that is largely underwriting the efforts. It reads as clarion call to medical science for a return to basic challenge, rather than promotion, of one’s own observations, so critical to the scientific method and to scientific progress. If medical science thrives through salesmanship and advocacy, questionable data and confirmation bias will find their way into high impact journals, the only question being the extent. In the meantime, Alzheimer’s disease patients and their families will continue to be victimized by false hope, paying for it with their time, their pocketbook, and their lives in some cases.
— Rudy Castellani, Northwestern University Feinberg School of Medicine
The response
Charles Piller’s recent opinion in STAT raises important questions about the mechanistic role of amyloid and highlights issues related to limited access to clinical trial data, both of which have profound implications for research, regulation, and treatment. In two meta-analyses on amyloid-targeting drugs (British Medical Journal, 2021; Alzheimer’s & Dementia, 2024), I have demonstrated a small but statistically significant effect of amyloid removal on cognitive decline, though only in aggregated treatment-group data. However, such group-level analyses may obscure a true, mechanistic link between amyloid reduction and cognitive outcomes: Could participants who experienced the greatest amyloid reduction also have seen the greatest cognitive benefit? Or could participants with the least residual amyloid experience the greatest benefit, irrespective of the amount removed?
Answering this kind of mechanistic question, with data that already exist, would be strong evidence of a causal role for amyloid. Skeptical biologists have proposed alternative mechanisms for the effects of anti-amyloid agents, suggesting that their impact on cognitive decline may stem from immunologic effects rather than amyloid removal. Skeptical methodologists, meanwhile, posit that even minor side effects could unblind caregivers, skewing trial results in favor of treatment. Access to individual-level data would enable testing the true mechanisms behind these agents’ cognitive effects. Demonstrating a causal role for amyloid in treatment is not merely an academic exercise. Amyloid removal has been used as a surrogate outcome in trials as the basis for accelerated approval of aducanumab and lecanemab. Establishing a strong link between amyloid reduction and cognitive benefit is essential for evaluating whether amyloid is in fact a valid surrogate for cognition. If amyloid removal is driving cognitive changes, this evidence could be used to advocate for full approval of future agents based on biomarker changes alone.
On the other hand, if amyloid is not the key driver, accelerated approval based on reduced amyloid is not warranted. Outstanding mechanistic questions continue to drive controversy around anti-amyloid therapies. But the answers may be within our reach. The necessary data already exist, in individual-level results from recent trials of aducanumab, lecanemab, and donanemab — if only it could be made available to researchers with the necessary expertise.
— Sarah Ackley, Brown University School of Public Health
The story
“What my sister’s life and death taught me about the NIH,” by Ariel Reinish
The response
The similarities between this experience and my own are uncanny. A decade ago, in the earlier days of CAR-T, I was also at the National Cancer Institute for a sibling’s treatment — my then-12-year-old brother, Samuel, who had relapsed/refractory ALL. For months, my family and I crossed the street from the Children’s Inn at NIH to the pediatric wing in Building 10, where Sam’s hospital room was, and where he ultimately died. The incessant, critical headlines have been equal parts heartbreaking and infuriating, and similarly, do not at all reflect the NIH that I know. Thank you, Dr. Reinish, for submitting this piece. What a lovely tribute, one that captures the critical, yet missing, perspective that I am still struggling to put into words.
— Claire Whetzel, American Society of Hematology
the response
As a doctor for 35 years and now a patient with metastatic kidney cancer, I have experienced two sides of life. As an M.D. I always kept up with the best research results, referring hundreds to NIH, MD Anderson, and others, which often prolonged life and decreased suffering. As a patient, my treatment has kept me alive and symptom-free for over eight years. These institutions are very necessary and give hope to the desperate. Let them continue to help the anxious and desperate with their research and treatments. Their staff are among the best people, trying to heal the hopeless. It’s cruel and ignorant to save money by shrinking these institutions.
— Alberto Garcia-Romeu, retired internal medicine physician
The story
“The health policy cult’s misplaced faith in government,” by Charles M. Silver, David A. Hyman, and Michael F. Cannon
The response
Charles M. Silver, David A. Hyman, and Michael F. Cannon criticize PatientRightsAdvocate.org for “a misplaced faith in government” when calling on regulators to robustly enforce existing health care price transparency rules and laws. But later, the authors call for “treating health care like an ordinary service that people buy and sell through ordinary market mechanisms.” They miss how the most fundamental market mechanism needed to empower consumers to shop for affordable care and benefit from competition is upfront prices. Price transparency is the keystone of the pro-consumer, free-market healthcare system we all seek, and it deserves adequate government enforcement.
— Cynthia Fisher, PatientRightsAdvocate.org
The story
“Will PBM reform save pharmacies from closing?” by T. Joseph Mattingly II and Kelly E. Anderson
The response
The authors state, “Today, the largest portion of prescription drug revenue for traditional pharmacies is tied to insurance, and the three largest PBMs pay for nearly 80% of all prescriptions in the U.S. That means any price concessions PBMs try to extract out of their pharmacy networks to deliver savings to employer- or government-sponsored health plans would in the end come out of pharmacies’ bottom lines. Whether the payer is a for-profit PBM in the U.S. or a single-payer government entity in France or the U.K., attempting to secure the best prices for prescription drugs will hurt most retail pharmacies.”
However, the dynamics in single-payer systems (like in France or the U.K.) are structured differently. There, the government sets reimbursement rates and often includes fixed dispensing fees to protect pharmacies’ viability. While both models aim to secure the best prices for drugs, in single-payer systems the negotiation and reimbursement mechanisms are usually designed to balance cost savings with ensuring pharmacies remain solvent. In contrast, the U.S. system’s fragmented nature and heavy reliance on private insurers and PBMs can make pharmacies more vulnerable to squeezing.
— Tom McHugh, Optum Rx