The Bad Medicine of “Doctored”

The journalist Charles Piller’s recently released book “Doctored: Fraud, Arrogance, and Tragedy in the Quest to Cure Alzheimer’s”¹ expounds four examples of alleged scientific misconduct within the field of Alzheimer’s disease (AD) research. Described as a “shocking tale with huge ramifications,”² the book has received extensive media coverage and its central premise was even mentioned in recent Congressional hearings.

Scientific misconduct happens in every field of research and is without question dangerous and unacceptable. But science self-corrects—observations and hypotheses that do not stand up to replication are abandoned. To wrongly extrapolate to an entire field the actions of a few bad actors, no matter what career heights they have ascended to, is misleading and potentially even more harmful.

Doctored attempts to make the case that the central amyloid cascade hypothesis within AD research is not only supported by falsified data, but that it has been the product of a “mafia” of powerful researchers who put down alternative hypotheses and areas of study. The book also incorrectly asserts that the unearthed misconduct and falsified data were essential to recently approved amyloid-lowering therapies, which are described as woefully inadequate and dangerous for patients.

In fact, among the four vignettes of alleged scientific misconduct emphasized in Doctored, only one is principally related to the amyloid cascade hypothesis. That is the now retracted 2006 Nature paper by Sylvain Lesné and colleagues that identified a novel soluble oligomeric form of Amyloid-β (Aβ) known as Aβ*56. Though the paper (and others by this group on the topic) was highly cited, it is a mischaracterization to suggest that the newly identified species played an outsized role in AD research, or that it played a role in the development of the recently approved amyloid plaque-lowering therapies.

The amyloid cascade hypothesis is among the most well-supported in neurologic disease research. For over a century, AD has been defined by neuropathological lesions, Aβ plaques and tau neurofibrillary tangles, that accumulate in the brain in highly stereotyped and well-characterized patterns. Converging cellular and animal model as well as longitudinal human biomarker studies have demonstrated that Aβ accumulation triggers post-translational modifications of tau, accumulation and spread of tangles, synaptic and brain network dysfunction, and ultimately cognitive and functional decline. Rare autosomal dominant disease-causing mutations are exclusive to genes that are directly involved in the production of Aβ.³ Trisomy 21 leads to overproduction of Aβ and cognitive decline due to AD neuropathologic changes.⁴ The argument that amyloid accumulation represents a benign sequelae of aging since older adults can demonstrate normal cognitive function despite the presence of substantial amyloid burden is quickly becoming antiquated, as it is clear that amyloid burden is tied directly to risk and timing of the onset of cognitive problems in older adults.⁵ Most recently, the amyloid plaque-lowering monoclonal antibodies lecanemab and donanemab have demonstrated efficacy in modestly slowing the rate of cognitive and functional decline in early AD, with hints of impact on downstream biomarkers of tau,⁷ through large, double-blind, randomized, placebo-controlled clinical trials, the gold-standard for medical evidence.⁶ Treatment-associated amyloid-related imaging abnormalities (ARIA), focal areas of brain edema or hemorrhage, are mostly asymptomatic and can be mitigated by careful patient selection and MRI surveillance. Serious ARIA-related clinical outcomes occur in <2% of treated patients (including very rarely death), commensurate with risks associated with therapies used to treat other relentlessly progressive illnesses. The emphasis on the amyloid cascade hypothesis as a leading model for disease pathogenesis and drug development is not due to fraudulent efforts to mislead, it is the result of logical pursuits based on available evidence and extensive scientific replication.

Piller asserts that we’ve lost 20 years in the fight against AD due to fraudulent research, but the reality is that AD research is anything but lost. Tremendous progress has been made over the last decades that includes amyloid-targeting treatments, which offer meaningful, if modest, clinical benefit. Discovering better, safer, and more accessible therapies is a major goal of current research and, importantly, candidate therapies have targets well beyond Aβ. The National Institute on Aging, for example, is supporting 495 clinical trials, including drug trials testing a multitude of therapeutic targets, non-pharmacologic intervention trials, caregiving studies, and trials of novel diagnostic tools. Of these, 12 are directly related to Aβ. This diverse approach reflects an understanding in the field that AD therapy will ultimately require a multi-pronged approach, potentially targeting numerous elements of the disease’s complex pathophysiology beyond Aβ (e.g., tau, neuroinflammation, synaptic activity, neurotransmitters, etc.) as well as treatable disease risk factors and psychosocial elements.

Furthermore, it is increasingly clear that most cases of late-life cognitive impairment are underpinned by multiple etiologies. Beyond Aβ and tau, other pathological protein aggregates (e.g., α-synuclein, transactive response DNA-binding protein 43) and cerebrovascular changes are often found at autopsy in older adults who died with dementia. Multiple etiology dementia also may be more common among members of specific communities, emphasizing the need to continue every possible effort to discover treatments that target the many neuropathologies that contribute to cognitive impairment and dementia. Consensus scientific opinion is that more precise combinations of approaches will be needed to maximize each patient’s clinical benefit.

The last decades of research progress in AD and related disorders have been exciting, important and hard-earned. Progress has been the direct product of investments in research funding, as well as increased participation in research by patients and their families. Yet the highly publicized mischaracterization of AD research by Doctored contributes to a false narrative that threatens to slow or halt this momentum. Misconduct is reprehensible and should result in the highest levels of accountability. Yet unjustifiably casting a shadow of doubt on an entire field based on the misconduct of a few further erodes trust in science and scientists. Amid sweeping changes in federal funding and a steadily swelling population of older adults, to even slightly decelerate investments in dementia research based on misconceptions about the state of the field could delay progress, harm public health and the economy, and place the health of millions of aging Americans at risk.

Media headlines that repeat sensationalist claims sway public opinion and change behaviors. Some participants have withdrawn from AD prevention trials based on the media attention paid to Doctored and even the slightest hindrance of already challenging clinical trial recruitment delays further advances. It is critical that the public is informed of the progress made by scientists and the critical role citizens play by participating in research. Scientists must also endeavor to be more accessible and to serve as trusted sources of credible information, particularly for people enrolled in our studies. Scientists must clearly and directly engage the public, distilling all we are learning and how it impacts everyday citizens’ lives in plain language. It is critical that the public be able to turn to and trust true experts as their source for information, rather than leaving them to grasp at the latest misinformation and conspiracy theories.

AD was once untreatable and could only be diagnosed with certainty at autopsy. Now, diagnosis can be supported with simple blood tests and patients can be offered meaningful therapeutic options. Today more than ever, there is a need to accelerate progress to discover even more effective therapies for AD, treatments for other neurodegenerative processes that cause dementia, and means of staving off dementia for all. To ignore the progress being made by thousands of high integrity researchers engaging in this critical and challenging work—let alone to let the actions of a few individuals derail this important work—would be a real tragedy.