Have We Got Alzheimer’s All Wrong? Research Fraud Threatens Science

Alzheimer’s disease is a terrifying illness that slowly destroys sufferers’ memory, personality, and sense of self. It is a progressive neurodegenerative disorder that causes brain atrophy (shrinkage) and neuron death [1]. Brain and bodily functions decline as the disease progresses, and average life expectancy post-diagnosis is only 3-10 years [2]. No true treatments exist, and we currently have no way to stop or reverse its progression – only slow it down.

Neuroscience | Katherine McLean

In 2006, Nature published a breathtaking study that shaped the direction of Alzheimer’s research for years to come. Sylvain Lesné was a neuroscientist on the rise at the time, working in the University of Minnesota, Twin Cities lab of the renowned researcher Karen Ashe. Lesné and his team reported the first definitive identification in brain tissue in Alzheimer’s research of a substance shown to cause memory impairment – a long-awaited discovery that seemed to finally validate the influential yet contentious amyloid hypothesis of Alzheimer’s disease [3].

The amyloid hypothesis identifies a type of protein named amyloid beta (Aβ) as one of the disease’s primary drivers [4]. Imbalances in the production and ‘clean-up’ of these proteins lead to accumulated amyloid beta ‘plaques’ in the brains of Alzheimer’s sufferers. The amyloid hypothesis postulates that these cytotoxic (toxic to cells) plaques are not simply a by-product of the disease, but the trigger behind the cascade of harmful changes visible in Alzheimer’s patients’ brains – the first domino in the deleterious chain, so to speak. Lesné’s study identified a specific subtype Aβ protein – Aβ*56, or “amyloid beta star 56” – as causing memory loss in rats. Suddenly, amyloids were confirmed as an active agent of the disease. This smoking gun bolstered support for the amyloid hypothesis, validating proponents and spurring myriads of other Alzheimer’s researchers to turn away from other theories and towards Aβ plaques.

However, in late July this year, just as researchers from around the globe were coincidentally sitting down for the 2022 Alzheimer’s Association International Conference, the ordinarily staid field was shaken to its core. A bombshell investigation published in Science unveiled potential fabrications in both Lesné’s original 2006 paper and his later works [5].

Whistleblower Matthew Schrag, a neuroscientist focused on Alzheimer’s disease, first raised the alarm last year after finding what appeared to be edited and duplicated sections in the papers’ images. He brought his concerns to Science, who decided to conduct their own 6-month investigation into this potential image doctoring. Science reached out to two independent image analysts to corroborate Schrag’s findings – Jana Christopher, an image data integrity analyst, and Elizabeth Bik, a microbiologist and forensic image consultant whose identifications of manipulated imagery in scientific publications have resulted in 879 retractions, 116 expressions of concern, and 952 corrections (as of July 2022). Bik and Christopher agreed that many of the images flagged by Schrag appeared to have been tampered with and even identified further suspicious images in additional papers. In total, the investigation found over 20 “suspect” papers by Lesné, including more than 70 individual instances of image doctoring – ranging from selective enhancement to “copy and paste”. In experiment after experiment, serious anomalies kept occurring. It appears Lesné deliberately faked data to better fit his hypothesis. Without access to the raw data we cannot know for sure, but this seems to be a case of systemic, deliberate academic fraud.

This devastating news indicates that decades of research may have been misdirected and billions of dollars in research funding and pharmaceutical development allocated on false pretences. The amount of time and money that may have been wasted due to this fraud cannot be overstated. Other promising avenues of Alzheimer’s research, such as the role of inflammation due to infection, have been consistently sidelined by funding and conferences in favour of the promise of Aβ proteins and plaques [5].

Funding allocated by the American National Institutes of Health (NIH) to Aβ has exponentially increased since 2006, largely due to Lesné’s paper [5]. Approximately $1.6 billion of funds allocated to Alzheimer’s research by the NIH last fiscal year was directed to projects mentioning “amyloid” in their title – around half of all Alzheimer’s funding. How many of these projects were based on incorrect assumptions? How many were doomed to fail from the start? Lesné’s 2006 paper has been cited over 2000 times since its publication, making it one of the most-cited in the field. Nature has now added an editor’s note, stating that “the editors of Nature have been alerted to concerns regarding some of the figures in this paper” and warning readers to utilise data and results from the paper with “caution” [3], but countless pieces of work have already taken Lesné’s spurious conclusions as fact.

Pharmaceutical companies have spent years developing drugs designed to attack Aβ plaques in the hopes of preventing and treating Alzheimer’s disease. Clinical trials have frustratingly failed to provide clear-cut evidence of anti-amyloid therapies slowing cognitive decline [6], yet the promise of Lesné’s papers has spurred research onwards despite repeated failures. Anti-amyloid drugs have even been successfully pushed through FDA approval processes despite dubious, even dangerous, results in trials, based largely on blind faith and desperation [7]. If it were not for this near-total dominance of the amyloid hypothesis, research in Alzheimer’s prevention and treatment could be years ahead of where we are now.

The Big Picture

If scientific research worked as it should, this fraud should never have been able to go unnoticed. Our discipline is deeply flawed. I hope, however, that this can become a teachable moment. If we want to prevent incidents like this from reoccurring, then at least two core things must change: the attitudes of our institutions and organisations towards publishing and the unyielding pecking order of academia itself.

Firstly, we must acknowledge that the natural hierarchy of academic seniority has become toxic. Junior scientists cannot speak up or voice concerns about research by senior investigators without jeopardising their own careers. One of the main reasons that the 2006 paper remained significantly unquestioned for so long was the highly respected status of the laboratory head, Karen Ashe; Lesné’s subsequent work also remained unquestioned due to the status that he gained for himself as Ashe’s ‘rising star’ [5]. Only a few researchers even attempted to replicate any of Lesné’s results, and, when those that did were unable to reidentify Aβ*56, they automatically assumed that they must be the ones who messed up – not Lesné. For 16 years, scientists were held back by their fear of being reprimanded for daring to question the leaders of their field. This toxic culture needs to change. We must be able to question the work of our seniors without jeopardising our reputations.

Secondly, the constant push to publish novel research needs to stop. Top-tier journals are consistently reluctant to publish identical replications or experiments with negative results, forcing researchers to avoid replicating prior studies or questioning standard, broadly-accepted hypotheses. In this case, research that doubted the amyloid hypothesis’s strength has been consistently relegated to second-tier journals (at best). Researchers also cannot afford to spend valuable time on a project that might not end up being publishable, as a lack of regular publication will stall their career progression (the classic ‘publish or perish’ situation). Consequently, a vast majority of studies never get questioned after their initial publication. Questioning, replicating, and accepting negative results as positive outcomes may be ‘good’ science, but good science is not currently earning those coveted tenured professorships.

To avoid repeating the failures that led to this situation, we must hold science accountable. However (and that is a very big ‘however’), we cannot undermine its efforts and provide ammunition to the opponents of science. Far too many scientists have been speaking out about Science’s investigation in ways that cause further harm. I have been watching in various online forums as science deniers enthusiastically latch onto experts’ criticisms and use them to ‘prove’ that science is broken and scientists cannot be trusted. When talking about events like these, we must never present an incomplete picture for others to fill in. For example, instead of saying “that was bad science” and leaving space for deniers to expand your statement, be explicit and say “most science is good science, but that specific experiment was not.” How you say things matters almost as much as what you say. Try to contextualise adverse facts by explaining, for example, that we became aware of this individual’s academic dishonesty thanks to other scientists continuing to search for the truth, think critically, and work to do good science.

We must also be careful of where we comment. Social media has become increasingly integral to academic networking, and many scientists now have a professional online persona. However, the statements and criticisms shared in private with scientific peers are not always appropriate to be shared on social media. It is too easy for non-scientists to misinterpret valid, targeted criticisms of a scientific study as much broader statements on science as a whole. In public, we need to be seen to support each other as scientists – the overarching message the public needs to receive is that, in general, scientists have faith in science. It is like parenting – duke it out behind the scenes but present a unified front to the kids. While we must hold science accountable, we need to think about what we say and how and where we say it

These events have emphasised how desperately science needs a dual culture shift: institutions and organisations need to stop forcing shallow novelty in research and allow researchers to question and replicate without fear of reprisal, and scientists need to stop prioritising seniority and work towards a more egalitarian discipline. Reducing the toxic "old boys" culture and making science more equal and open may also help alleviate public mistrust of science. In a time of increasing scepticism, events like these can be enormously damaging – they are precisely the sort of thing that erodes the public’s trust in scientists and scientific research. To insulate science against future damaging dishonesty, we must turn this mess into a learning opportunity.

Acknowledgements

Acknowledgements to Alexander Swain, whose opinions helped shape this discussion.

Katherine McLean - BA (Hons), Biological Anthropology

Katherine is an Honours student in Biological Anthropology with focuses in palaeoanthropology and the evolution of cognition. She is currently working as a mentor and tutor for Anthropology Tuākana and is on the 2022 editorial team for UoA’s Interesting Journal.