Alzheimer’s disease, known as the “eraser in the brain,” is a neurodegenerative disease with an unclear and incurable pathogenesis. The journal Science recently published an investigative report that a 16-year-old seminal research paper in the field of Alzheimer’s disease is suspected to be fraudulent, threatening the mainstream theory of “beta amyloid deposition (Aβ)” and possibly impacting the direction of research and new drug development.
Suspected falsification
For many years, Alzheimer’s disease drug development has been based on the most accepted “hypothesis” – beta amyloid deposition. The abnormal deposition of beta amyloid in the brain may trigger a series of reactions such as Tau protein hyperphosphorylation, neurotransmitter disruption and oxidative stress, leading to neuronal damage and subsequent dementia. And stopping β-amyloid deposition is considered the most reliable treatment strategy. However, over the decades, hundreds of clinical trials targeting beta-amyloid therapies have ended in failure, and more and more researchers have begun to doubt the hypothesis.
It was not until 2006 that University of Minnesota graduate student Sylvain Lenné published a paper as the first author in the British journal Nature, directly demonstrating in a mouse model that the subtype of beta amyloid, Aβ56, is neurotoxic and causes dementia in mice, which is equivalent to re-injecting the beta amyloid hypothesis into the “strong heart”. This was the “strongest shot in the arm” of the beta amyloid hypothesis, when Nature reviewed it and called Aβ56 the “prime suspect” for Alzheimer’s disease.
In 2021, Schrager accidentally discovered problems with the images in several of Lehner’s papers, most of which were related to Aβ*56, including the paper published in Nature.
Schrager sent his findings to Science, which then conducted a six-month investigation, and the evidence strongly supported Schrager’s suspicions. Independent image analysts and a number of top Alzheimer’s disease researchers reviewed the images at the request of Science and agreed that dozens of images in the Lehne paper may be faulty.
However, the jury is still out on whether the paper is a confirmed forgery. Science said it would require complete, unpublished images and raw data from the researchers involved to discern. The University of Minnesota is also reviewing the points of contention in the Lainé study, which will probably take several years.
Controversy is hard to dispel
Science says Schrager’s findings could threaten major theories in the field of Alzheimer’s disease, and statistics show that the paper has been cited more than 2,300 times. The National Institutes of Health has reportedly spent about $1.6 billion on beta amyloid-related projects this fiscal year, about half of its total funding for Alzheimer’s disease research.
However, some neuroscience experts interviewed by the reporter said the questioned paper cannot yet shake the current mainstream status of the beta amyloid hypothesis. Li Yanfeng, chief physician of the Department of Neurology at Peking Union Medical College Hospital, told reporters that even if the paper is confirmed to be falsified, the impact on related research will be limited. At present, the mainstream conclusion of the academic community on the pathogenesis of Alzheimer’s disease is still the beta amyloid hypothesis, beta amyloid deposition is still an important pathological marker of Alzheimer’s disease, is the cause of the trigger neurodegeneration.
In fact, controversies about the β-amyloid hypothesis have persisted. Dr. Qiu Zhihai from Guangdong Institute of Intelligent Science and Technology told reporters that it is generally believed that extracellular amyloid plaques form first, followed by neuronal cell death, but recently there are also articles suggesting that “neuronal cell death occurs first, followed by extracellular amyloid plaques”, and subsequent related research is worth looking forward to.
R&D Black Hole
Alzheimer’s disease drugs have always been a “black hole” for pharmaceutical companies, with huge investment over decades but little success. Research and development mainly revolves around beta amyloid and Tau protein deposition. However, in recent years, there have been few successful clinical trials of drugs targeting these two targets, leading to increasing questions about the beta amyloid hypothesis, which has been the “monopoly” of the field for nearly 30 years.
A report by the American Association of Drug Research Institutes and Pharmaceutical Manufacturers shows that 146 clinical trials of Alzheimer’s disease drugs failed between 1998 and 2017.
However, experts believe that new drug development for Alzheimer’s disease is moving forward amidst controversy, with new targets and new hope emerging, and has entered the “era of great voyages.
According to a report released by the Alzheimer’s Disease Drug Discovery Foundation, the existing Alzheimer’s disease R&D pipeline is not only focused on beta amyloid and Tau proteins, but also on a wide range of innovative targets. There are currently 118 therapies in clinical development aimed at altering the course of Alzheimer’s disease, with up to 77% of therapies addressing multiple areas related to the pathogenesis of aging and neurodegenerative disease, including neuroprotection, inflammation, mitochondrial and metabolic function, synaptic function and neurotransmitters, genetics and epigenetics.
