‘Red flags’ spark concern over validity of key Alzheimer’s research

Serious concerns have been raised about the quality of landmark Alzheimer’s research, undermining commonly held beliefs about the disease

The paper in question was published in Nature in 2006 and is considered highly influential in the field. According to Science, it has helped to guide billions of dollars in US federal government research into Alzheimer’s disease.

The study, which examined cognitive decline in mice, proposed that a specific amyloid protein may be responsible for mental deterioration. This hypothesis has since dominated Alzheimer’s research and sparked years of efforts to understand the mechanism by which such proteins may lead to decline.  

The first author of the study, Sylvain Lesné, is now under investigation by the University of Minnesota, where he is an associate professor.  

Claims related to the study’s validity come from Matthew Schrag, a neuroscientist and professor at Vanderbilt University in Tennessee. Schrag, who revealed his role as a whistleblower in the Science report, said he and other reviewers had found as many as 10 papers on the protein that require further examination. Schrag claims that some images in these papers may have been manipulated to better support a hypothesis, but has stopped short of alleging fraud.  

Speaking to Science, he said: ‘I focus on what we can see in the published images, and describe them as red flags, not final conclusions. The data should speak for itself.’  

He does not claim to have proved misconduct, which he says would require access to original, complete, unpublished images and in some cases raw numerical data.  

Over the course of a six-month investigation, Science sought the advice of a leading independent image analyst and several top Alzheimer’s researchers, who supported Schrag’s overall conclusions. Donna Wilcock, an Alzheimer’s expert at the University of Kentucky, said some images showed ‘shockingly blatant’ signs of tampering, while Elisabeth Bik, a forensic image consultant, said the authors ‘appeared to have composed figures by piecing together parts of photos from different experiments.’  

‘The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis,’ Bik said.  

Schrag’s work, which was done independently of Vanderbilt University and its medical centre, raises concerns that millions of dollars in US federal funding may have been misspent on research and related efforts in the 16 years since the influential study’s publication.  

Alzheimer's is the most common form of dementia, affecting 6 million people in the United States alone. This number is projected to rise to nearly 13 million by 2050, according to the Alzheimer’s Association.  

Search for the 1% 

Alzheimer’s drug trials have a notoriously high failure rate – 99% for therapies and 100% for disease-modifying therapies (DMTs), meaning there is currently no cure for the disease.  

Alzheimer’s is characterised by memory loss, confusion and the inability to care for oneself. Although there are drugs to treat the symptoms of early and middle stage Alzheimer’s, only one drug has been approved by the FDA to treat the protein plaques associated with the disease – Aduhelm (aducanumab).  

Aduhelm, which is developed by Biogen, was the subject of controversy last year as only one of two late-stage trials showed that it helped slow cognitive decline. An FDA panel of external experts subsequently said there was insufficient evidence to support its approval. Nonetheless, the agency approved the drug, prompting the resignation of three FDA officials. Matthew Schrag publicly criticised the approval of Aduhelm last year. 

Biogen originally priced Aduhelm at $56,000 per patient but halved the price to $28,200 in January this year. The company said uptake of the drug had been slower than expected during its Q3 results in 2021, reporting revenue of just $300,000 in October.  

Biogen has a second Alzheimer's drug candidate in the works with its partner Eisai. The drug, called lecanemab, is under fast-track review by the FDA, with a decision expected by January 6, 2023.  

Like Aduhelm, lecanemab is an antibody designed to remove sticky deposits of the amyloid beta protein from the brains of people with early-stage disease.  

Criminal probe 

Before whistleblower Matthew Schrag uncovered possible manipulation in the 2006 Nature study, his attention was focused on another Alzheimer’s drug – Simufilam, developed by Cassava Sciences. Last year, Schrag was approached by an attorney representing two neuroscientists who claimed research related to Simufilam may have been fraudulent. The neuroscientists were also short sellers who profit if the company’s stock falls. They asked Schrag to investigate the research and paid him $18,000 to do so, according to Science.    

Schrag identified images that appeared to have been altered or duplicated in dozens of journal articles, which ultimately led to his discoveries related to the 2006 study.  

Now, it has been reported that the US Justice Department has opened a criminal investigation into Cassava Sciences over possible manipulation of research results related to its Alzheimer’s drug. The news broke in a Reuters exclusive on Wednesday, which featured comments by two people familiar with the inquiry.  

The sources did not provide details of the focus of the investigation and whether the department was looking into any specific individuals. 

In a statement to Reuters, a lawyer representing Cassava said: ‘To be clear: Cassava Sciences vehemently denies any and all allegations of wrongdoing’ and added that the company ‘has never been charged with a crime, and for good reason - Cassava Sciences has never engaged in criminal conduct.’ 

On Wednesday, Cassava said in a statement that the report refers to disclosures from November 2021 that certain government agencies had requested information from the company in response to allegations of research misconduct made by investors earlier that year. They added that the short sellers whose claims prompted the information request have been ‘pursuing an unprecedented attack on Cassava Sciences’.