Manipulated results in Alzheimer’s study with gave false hope to families, scientists say

Science leaders are demanding a crackdown on medical research fraudsters, warning that the worst offenders pose a threat to public health and should be handed prison sentences.

And they have also called for academic journals that publish dodgy data to be slapped with hefty fines if they fail to act swiftly when fakes are exposed.

The demands come after bombshell allegations that a pivotal study on the cause of Alzheimer’s disease contained manipulated results, potentially leading other scientists down a blind alley, hindering the development of effective treatments and giving false hope to patients and their families. 

It is just the latest in a string of revelations in recent months that have rocked the field of dementia research, and may see top neuroscientists face US government investigations, probes by financial authorities for misuse of public funds and deceiving shareholders, and criminal charges.

In one of the most egregious examples, allegedly falsified data led to patients on a trial risking the side effects of experimental drugs with no chance of seeing any benefit.

Some neuroscientists insist that, while deeply concerning, these problems are outweighed by the large amount of well-conducted research in the field. But others believe corruption will have significantly set back the search for an effective dementia treatment.

There are fears an Alzheimer’s study contained manipulated results that potentially led scientists down a blind alley

Importantly, doubts about some of these studies were raised almost a decade ago, The Mail on Sunday has learnt, leading many to ask why has it taken so long for problems to come to light.

The most recent study to fall under scrutiny, published in 2006, was the first to identify a protein named amyloid beta star 56 as the cause of memory loss in lab mice. 

Authored by Dr Sylvain Lesné, a rising star in Alzheimer’s research at the University of Minnesota, Minneapolis, along with his boss Professor Karen Ashe and colleagues, it went on to be cited in more than 2,000 subsequent studies carried out by other researchers looking for a drug treatment for the devastating illness. 

But some experts expressed concern that they were unable to replicate the study – a vital part of the scientific process that helps confirm findings.

More worryingly, others warned on numerous occasions that images used in the report appeared to have been faked. They alerted the journals that published the studies, yet it wasn’t until June that a warning was put on the suspect paper.

These issues were finally made public a fortnight ago when the highly respected Science magazine published a report highlighting the issues. 

The article was based on findings made by neuroscientist Dr Matthew Schrag, who had analysed Dr Lesné’s work and uncovered manipulation. The key query is around lab tests, called western blots, that feature in the papers.

 The technique is a way to detect proteins in samples of tissue or blood, and the results are presented visually, in digital photographs, as a series of parallel bars or bands.

The suspicious paper was authored by  Dr Sylvain Lesné (pictured), a rising star in Alzheimer’s research at the University of Minnesota, Minneapolis, along with his boss Professor Karen Ashe and colleagues

The suspicious paper was authored by  Dr Sylvain Lesné (pictured), a rising star in Alzheimer’s research at the University of Minnesota, Minneapolis, along with his boss Professor Karen Ashe and colleagues

In Dr Lesné’s study the tests seem to show higher levels of amyloid beta star 56 in the brains of mice that were older, with signs of memory loss. Yet critics say that scores of these images look as if they have been doctored.

Top Alzheimer’s researchers and forensic image analysis backed Dr Schrag’s findings. Some appeared to be ‘shockingly blatant’ examples of image tampering, said Professor Donna Wilcock, a dementia expert at the University of Kentucky.

Dr Elisabeth Bik, a research fraud expert who also reviewed Dr Lesne’s western blots, adds: ‘It’s quite easy to spot. Manipulating images like these is simple to do with Photoshop. You can edit out parts you don’t want.

‘Both of these things appear to have been done in this case.’

Dr Bik has now identified 14 other studies by Dr Lesné that also appear suspicious. Despite this, in the majority of cases, no action has been taken against the journals that published them. The University of Minnesota declined a request to comment by The Mail on Sunday.

Millions spent by government on research

Every year, the UK Government spends approximately £75 million on research into dementia. 

The number of British scientists studying dementia almost doubled between 2009 and 2015, says Alzheimer’s Research UK.

Prof Ashe, a neuroscientist who runs the lab in which Dr Lesné performed his work and who is co-author of the paper, issued a statement saying: ‘Having worked for decades to understand the cause of Alzheimer’s disease, so that better treatments can be found for patients, it is devastating to discover a co-worker may have misled me and the scientific community through the doctoring of images.’

However, she went on to accuse Science magazine of misrepresenting their work and claimed that, despite the problems, the findings were valid.

Richard Smith, a former editor-in-chief of the British Medical Journal (BMJ), who has warned that research fraud is a ‘major threat to public health’, said that the case was ‘shocking but not surprising’. 

He cites research that suggests up to one in five of the estimated two million medical studies published each year could contain invented or plagiarised results, details of patients who never existed and trials that did not actually take place. He adds the problem is ‘well known about’ in science circles, yet there is a reluctance within the establishment to accept the scale of the problem.

In light of the recent debacle, he renewed calls for major changes, saying: ‘Scientific journals make vast amounts of money. If they publish fraudulent work and fail to swiftly put things right, it’s a very serious matter and they need to be held accountable. I would support fines. There also needs to be some sort of global regulator, and criminal prosecutions against those found to have carried out fraudulent research – just like there is with financial fraud.’

Dr Bik agrees that publishers seem reluctant to take responsibility. She says: ‘We need a regulator with teeth. I’ve flagged more than 6,000 studies as potentially fraudulent, but just one in six have been retracted by publishers. Without penalties and the threat of punishment, nothing will change.

‘We know if we break the speed limit in our car we’ll get fined and points on our licence, so we don’t do it. Without these rules, it would be like the Wild West on the roads.

‘The same principles apply here – publishers act with impunity because they can.’

Perhaps even more troubling is that the recent incident isn’t an isolated one.

Biotech firm Cassava Sciences has come under fire for alleged irregularities in research behind its dementia drug simufilam. The medication initially showed great promise. In early studies, two-thirds of patients who took simufilam showed improvement after a year – news that sent Texas-based Cassava’s stock soaring. The company was worth more than £4 billion last summer, according to reports.

It subsequently launched two large-scale trials, which are ongoing and aim to recruit and treat roughly 1,000 dementia patients.

Despite this, many scientists were sceptical about the results presented, claiming the studies were flawed and results ‘cherry-picked’ to show the best possible outcome. Some went further, accusing two researchers, Dr Hoau-Yan Wang of City University New York, and Cassava’s own Dr Lindsay Burns, of tampering with western blots.

Cassava hit back, claiming critics had financial conflicts of interest. But in December the Journal Of Neuroscience issued an ‘expression of concern’ regarding one key study by the pair. 

In March another study they authored was hit with a similar warning from the journal Neurobiology Of Aging. The editors ‘did not find compelling evidence of data manipulation intended to misrepresent the results’, but admitted there were methodological errors on the paper.

The same month, journal PLOS One retracted five papers by Dr Wang, citing ‘serious concerns about the integrity and reliability of the results’.

Two of these studies, co-authored by Dr Burns, focused on the brain protein that simufilam targets. In June, science journal Alzheimer’s Research & Therapy retracted a 2017 study by Dr Wang due to concerns over some western blot images. Yet others, including the prestigious Journal Of Neuroscience, claimed they found no evidence of data manipulation.

More than a dozen journals have failed to respond in any way to concerns raised about papers by Dr Wang and colleagues.

On Wednesday the US Department of Justice launched an investigation into Cassava, looking at whether it may have defrauded investors or government agencies that funded the research. 

A Cassava spokesman said: ‘Cassava Sciences vehemently denies any and all allegations of wrongdoing,’ adding that the company ‘has never been charged with a crime, and for good reason – Cassava Sciences has never engaged in criminal conduct’.

However, Boston University data expert Adrian Heilbut says that if the claims of fabrication were proved correct, then the patients on the current trial ‘are being treated with an imaginary drug that does nothing’. 

He adds: ‘We expect some of the researchers involved to face criminal charges.’

Meanwhile, another dementia medication, aducanumab, sold under the brand name Aduhelm, has also become mired in controversy.

In June last year it became the first anti-amyloid dementia treatment to be approved by US drug watchdog the Food and Drug Administration (FDA).

It was hailed as a watershed moment by the Alzheimer’s Association, America’s biggest dementia campaign group, which has pressed for the medicine to be given the green light. But three members of the FDA advisory committee subsequently resigned in protest and the regulator was accused of collaborating too closely with the drug’s maker, Biogen, sparking an internal investigation, which is ongoing.

Dr Hoau-Yan Wang (pictured), an Alzheimer's researcher, has had five papers retracted journal PLOS One over 'serious concerns about the integrity and reliability of the results’

Dr Hoau-Yan Wang (pictured), an Alzheimer’s researcher, has had five papers retracted journal PLOS One over ‘serious concerns about the integrity and reliability of the results’

One of the committee members who stepped down, Harvard professor of medicine Aaron Kesselheim, branded aducanumab ‘probably the worst drug approval decision in recent US history’. 

NHS chiefs and UK dementia charities have so far refused to back the £40,000-a-year treatment, saying more research is needed.

The key concern was that, despite early studies showing promise, in clinical trials it failed to work.

Biogen re-evaluated the data a number of times and eventually suggested there was an improvement in mental capacity among dementia sufferers – of less than one per cent. 

Professor Robert Howard, a dementia expert at University College London, says: ‘They broke the rules of how you analyse clinical trial results to make it look like there was a benefit when there wasn’t. I see this as fraudulent.’

Worryingly, safety data published in November showed that 41 per cent of patients who took the drug suffered major side effects. The most serious of these include a type of swelling and bleeding in the brain known as ARIA-E. An FDA Adverse Event Reporting System case report shows that at least one woman died from this complication. 

‘Patients have been harmed and some have died as a direct result of taking a drug that didn’t even work,’ says Prof Howard.

Despite this, Biogen is pressing on with a trial into another amyloid drug, lecanemab, while pharmaceutical giants Roche and Eli Lilly continue to develop their versions, gantenerumab and solanezumab.

All the experts we spoke to agree the controversies that have emerged in dementia research are troubling. Both Dr Lesné’s and Dr Wang’s studies were carried out in collaboration with numerous other leading names in neuroscience, and although the degree of their involvement in the alleged fraud isn’t clear, it raises questions about all of their integrity.

‘Could there be a problem with the culture in these labs? We just don’t know. That’s why it’s so concerning,’ says Professor Malcolm MacLeod, a neuroscientist at the University of Edinburgh. 

‘These things cast doubts over everyone involved.’

Prof MacLeod and other experts still hold out hope that amyloid drugs may prove beneficial. ‘There is a lot of good research in this field,’ he adds. 

There are concerns that research papers containing manipulated results have caused delays in creating treatments for Alzheimer's (stock image)

There are concerns that research papers containing manipulated results have caused delays in creating treatments for Alzheimer’s (stock image)

Others, however, are less optimistic. 

Prominent neuroscientist Baroness Greenfield has long voiced doubts over amyloid drugs, saying the build-up of the protein in the brain is a symptom, not a cause of Alzheimer’s.

Prof Greenfield adds: ‘This study was framed as the be-all-and-end-all by scientists who believed amyloid plaque causes Alzheimer’s. People built the whole amyloid story around it. Whenever I argued that theory made no sense, multiple scientists pointed at this paper as proof I was wrong. So while my heart goes out to the researchers who spent years trying to develop this study, I also feel vindicated.’

Professor Robert Howard, a trustee of Alzheimer’s Research UK, says: ‘We mustn’t throw the baby out with the bathwater. We are only going to beat this disease through scientific study and it is vital this continues as there are a lot of people doing good work out there.’

At present there are no drugs that can fight Alzheimer’s. The first company to invent one would no doubt have a billion-dollar blockbuster on its hands – and this, says Adrian Heilbut, has incentivised misconduct. 

He agrees that ‘too much focus on amyloid’ has held back the search for other effective treatments.

Dr Bik agrees that research into other promising avenues of dementia treatment might have missed out on funding after Dr Lesné’s studies were published. 

‘It’s a setback, for sure. We should all be mad about wasted research money, but this really isn’t a unique case.’

The biggest problem, she says, is just how frighteningly common research fraud is. Which begs the question: what can be done to stop it happening in the first place?

Cardiff University neuroscientist Professor Chris Chambers agrees with Dr Bik and Richard Smith. ‘We need to levy fines at academic publishers for every instance of published fraud within their records. Fining them would motivate them to check results before publication.’

Prof Chambers also suggests journals approve studies for publication before they are carried out, on the basis of a proposal. He explains: ‘The main reason researchers fake results is because beautiful results are more likely to be published than boring results. We can solve this problem if journals evaluate study plans and then accept papers based on the quality of the plan rather than the sexiness of the results.

‘Some journals do this, but others fear that publishing science based on quality rather than flashiness will reduce their journal’s newsworthiness. The price for their arrogance is the kind of fraud we see in this case. Until we hold them accountable, it will be the public that suffers the consequences of fraud.’