University of Minnesota researcher seeks to put tarnished Alzheimer's discoveries back on track

A star Alzheimer's researcher at the University of Minnesota is working to restore the credibility of her discoveries and funding, following accusations last year that a scientist on her team manipulated or even falsified published images.

Step one for Karen Ashe was redoing her seminal but disputed 2006 paper that turned researchers to a new potential cause of Alzheimer's-related dementia and a target for drug therapies. That occurred in late March, when Ashe and colleagues reported that they used new techniques to once again identify clusters of molecules, Aβ*56, in the brains of mice exhibiting age-related memory loss.

Research has moved on to other molecules that may play a role in the age-related disease, which has inflicted memory loss and cognitive decline on more than 6 million Americans. Ashe herself is focusing on other causes and treatments, but she said that Aβ*56 — phonetically called abeta star 56 — still appears to play an early role in dementia and that she needs to back up her original findings.

"As a lab head and the senior author, it's my responsibility to establish the truth of what we've published," said Ashe, who in 2006 earned the Potamkin Prize, the highest honor in neurology.

Questions about the accuracy of images in as many as 20 papers have emerged on the PubPeer academic website and in an investigation last year by Science magazine. Some papers include Ashe as an author, but all include another U neuroscientist, Sylvain Lesné, and focus on whether Aβ*56 or related molecules cause plaque formations that inhibit the brain's thinking cells.

A U investigation is ongoing, and the journal Nature has flagged the 2006 paper, urging caution in using it for future research until its review is complete.

"Sylvain Lesné is currently employed at the University," said Jake Ricker, a senior U spokesperson. "The review into the previous allegations is ongoing. I'm unable to share further details about that at this time due to privacy laws."

Ashe said she no longer collaborates with Lesné — who wasn't a co-author of the most recent paper — and that she trusts the senior academics conducting the U investigation to sort out the responsibility for any image tampering.

Her current research is focused on Caspase 2 , a human enzyme that can become overactive in the brain and cause memory loss. Ashe is studying a potential drug that could overcome that process and even restore memories. She received more than $700,000 this year from the National Institutes of Health to study Caspase 2, but said that she lost substantial private funding over the imaging controversy.

The updated findings on Aβ*56 were only posted on a preprint server, and Ashe said she is seeking publication in a peer-reviewed medical journal.

The original study involved the identification of Aβ*56 in mice that Ashe genetically engineered to simulate the onset of Alzheimer's. The researchers then injected the molecular clusters into healthy rats, which exhibited signs of memory loss as they tried to navigate a water maze.

The latest study was a reexamination of the original data, but Ashe said it is possible that journal editors will require the identification of the molecules in a new set of mice.

The imaging concerns in the earlier papers centered on western blotting, which is commonly used in labs to create visual representations of the amount of proteins found in blood or tissue. A key question for U investigators is whether manipulations were cosmetic, or whether they produced thicker or darker blots, inflating the strength of the research results.

The concerns already resulted in corrections to images in a 2013 study in the journal Brain, which had documented the role and presence of Aβ*56 and other molecular clusters in people. Later, critics raised concerns about whether the corrected images had also been manipulated.

One of the whistleblowers was Elisabeth Bik, a forensic imaging consultant in California, who said she wasn't surprised when she scanned Ashe's latest paper on Friday and found no immediate concerns. "All her new papers will be looked at for image problems, so I would expect that she did a super careful check."

A problem dogging the U study even before the research controversy was the struggle by other labs to replicate the findings, or even produce Aβ*56 in other mouse models, animals, or people. The benefit of the updated research, Ashe said, is that it used more precise antibodies that more clearly isolated these molecular clusters. The paper offered guidance for others on how to find the molecules, and noted that an independent lab on the U campus used this process successfully.

The discovery of Aβ*56 was a boost to scientists who believed that amyloid beta proteins in general caused harmful plaque formations. Ashe said it directed researchers to focus on clusters of molecules, called oligomers, rather than individual molecules, and led to tests of the first new drugs for Alzheimer's in 20 years.

New options include Aduhelm, a plaque-reducing antibody that received approval in 2021 from the U.S. Food and Drug Administration, despite objections from scientific advisers and lackluster proof that it helped Alzheimer's patients.

This month, drugmaker Lilly reported that an experimental plaque-removing treatment, donanemab, slowed the rate of decline in people with early-onset Alzheimer's. Clinical trial results showed that 47% of treatment recipients experienced no cognitive declines for a year. However, 29% of participants in a comparison group who received non-medicating placebos also experienced no decline.

Ashe said the results underscore the need for more research, because it will likely take multiple drugs targeting multiple molecules to broaden the fight against Alzheimer's and other causes of dementia.

"It's not just abeta star, but other targets as well," she said. "There are maybe a half dozen or more that are very compelling right now."

Lesné did not comment for this story, or for the Science magazine investigation last July. The U professor has published research since the controversy, including a study that found that a gene therapy surprisingly alleviated cognitive symptoms in male mice, but not females.

Lesné has earned more than $5 million in NIH grants since 2018, including a $765,000 award this year to study genetic approaches to inhibiting tau, a protein that can form tangles in the brain and contribute to Alzheimer's and dementia.