Critical elements of one of the most cited pieces of Alzheimer’s disease research in the past two decades, published in 2006, may have been purposely manipulated, according to a report in Science, with a group of scientists saying the findings deserve more scrutiny.
Alzheimer’s is the most common cause of dementia globally, according to the World Health Organisation. The highly influential paper, which was published in Nature in 2006, has helped guide billions of dollars in US federal government research into Alzheimer’s, reports Science.
The study, which looked at cognitive decline in mice, proposed that a specific amyloid protein might be responsible for cognitive decline. The hypothesis has since dominated the field, and researchers have worked for years to understand the mechanism by which such proteins may lead to decline, reports The Guardian.
But now a neuroscientist in Tennessee, Vanderbilt University, Professor Matthew Schrag, has written a recent Science article saying he and other reviewers have identified as many as 10 papers on the protein that deserve deeper scrutiny. The report also cited other prominent researchers who have had difficulty replicating results of the studies on the specific proteins.
“I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he told Science, when revealing his role as a whistle-blower. “The data should speak for itself.”
The heart of the matter is whether images in multiple papers were manipulated to better support a hypothesis, with the work of researcher Sylvain Lesné under particular examination. Lesné, an associate professor at the University of Minnesota, is now under investigation by the university.
His co-author on several papers is Dr Karen Ashe, also a University of Minnesota researcher and one of the most prominent Alzheimer’s researchers in the country. She told the Minneapolis Star Tribune the potential manipulation of images was “devastating” but criticised the idea that her research into amyloid proteins singularly guided federal and drug company spending.
Finding a treatment for Alzheimer’s has eluded scientists for decades. Although there are drugs to treat the symptoms of early and middle stage Alzheimer’s, only one drug has been approved by the US Food and Drug Administration (FDA) to treat the protein plaques associated with Alzheimer’s: aducanumab.
That drug, sold under the brand name Aduhelm and developed by Biogen, was the subject of its own controversy last year. As it was being considered for approval in 2021, multiple FDA officials said there was not enough evidence of its benefit to support approval.
Nevertheless, the agency approved the drug, which Biogen priced at $56,000. That prompted the resignation of three FDA officials, one of whom said there was “no good evidence the drug works”.
More than 6m Americans are believed to be diagnosed with Alzheimer’s, says the National Institute on Aging. More than 850,000 people in the UK suffer from dementia, according to the Alzheimer’s Society.
2006 Study details
A specific amyloid-β protein assembly in the brain impairs memory
Sylvain Lesné, Ming Teng Koh, Linda Kotilinek, Rakez Kayed, Charles Glabe, Austin Yang, Michela Gallagher & Karen Ashe.
Published in Nature on 16 March 2006
Abstract
Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-β precursor protein (APP) variant linked to Alzheimer’s disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-β protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6–14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-β. We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which we term Aβ*56 (Aβ star 56). Aβ*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Aβ*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer’s disease.
Science article (21 July 2022) – Blots on a field? (Open access)
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