Letter from Leading Alz Researchers: Journal “overstates and distorts” influence of flawed 2016 study

August 26, 2022 -

In a letter to the editor published in Science responding to the journal’s recent article on the apparent manipulation of data in a 2006 study of amyloid-β, two respected Alzheimer’s researchers state that the piece “overstates and distorts the effect of this paper on the Alzheimer’s field” and “does not threaten the ‘reigning theory’ of Alzheimer’s pathobiology, known as the ‘amyloid hypothesis’.

The authors—Drs. Dennis Selkoe, The Vincent and Stella Coates Professor of Neurologic Diseases Harvard Medical School and Jeffrey Cummings, Director of the Chambers-Grundy Center for Transformative Neuroscience at UNLV—explain how the data in question is not a factor in recent research and doesn’t affect current treatment development. Read the full piece below.

As experienced researchers in the Alzheimer’s disease field, we have serious concerns about the News story “Blots on a field?” (C. Piller, 22 July, https://scim.ag/3T1evDh). The article summarizes the apparent manipulation of data in a2006 study (1) and suggests that coauthor Sylvain Lesné committed egregious scientific misconduct when preparing figures supporting a central role for the specific amyloid-b (Ab) peptide, Ab*56, in memory loss in mouse models of Alzheimer’s disease. Such investigative reporting is important to correct potential fraud. However, the article overstates and distorts the effect of this paper on the Alzheimer’s field.

Lesné’s alleged malfeasance does not threaten the “reigning theory” of Alzheimer’s pathobiology, known as the “amyloid hypothesis.” The tone and content of the News story and the sensationalized media coverage it generated could derail Alzheimer’s drug discovery and development based on the amyloid hypothesis, which is supported by a vast body of well-conducted research.

By 2008, 2 years after the Lesné paper, Alzheimer’s researchers determined that the findings supporting Ab*56’s role in cognitive decline could not be replicated. Several, including one of us (D.S.), tried (2, 3). Although unaware of malfeasance, the field policed itself by not confirming these findings. Rather than being a “key element” of today’s theory supporting the association between Ab accumulation and cognitive decline, Lesné’s “star suspect” rapidly became history as the science of Ab oligomers moved ahead. Simply put, the 2006 Lesné et al. study had minimal, if any, impact on the evolution of the amyloid hypothesis.

Today, approximately 16% of Alzheimer’s drugs in development are predicated on the amyloid hypothesis. Only a few of these directly target Ab oligomers, and none targets Ab*56 specifically. No patients have been misled and entered trials based on the Ab*56 observation. Targeting Ab-associated neuronal dysfunction represents one of the field’s most promising approaches to prevent and treat Alzheimer’s disease.

Dennis Selkoe1* and Jeffrey Cummings2 1Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA. 2Chambers-Grundy Center for Transformative Neuroscience, Pam Quirk Brain Health and Biomarker Laboratory, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV 89052, USA. *Corresponding author. Email: [email protected] REFERENCES AND NOTES 1. S. Lesné et al., Nature 440, 352 (2006). 2. G. M. Shankar et al., Nat. Med. 14, 837 (2008). 3. M. B. Rogers, “Sylvain Lesné, who found Ab*56, accused of image manipulation,” Alzforum (2022); www. alzforum. org/news/community-news/sylvain-lesnewho- found-av56-accused-image-manipulation. COMPETING INTERESTS D.S. is a director and consultant to Prothena Biosciences and an ad hoc consultant to Eisai. J.C. has provided consultation to Acadia, Alkahest, AlphaCognition, AriBio, Biogen, Cassava, Cortexyme, Diadem, EIP Pharma, Eisai, GemVax, Genentech, Green Valley, Grifols, Janssen, Lilly, LSP, Merck, NervGen, Novo Nordisk, Oligomerix, Ono, Otsuka, PRODEO, Prothena, ReMYND, Resverlogix, Roche, Signant Health, Suven, and United Neuroscience pharmaceutical, assessment, and investment companies. 10.1126/science.ade1872