2006 paper key to amyloid hypothesis to be retracted. Senior author admits doctored images

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TheresaB
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2006 paper key to amyloid hypothesis to be retracted. Senior author admits doctored images

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This article was just published by Science, Researchers plan to retract landmark Alzheimer’s paper containing doctored images (Charles Piller, 4 Jun 2024)

The paper in question, A specific amyloid-β protein assembly in the brain impairs memory (Sylvain Lesné et al, 16 March 2006) underpins a key element of the amyloid hypothesis of Alzheimer’s. It is one of the most cited Alzheimer’s studies of this century, having been cited nearly 2500 times. Many researchers have used the results of this paper as a starting point for their own experiments.

From the just published Science article:
The 2006 paper suggested an amyloid beta (An) protein called Ar56 could cause Alzheimer's. AO proteins have long been linked to the disease. The authors reported that AB*56 was present in mice genetically engineered to develop an Alzheimer's-like condition, and that it built up in step with their cognitive decline. The team also reported memory deficits in rats injected with AB*56.
For years researchers had tried to improve Alzheimer's outcomes by stripping amyloid proteins from the brain, but the experimental drugs all failed. AB*56 seemed to offer a more specific and promising therapeutic target, and many embraced the finding. Funding for related work rose sharply.
A red flag on this paper was raised in 2022, when Science published Blots on a Field (Charles Piller, Science, 21 Jul 2022) which discussed how a neuroscientist/physician discovered suspect images in dozens of research papers on Alzheimer’s disease including the subject 2006 paper.

July 2022, the 2006 paper came with this caution:
Editor’s Note: The editors of Nature have been alerted to concerns regarding some of the figures in this paper. Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein.
Now, as just reported by Science the paper’s senior author acknowledged the paper contained doctored images. From the article in quoting the senior author,
Although I had no knowledge of any image manipulations in the published paper until it was brought to my attention two years ago," Ashe wrote on PubPeer, "it is clear that several of the figures in Lesne et al. (2006) have been manipulated ... for which I as the senior and corresponding author take ultimate responsibility."
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Re: 2006 paper key to amyloid hypothesis to be retracted. Senior author admits doctored images

Post by NF52 »

TheresaB wrote: Thu Jun 06, 2024 5:28 am This article was just published by Science, Researchers plan to retract landmark Alzheimer’s paper containing doctored images (Charles Piller, 4 Jun 2024)...

From the just published Science article:
The 2006 paper suggested an amyloid beta (An) protein called Ar56 could cause Alzheimer's. AO proteins have long been linked to the disease. The authors reported that AB*56 was present in mice genetically engineered to develop an Alzheimer's-like condition, and that it built up in step with their cognitive decline. The team also reported memory deficits in rats injected with AB*56.
For years researchers had tried to improve Alzheimer's outcomes by stripping amyloid proteins from the brain, but the experimental drugs all failed. AB*56 seemed to offer a more specific and promising therapeutic target, and many embraced the finding. Funding for related work rose sharply.
...
July 2022, the 2006 paper came with this caution:
Editor’s Note: The editors of Nature have been alerted to concerns regarding some of the figures in this paper. Nature is investigating these concerns, and a further editorial response will follow as soon as possible. In the meantime, readers are advised to use caution when using results reported therein.
Now, as just reported by Science the paper’s senior author acknowledged the paper contained doctored images....
I have nothing but contempt for Lesne, the co-author of the paper, who still resists the admission that the senior author (and I assume his lab director at the time) has made. His claim that Ab56 is the key form of amyloid in the brains of those with Alzheimer's was never validated.

Yet, regardless of how many times it was used as a reference for one of the studies of amyloid beta, Dr. Bredesen and any AD researcher in the last 15 years would attest that the Alzheimer's field has advanced as far from 2006 as the current iPhone model has from the bulky cell phones of 2006.

The p-tau217 test that Apollo Health plans to offer, along with the Precivity AD, which received FDA designation as a "breakthrough medical device" in 2019 are all designed to predict through a blood test, with a high degree of accuracy, who would show amyloid beta plaques on a PET scan using Abeta 40 and 42. Not because amyloid plaques are sufficient to predict Alzheimer's, but because they have a high association with later biomarkers of neurodegeneration, including tau, GFAP, NfL and loss of hippocampal volume. Amyloid beta is also the central player in cerebral amyloid angiopathy, a condition which is more likely in ApoE 4/4 carriers.

Here's an excerpt from an abstract of a study published November 2023 in JAMA Neurology, from researchers in Munich (with no connection to Dr. Lesne) on why amyloid beta is especially toxic in ApoE4 carriers :ApoE4 and Connectivity-Mediated Spreading of Tau Pathology at Lower Amyloid Levels
Objective To assess if ApoE4 carriers show accelerated amyloid-related tau spreading and propose amyloid positron emission tomography (PET) thresholds at which tau spreading accelerates in ApoE4 carriers vs noncarriers.

Design, Setting, and Participants This cohort study including combined ApoE genotyping, amyloid PET, and longitudinal tau PET from 2 independent samples: the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 237; collected from April 2015 to August 2022) and Avid-A05 (n = 130; collected from December 2013 to July 2017) with a mean (SD) tau PET follow-up time of 1.9 (0.96) years in ADNI and 1.4 (0.23) years in Avid-A05. ADNI is an observational multicenter Alzheimer disease neuroimaging initiative and Avid-A05 an observational clinical trial. Participants classified as cognitively normal (152 in ADNI and 77 in Avid-A05) or mildly cognitively impaired (107 in ADNI and 53 in Avid-A05) were selected based on ApoE genotyping, amyloid-PET, and longitudinal tau PET data availability...

Results The mean (SD) age was 73.9 (7.35) years among the 237 ADNI participants and 70.2 (9.7) years among the 130 Avid-A05 participants.A total of 107 individuals in ADNI (45.1%) and 45 in Avid-A05 (34.6%) were ApoE4 carriers. Across both samples.. we found a significant association between ApoE4 status by amyloid PET interaction and annual tau PET increases... amyloid-related tau accumulation was accelerated in ApoE4 carriers vs noncarriers at lower centiloid thresholds, corrected for age and sex.

Conclusions and Relevance The findings in this study indicate that amyloid-related tau accumulation was accelerated in ApoE4 carriers at lower amyloid levels, suggesting that ApoE4 may facilitate earlier amyloid-driven tau spreading across connected brain regions. Possible therapeutic implications might be further investigated to determine when best to prevent tau spreading and thus cognitive decline depending on ApoE4 status.
Even more important, there is little dispute that people with ApoE 4, and especially those with ApoE 4/4, form toxic amyloid oligomers from the non-toxic amyloid monomers at rates far outpacing those ApoE 3/3. The Nature article APOE4 homozygozity represents a distinct genetic form of Alzheimer’s disease which has received a lot of attention in the media and here makes clear that amyloid beta plaques reach an elevated level in ApoE 4/4 carriers at about 10 years younger on average than ApoE 3/3 carriers, with corresponding decreases in ages of diagnosis of MCI and AD in the studied populations.
Dr. Sterling Johnson, a study author who leads the Wisconsin Registry for Alzheimer’s Prevention at the University of Wisconsin, said it would be very important for clinical trials to start to take participants’ APOE4 status into account. “We may need to start treating these as a separate group in our research papers so that we can really understand the relationship between amyloid and tau and symptoms” in people with two copies of the APOE4 gene, in a way that we kind of have not been able to before, Johnson said in the news briefing.
If nothing else, Dr. Lesne deserves to be banished professionally, while we focus on what is more important and now known about the toxicity of other forms of amyloid in ApoE 4 carriers.
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Re: 2006 paper key to amyloid hypothesis to be retracted. Senior author admits doctored images

Post by Fiver »

Those manipulated figures can be seen online, on various sites that check for these things. Those sites are referenced in the Blots in a Field article. Seeing them all together, with the manipulations highlighted, is shocking. It’s terrible for the collaborators, the field, the lost funds. Science journals are very slow to respond to fraud, if they do at all. In this case, 18 years. But it’s not uncommon, unfortunately.
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Re: 2006 paper key to amyloid hypothesis to be retracted. Senior author admits doctored images

Post by mike »

Not to mention lost time. My father went too soon.
Sonoma Mike
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