Possible fabrication in Alzheimer's research

elainechem

https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

harshedbuzz

Yikes!

Twin Mom

Wow, thanks for posting.  Sickening and unbelievable if it is ever proven to be true..but the bureaucratic wheels will probably be too slow to have any real affect.

Ed1937

Hi Elaine. Good to hear from you. How are you doing?

Thanks for the article. It's quite long, and I haven't finished it yet, but always good to see something like that. We just never know, do we?

[Deleted User]

The user and all related content has been deleted.

Crushed

https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

 

 hotlink

elainechem

Ed1937 wrote:

Hi Elaine. Good to hear from you. How are you doing?

Thanks for the article. It's quite long, and I haven't finished it yet, but always good to see something like that. We just never know, do we?

Hi to you. My hubby died just three weeks before the COVID-19 lockdowns started. I will always be grateful that I didn't have to be a caregiver during that time. My heart goes out to all of you who did. I have learned how to live alone. This is the first time in my life that I ever have. I am helping current caregivers by attending Alzheimer's Association support group meetings. I learned a lot along the way. I am focused on my family, which now includes two young granddaughters. I spend most of my time alone, but I'm usually good with that since I am on the autism spectrum and I'm not comfortable being around other people for long periods of time. 

OrganizerBecky

I read that this morning - makes me so MAD.

dayn2nite2

Not surprised.  And wouldn’t be surprised at other “science” that’s been published under false pretenses, not just regarding Alzheimer’s.

Joe C.

Crushed, I would be very interested in your thoughts on this article.

Larrytherunner

I'd like to make a few points.

1. It appears that billions of dollars of government money have been waisted on amyloid beta research as a result of the supposed discovery in transgenic mice of amyloid beta*56, which may not even exist. This money could have been better used in other dementia research.

Why was so much money given out for amyloid research? One reason is the universities are working together with pharmaceutical companies to get research grants. If a company wants research on amyloid beta, it can contribute money to the university and help the university to write a research proposal. The company can then benefit from research paid for by the government. Meanwhile a lot of research proposals that do not have a pharmaceutical backer gets shelved.

2. The AB*56 research project used transgenic mice. Wild type mice don't have the same type of amyloid beta as humans and don't get Alzheimers. Therefore the research in question used  genetically altered mice, which many researchers believe is not a good model for Alzheimers.

3. Lane, please don't jump in with your oxidation and ginseng theories, which we have heard a hundred times before. Researchers and medical people most often speak of inflammation rather than oxidation because inflammation is measurable and observable.

dayn2nite2

Lane can jump in with any theory Lane wishes, because at this point ANY theory is open.  We have said here on this forum for years that the amyloid path only produces failed drug trials and the pharmaceutical companies refuse to investigate other theories.

Any possibility is on the table here.

Lane Simonian

Maybe this is too important of a topic not to jump in.

There are different forms of amyloid oligomers, so this finding does not necessarily wipe out the amyloid oligomer hypothesis for Alzheimer's disease.  What wipes out the amyloid hypothesis for Alzheimer's disease are years of failed clinical trials.  It does not matter how early you begin, or how much amyloid you remove, the results are always the same.  It does not matter much what type of amyloid you remove either, except that removing amyloid oligomers seems to minimally slow down the progression of the disease in ApoE4 carriers but not at all in non-carriers (but with the risk of brain bleeds and swelling).  This may be because ApoE4 carriers have more oligomers in their brain to begin with.

The critical point is that amyloid is largely the results of other factors that cause oxidative and nitrostative stress.  Under certain circumstances (such as in ApoE4 carriers) amyloid oligomers can add to that stress, but removing amyloid oligomers does not address the factors that caused the disease in the first place (air pollutants, environmental toxins, pyschological stress, heavy chronic smoking, chronic infections, genetic mutations, a diet high in sugar and other carbohydrates, etc.) nor do they reverse the damage that has already been done.  The problem with the amyloid hypothesis is not that anti-amyloid drugs are given too late in time, the problem is that the intervention is too late in the process.

In response to Larry's point, oxidation and nitration can be measured. The oxidant hydrogen peroxide (which is cut off by the production of plaques) is easier to measure  than peroxynitrite, but scientists are getting better and better at measuring the latter.  It is oxidants that produce most inflammation in Alzheimer's disease in the first place and just like amyloid, inflammatory mediators can then increase oxidation and nitration.  Inflammation is probably more central to Alzheimer's disease than amyloid but it too is a secondary factor.

Oxidation and nitration damage receptors, transport systems, and enzymes responsible for the regeneration of neurons in the hippocampus, for the production of neurotransmitters needed for the retrieval of short-term memories, sleep, mood, social recognition and alertness, for the lack of delusions and hallucinations, and for the survival of neurons.

I will not repeat here the natural products that have limited and partially reversed oxidation and nitration in Alzheimer's disease, only to note that they have worked much better than anti-amyloid, anti-tau, and anti-inflammatory drugs to date.  I keep watching Anavex 2-73 (blarcamesine) because it lessens oxidation and nitration and because at three years it performed considerably better than the standard of care, coming fairly close to stabilizing the disease.  I have found hints that it also partially reverses oxidation and nitration, but nothing definitive.

So there is some hope, especially as those academics and drug companies that have promoted the amyloid hypothesis for years slowly begin to lose their grip on the field.

Crushed

The posts by scientists on the Alzheimr's forum are very revealing
 

https://www.alzforum.org/news/community-news/sylvain-lesne-who-found-av56-accused-image-manipulation

The fact that no one could replicate the 2006 paper meant it had very limited effect on the field.   for example  

 "When the Aβ*56 gels were published, we looked and were a little surprised, since we and others had not seen these bands before. And indeed, we’ve not seen them since. So we’ve never relied on these data for our ongoing studies."
Colin Masters
University of Melbourne
 
. Regarding Aβ56*, we were skeptical about the data from the beginning, and our lab never started a project on it.  Christian Haass
Biomedizinisches Centrum  

  

 

  

 
  

Crushed

Lane Simonian wrote:

Maybe this is too important of a topic not to jump in.

Absolutely none of the prominent researchers responding in the Alzhimer's forum go down this road , nor does lane post peer reviewed double blind studies of treatments

 

  

Lane Simonian

Of the various comments on Alzforum, this one was by far the best:

• Grace Stutzmann
  Rosalind Franklin University/The Chicago Medical School
• Posted: 22 Jul 2022

There are many layers of disappointment, dismay, and anger to disentangle if these strongly supported allegations of scientific fraud attributed to a member of the AD field are true. On a broader scale, it makes me question how a protein associated with AD that has been studied for over 35 years, with billions of dollars of research funding and hundreds of scientists dedicated to unraveling its role, has yet to generate a clear answer, or even a consensus.

That raises a red flag. At best, I see the field agreeing that Aβ species, whether soluble oligomers or plaques, are a feature of the disease, largely because it in the definition of an AD diagnosis—making it a somewhat circular argument. But we see increasing evidence that Aβ is not necessarily the center of the AD mechanism universe, including the long list of Phase 3 Aβ immunotherapy clinical trials that failed to alter the slope of cognitive decline. Most recent among these are the recent preliminary findings from the Colombia API ADAD prevention trial with fAD patients.

We also see the rise of alternative mechanisms independent of amyloid pathology, including neuroinflammatory cascades, synaptic pathophysiology, calcium mishandling, and mitochondrial dysfunction—none of which are mutually exclusive. The recent flood of omics data also support these mechanisms at the molecular and protein levels.

On this backdrop, there remains a critical mass of scientists committed to the amyloid hypothesis. One wonders if this case of alleged long-standing scientific misconduct is symptomatic of committing to a theory that is "too big to fail" and defending it, and the large NIH dollars and resources that go with it, at all costs. These questions are being increasingly asked, and I feel with good reason.   

Beyond the disdain for undermining the integrity of science, and the damage caused by misleading researchers for decades, there is another layer that is deeply problematic for the field. Falsely representing data in order to uphold the amyloid hypothesis creates impediments to funding alternative hypothesis that are worthy of exploration. Even "wrong" hypothesis are valuable at this stage, as they can inform us where not to look, and thus refocus efforts onto a self-correcting pathway. 

In this case with Dr. Lesné, it seems that the iterative self-correcting scientific method has been compromised. In light of these allegations of misconduct intended to support a theory in need of some correcting, one hopes that the governing bodies overseeing funding and resources will take more proactive steps to allow newer or marginalized ideas to be effectively tested.

Crushed

I'n the sense that she agrees with you on a few non non scientific points  I can certainly see why you might like it

Lane Simonian

And the science parts as well.

The Pathogenesis of Alzheimers Disease—Is It a Lifelong “Calciumopathy”?

Grace E. Stutzmann

Indeed, upon reviewing the current body of literature, increased calcium levels are functionally linked to the major features and risk factors of AD: ApoE4 expression, presenilin and APP mutations, beta amyloid plaques, hyperphosphorylation of tau, apoptosis, and synaptic dysfunction. In turn, the histopathological features of AD, once formed, are capable of further increasing calcium levels, leading to a rapid feed-forward acceleration once the disease process has taken hold. The views proposed here consider that AD pathogenesis reflects long-term calcium dysregulations that ultimately serve an enabling role in the disease process. Therefore, “Calcinists” do not necessarily reject βAptist or Tauist doctrine, but rather believe that their genesis is associated with earlier calcium signaling dysregulations.

When I first began studying Alzheimer's disease in 2004, I went through all the major hypotheses for Alzheimer's disease and found that the only factor that was always present was high levels of calcium.  But what I then found was that calcium was not at the beginning of the process nor at the end of the process but right in the middle.  It was what linked the various proposed triggers for Alzheimer's disease to the formation of oxidants.  Reducing calcium levels (such as Anavex's blarcamesine does) inhibits both the formation of oxidants and the formation of amyloid, but it is the former that is central to the progression of the disease.  

Crushed

Lane Simonian wrote:

But what I then found was that calcium was not at the beginning of the process nor at the end of the process but right in the middle.  It was what linked the various proposed triggers for Alzheimer's disease to the formation of oxidants.  Reducing calcium levels (such as Anavex's blarcamesine does) inhibits both the formation of oxidants and the formation of amyloid, but it is the former that is central to the progression of the disease.   

My underlining

Feel free to post a citation where she or anyone else agrees on the underlined point

 I am aware of the recognition of the scientific interest in the hypothesis. but nothing at your level of confidence 
 

J Alzheimers Dis Parkinsonism. Author manuscript; available in PMC 2017 Dec 4.

Published in final edited form as:

J Alzheimers Dis Parkinsonism. 2017 Aug; 7(5): 374.

Published online 2017 Sep 15. doi: 10.4172/2161-0460.1000374

PMCID: PMC5713908

NIHMSID: NIHMS922518

PMID: 29214114Calcium Dysregulation in Alzheimer’s Disease: A Target for New Drug Development

This review comprehensively explores the relationship between calcium homeostasis and the pathogenesis of AD to provide a theoretical basis for the future exploration of AD and the development of novel therapeutic drugs.

    Role of Calcium Homeostasis in Alzheimer’s Disease 

https://www.alzconnected.org/discussion.aspx?g=postquote&t=2147561734&m=2148144448

  

 

Lane Simonian

Thank you for posting the highly useful articles, Crushed.

Once I understood that calcium dysregulation was a critical feature in Alzheimer's disease, I tried to figure out what caused this calcium dysregulation.  There turned out to be dozens of factors that acted through various sets of receptors.  If it were just one factor such as amyloid this would be an easy disease to treat (and amyloid is only a secondary factor).  But usually more than one factor is involved at the start.  

Secondly, I tried to figure out the results of calcium dyregulation.  The two main results of calcium dysregulation are oxidation and inflammation.  And the main oxidant was peroxynitrite (ONOO-).  For some great charts showing these links see below:

https://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

 https://www.genome.jp/pathway/hsa05010

The last part of it was trying to figure out the best ways to inhibit, scavenge, and partially reverse oxidation and nitration in Alzheimer's disease.

The inflammatory mediator peroxynitrite, when generated in excess, may damage cells by oxidizing and nitrating cellular components. Defense against this reactive species may be at the level of prevention of the formation of peroxynitrite, at the level of interception, or at the level of repair of damage caused by peroxynitrite.

https://pubmed.ncbi.nlm.nih.gov/12676458/

To date, the two best ones that I have found are the compounds in panax ginseng, and in various essential oils via aromatherapy.  There may well be (and hopefully there are) better ones.

Yes, I am far more aggressive at pushing this hypothesis than anyone else (although there are a number of outstanding scientists who more gently advocate for it).  But that is because I have full confidence in the range of evidence behind it.  

Larrytherunner

Lane, as Ronald Reagan would have said, "There you go again". 

To have an understanding of things at the level you are talking about, you need a high level knowledge of biochemistry, which you can't get by just reading research papers. I wish you would take a college level chemistry course just to find out how little you know.

Lane Simonian

Look at the charts, Larry and you will understand what you need to understand about Alzheimer's disease.  It is not what I know, it is what Alzheimer's researchers know.  This is not my hypothesis, it is a hypothesis that has been developed over several decades by people who are experts in the field.

Crushed

Lane Simonian wrote:

Look at the charts, Larry and you will understand what you need to understand about Alzheimer's disease.  It is not what I know, it is what Alzheimer's researchers know.  This is not my hypothesis, it is a hypothesis that has been developed over several decades by people who are experts in the field.

Feel free to cite the papers .  Scientists PUBLISH  No one denies it's an interesting hypothesis.  Who claims to KNOW the answer and HOW?

Publication  is the beginning not the end  of the process.  You have to convert the hypothesis into a SCIENTIFIC hypothesis   .  Then you have to start doing and replicating scientific experiments .  The data from those experiments then goes for peer review .  Qualified experts look for gaps in the assumptions or data or experiment.  Other researchers replicate the experiment 
Its a long process which you short circuit in you enthusiasm .  Write an article , submit for peer review  BE MY GUEST
 
I gave my first lecture on the nature of scientific knowledge At the Humboldt University In Berlin in the Department of the Theory and Organization of Science in 1982.  Next Mondya I will be in Berlin with Prof. Fuchs Kittowski    who invited me.

Lane Simonian

For the charts cited above: the KEGG Pathway is "a collection of manually drawn pathway maps representing our knowledge of the molecular interaction, reaction and relation networks." 

They are based on an accumulation of the existing knowledge for biological processes.  Again for Alzheimer's disease:

https://www.genome.jp/pathway/hsa05010

More accurate, yet, is the chart (within article) that captures the pathways involved in Alzheimer's disease and other diseases related to excitotoxicity (excess glutamate).  

https://www.frontiersin.org/articles/10.3389/fncel.2015.00091/full

You have a field that has been dominated by the amyloid hypothesis for over a quarter century.  Even highly respected scientists have troubles getting their papers accepted by journals or at top conferences, and are often denied funding.  And to get funding for a clinical trial using natural products to treat the disease is nearly impossible (although I keep trying).

French

I am a researcher but not in this field. I won’t be able to understand where is the scientific failure, but what I know is that « Publish or perish » and the very strong competition to have a position is sometimes unfortunately leading to cheating. 

The presumed cheater was in a post doctoral position hoping a better position. There were industrial challenges at stake, money…

It is still a shame and not excusable. Unfortunately, as governments give less and less money to fundamental research (it is the case here) it is likely to happen again.

And I am so sorry that he is French

Paris20

I read about this the other day. It reminds me of the now discredited “research” linking autism to vaccines. The danger was not just in promoting misinformation, but also in creating the ominous anti-vax movement that likely cost thousands of lives during the Covid pandemic. And now a case of polio has emerged in NY state. There was an outbreak of measles a few years ago. I’m old enough to remember what those diseases did to their victims. Alzheimer’s research can be a goldmine and in a publish-or-perish atmosphere, the temptations to do the unethical can be great.

JJAz

The Department of Justice announced that it has opened an criminal investigation into this research.

https://www.medscape.com/viewarticle/978257