Yves here. A striking feature of KLG’s discussion of some of the problem with Alzheimer’s research is anchoring: that once a plausible-seeming theory is adequately substantiated, it can soon determine how scientists and clinicians view a phenomenon. That in turn makes them prey to confirmation bias and blinkering. Yet another manifestation of the Max Planck observation that science advances one funeral at a time.
By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health
As we age, as individuals and as a society, is there anything more frightening than Alzheimer’s Disease (AD)?
The answer was given more than 115 years ago by Auguste D, who was the first AD patient described by the German psychiatrist and pathologist Dr. Alois Alzheimer, when during an examination of Auguste D he asked her to write her name. Trying but failing she replied, “Ich habe mich verloren – I’ve lost myself.” What can be worse? Both for the patient, and his or her family. Frau Auguste D died at the relatively young age of 51, perhaps because she had familial AD, after an extended stay in a mental institution in Frankfurt, years that were financially ruinous to her husband Carl August Wilhelm Deter.
The dementia that became known as Alzheimer’s Disease was delineated in detail by Dr. Alzheimer in a lecture (recalled here) in Tübingen in1906, in which he described his patient and the neuropathology associated with her disease – including the amyloid plaques (Ab) and neurofibrillary tangles (tau) observed by Alzheimer and the Italian physician Gaetano Perusini (pdf) that since then have been diagnostic of AD.
The literature on Alzheimer’s disease is large (>200,000 articles in PubMed, 1913-August 2022), so in the interest of accessibility and concision, the description given here will follow that in Robbins & Cotran Pathologic Basis of Disease, 10thEdition, 2020, which is a standard comprehensive pathology textbook used in medical schools in the US. Remarkably, the current description in Robbins is largely that of Alzheimer and Perusini, albeit with a few additional details that could not have been known in 1906.
The known biochemistry of AD is straightforward, even simple. Amyloid precursor protein (APP) is a protein of unknown function found on the surface of cells in many tissues, including the central nervous system (CNS). Cleavage of APP by specific proteolytic enzymes (a-, b-, and g-secretases) can produce a non-amyloidogenic soluble fragment of APP or the amyloidogenic[1]fragment that first forms soluble oligomers of a relative few Abpeptides (i.e., smaller fragments of APP). These oligomers then aggregate into the insoluble Abplaques in AD brain tissue that were first observed over 100 years ago. It is thought that the oligomers lead to synaptic dysfunction and cell death and activate enzymes (kinases) that add phosphoryl groups to tau, which then leads to the formation of neurofibrillary tangles that are left behind after the death of affected brain cells. Familial (inherited, early-onset) forms of AD support the hypothesis that Abproduction is critical for the initiation of AD. Mutations in two genesPSEN1and PSEN2encode the proteins presenilin-1 and presenilin-2, which lead to a gain-of-function in the g-secretase complex that produces increased amounts of Ab, particularly the Ab42 thought to be a major source of Aboligomers and plaques.
In contrast, familial forms of amyotrophic lateral sclerosis (ALS) account for a small percentage of cases of ALS, the vast majority of which are sporadic and of no currently known origin. Tau, which is the primary component of the neurofibrillary tangles in AD, is a microtubule-binding protein required for normal function of neurons of the CNS. Microtubules can be thought of as railroad tracks that traffic cellular cargo long distances, relative to average cell sizes, from the neuronal cell body to a distant perimeter defined by axons and dendrites and from the axons and dendrites back to the cell body, where the nucleus generally remains (unparalleled illustrations of neurons in situ by Santiago Ramón y Cajal can be found here). Without this structural and transport mechanism neurons cannot function properly.
So, to summarize from Robbins & Cotran, p. 1275:
The fundamental abnormality in AD is the accumulation of two proteins (Aband tau) in specific brain regions, likely due to excessive production and defective removal…The two pathologic hallmarks of AD, particularly evident in the end stages of illness are amyloid plaques and neurofibrillary tangles. Plaques are aggregates of Abpeptides in the neuropil (gray matter), while tangles are aggregates of the microtubule binding protein tau that persist after neuronal death. Both plaques and tanglesappear to contribute to the neural dysfunction, and the interplay between the processes that lead to the accumulation of these two types of abnormal protein aggregates is a critically important aspect of AD pathogenesis that has yet to be fully unraveled (emphasis added, to which we will return).
The amyloid hypothesis of AD was first put forward in the 1980s when APP fragments were identified as the primary constituent of amyloid plaques. The hypothesis has dominated a large fraction of AD research ever since, especially after the use of transgenic mouse models of AD, in which human APP/Abforms plaques in the brains of the experimental mice and the toxic oligomers described in Robbins & Cotran may lead to brain dysfunction.
In 2006 a seminal paper was published in Natureon a somewhat larger, apparently toxic Abfragment showing that:
(M)emory 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.
A subsequent paper from the same laboratory was published in Brain in 2013 and concluded that
(I)n cognitively normal (human) adults Aβ*56 increased ahead of amyloid-β dimers or amyloid-β trimers, and pathological tau proteins and postsynaptic proteins correlated with Aβ*56, but not amyloid-β dimers or amyloid-β trimers.We propose that Aβ*56 may play a pathogenic role very early in the pathogenesis of Alzheimer’s disease.
The first author[2]of each of these apparently very strong papers published in very good journals[3]was Dr. Sylvain Lesné, who was a postdoctoral research fellow in the laboratory of Dr. Karen Ashe, the corresponding author and principal investigator of the laboratory.
In the large scientific literature on AD, these two papers had a major impact on AD research. The first paper from Nature has been cited in the scientific literature more than 2,300 times,[4]and the paper in Brain has been cited more than 200 times. This would be expected of seminal contributions that strengthened the foundation of the amyloid hypothesis of AD.
If Abpeptides are the “cause” of brain damage and consequent dementia in AD, then preventing their production should prevent AD or slow disease progression.
Alas, all is no longer well in this fundamental area of research on Alzheimer’s Disease. As described in a recent extensive news article by Charles Piller in Science, “Blots on a Field,” much of the data supporting the involvement of Ab*56 in the genesis of AD may have been fabricated.
The following notice has been added to the Naturearticle online: 14 July 2022 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. Similarly, the Brain paper has been corrected extensively, nine years after publication.
“Blots on a Field” (BOAF) covers this apparent mess in depth, so I will only summarize the facts as they are currently understood. “Fabricated” is a strong accusation.
For the most part, Dr. Lesné has been accused of “manipulating” images. Research on Abusing cells and tissues as the source materials requires that the amount and molecular size of Abpeptides be monitored carefully throughout the project. These measurements are accomplished using a technique called immunoblotting (Western blot) in which carefully prepared samples of proteins from brain tissue in this case are separated by size and transferred to a permanent membrane where both the amount and size of the target peptide/protein can be determined using antibodies specific for Ab.
The remarkable utility of Western blotting is that it identifies one protein/peptide (with proper controls under defined conditions) in a mixture of thousands of distinct proteins that are present in varying quantities in the sample.
Western blotting is straightforward and simple when a qualitative assay is required (e.g., present or not present). With minor technical differences, immunoblotting is the basis of the rapid antigen tests for COVID-19 that are widely used. The free test kits sent to me by the US government state “The iHealth COVID-19 Antigen Rapid Test is intended for the SARS-CoV-2 nucleocapsid protein antigen in anterior nasal (nares) swab samples.” A single band result (C for control) indicates the test is working properly. A double band result (C plus T for test) tells you the test is working and that you have SARS-CoV-2 nucleocapsid protein, and therefore the virus, in your nose, despite having been vaccinated and boosted and boosted. But I digress.
The COVID test kit provides a robust yes/no answer, but Western blots used to study Ab(or any other peptide/protein) must provide information on peptide size and quantity during the initiation and progression of AD. This is determined using any number of quantitative image analysis techniques. Because of this, digital image files from Western blots are the data and they are sacrosanct.
If images have been manipulated, the data are no longer valid, and any conclusions based on these data are suspect. Image manipulation is not the equivalent of a photographic “touch up” to make the data “prettier.” Much as scientists want their data to look good, Western blotting can be messy and convincing at the same time. Depending on the difficulty of the experiment, slightly ragged data are often more impressive than a perfect picture. And research on Abis very difficult and demanding, from the biochemistry and biophysics of Abin solution to connecting brain pathology to measurable defects in memory and cognition.
If the underlying data have been manipulated, how could this have happened? The failures are both institutional and personal. Despite 2300 citations of the Naturepaper and 200+ citations of the Brain paper in the Alzheimer’s Disease literature, why has this taken 16 years to come to light? The first reason is undoubtedly that AD has been a stunningly difficult problem for more than 100 years, and perhaps more so in the past 40 years as molecular concomitants of the disease have been identified. From BOAF:
The experience (of Matthew Schrag, the primary investigator of Dr. Lesné’s publications) introduced him to a disquieting element of Alzheimer’s research. With this enigmatic, complex disease, even careful experiments done in good faith can fail to replicate, leading to dead ends and unexpected setbacks.
There is also research momentum to consider. For nearly 40 years the amyloid hypothesis, despite its provisional nature, has largely dominated Alzheimer’s research.
As noted above, a standard pathology textbook now in its 10thedition and used by thousands of medical students and physicians, hedges on Alzheimer’s Disease. The fundamental abnormality in AD is the accumulation of two proteins (Aband tau) in specific brain regions…The two pathologic hallmarks of AD…..are amyloid plaques and neurofibrillary tangles…which appear to contribute to AD but remain a critically important aspect of AD pathogenesis that has yet to be fully unraveled.
I will simply note that a “fundamental abnormality” associated with a disease is not necessarily the cause of a disease. Nor are “pathologic hallmarks” which “appear to contribute” to pathogenesis but “have yet to be fully unraveled.” We should also note that the early toxic oligomers of Abare considered by much of the Alzheimer’s research community to be the toxic forms of Ab. If so, perhaps the focus on amyloid plaques and neurofibrillary tangles, which appear after oligomers have begun to do their damage and may be an irrelevant endpoint, is misdirected?
Nevertheless, although amyloid-directed therapies have yielded few tangible results. From BOAF:
NIH spent about $1.6 billion on projects that mention amyloids in this fiscal year, about half of its overall Alzheimer’s funding. Scientists who advance other potential Alzheimer’s causes, such as immune dysfunction or inflammation or an environmental cause, complain they have been sidelined…
The amyloid hypothesis has led directly to several monoclonal antibody-based therapeutics such as aducanumab (Aduhelm, Biogen), which was approved by the FDA in 2021. The literature on Aduhelm is large, and the drug has been justifiably controversial.
A recent summary from the American Medical Association states:
Aducanumab does not cure or reverse Alzheimer disease. In 2 clinical trials, after 18 months it reduced amyloid plaque levels, but that did not translate to any clinical effect in 1 trial or a noticeable effect in the other. Potentially serious harms are common. The FDA has required that another trial be completed by 2030 to decide whether aducanumab has a meaningful patient benefit.
Aduhelm may be weak for now, but the amyloid hypothesis remains strong. $1.6 billion contributes to a substantial research momentum, and grantsmanship[5]is essential if researchers are to be successful in gaining access to that rather large pot of money.
A cardinal rule of grantsmanship is to go with the flow, while presenting conventional wisdom as new, improved, promising, and innovative. Ab*56 was new in 2006, and it has remained promising in 2022. Dr. Karen Ashe, who was the senior/corresponding author and the only other author in common on the Nature and Brain papers, called the investigation of Dr. Lesné “sobering.” But she also replied that she still has “faith in Ab*56” and
….we have promising initial results, I remain excited about this work, and believe it has the potential to explain why Abtherapies may yet work despite recent failures targeting amyloid plaques.
This is grantsmanship at its finest. The first practical advice every novice biomedical faculty member is to “generate preliminary data and get promising results” and use them to write a grant proposal. How an Abpeptide identified when George W. Bush was President has provided “promising initial results” in 2022 is something of a puzzle. But that is the way grants are procured.
At the personal level, it must be emphasized that the results published by Dr. Sylvain Lesné are currently under investigation, but no final conclusions have been reached and no other scientist or coauthor has been implicated in the apparent data manipulation.
The available information outlined in Blots on a Field (BOAF) doesn’t look good for Dr. Lesné, however. Several “personal” anecdotes included in the article are especially troubling for the practice of science.
It appears that Dr. Lesné has had a reputation of sorts since he was a graduate student. One senior co-author who wrote five papers with Dr. Lesné early in his career as a graduate student identified “dubious” results provided by Lesné, that could not be replicated by other students. The senior scientist at Caen subsequently “withdrew the paper before publication ‘to preserve (his) scientific integrity’ and broke off contact with Lesné.”
Nevertheless, Sylvain Lesné apparently completed his PhD in good standing and proceeded to make a career for himself in Alzheimer’s research. A junior scientist who worked for Professor Lesné at the University of Minnesota “calls him passionate, hardworking, and charismatic. She and others in the lab often ran experiments and produced Western blots…but in their papers together, Lesné prepared all the images for publication.” This behavior is clearly reminiscent of another case that was covered well in Retraction Watch. That established scientist and professor would take data out of the hands of technicians[6]and use it to prepare figures for his papers and grant applications. The fraud was discovered only after the principal investigator hired a senior scientist with a PhD, who had a continuing career interest in the research and necessarily became a whistleblower.
On an institutional level, the NIH program officer for the grant, Austin Yang– a co-author on the 2006 Nature paper – “declined to comment” (BOAF) when asked about the R01 grant[7]
Dr. Lesné received from the National Institute on Aging (NIH) with a start date of June 2022. NIH has many funding mechanisms, with the R01 grant being the primary route to a successful and sustained career as an academic biomedical scientist. In my experience as a grant reviewer, the rule for evaluating the work of a former collaborator is that the relationship must have ended 3-5 years before. Dr. Yang was not a reviewer of the proposal by Dr. Lesné, but the current situation must be uncomfortable for him. This total mess should also be uncomfortable for scientists who now state that the amyloid hypothesis was always a stretch. If so, as reviewers and members of the research community, they were complicit in the expenditure of hundreds of millions on what may well be a chimera.
Although biological scientists have sometimes mistaken the agent of a disease for the cause of the disease (here and here, for example), there is still reason to believe that Abis fundamental to the etiology, development, and progression of AD, but perhaps with an environmental antecedent?
As pointed out to me in an email conversation not long ago, the pathology of Alzheimer’s seems to be something new and the result of an environmental insult, perhaps an infection. If toxic Aboligomers are the culprit, prevention of their formation should prevent Alzheimer’s Disease. However, if “current phase 3 clinical trials for three drugs targeting amyloid oligomers fail…the Abhypothesis is very much under duress” (BOAF).
Nevertheless, several things are certain. Institutional inertia, however plausible, should never be allowed to dominate any one field of biomedical research, particularly one as large and as important as Alzheimer’s Disease. Another is that a biological hypothesis that eludes capture, seemingly indefinitely, may not be correct. Plus, scientists who prove early they should be watched carefully cannot be allowed to escape notice. Ever. Otherwise, they “might further undercut public trust in science during a time of increasing skepticism and attacks” by being responsible for years of wasted money and effort by hundreds of scientists.” Dennis Selkoe is correct in this statement.
But public trust in scientists is indeed a trust. Once broken, it will be exceedingly difficult to regain, as we are reminded once more during a strange time.
________
[1] Amyloidogenic proteins are those that lead to the formation of insoluble protein aggregates in tissues. The amyloidosis caused by these proteins leads to distinct diseases (yes, Wikipedia, but this seemed to be the most useful non-paywalled link, especially the table included).
[2] By convention, the first author of a paper in the biomedical sciences made the largest contribution to the research and is generally viewed as the scientist “who did the work.” Papers often have several “first authors” who made equal contributions to the research. For example, the recent paperabout “super-vicious hamsters” (sic), naturally in Daily Mail, has three “first authors.” The last author, or corresponding author, is usually the principal investigator with overarching responsibility for the research project. Both the first and last author(s) receive equivalent credit for the work.
[3] Both papers appear upon first reading to be solid, in that they are well written and the data support their very significant conclusions. They were also published in excellent scientific journals. Any paper published in a legacy journal (something to which I plan to return) is cause for celebration. Brain: A Journal of Neurology was established in 1878 and is published by Oxford University Press. A biomedical paper published in Nature (1869) or Science(1880) or Cell (1974) is cause for champagne and dinner for the laboratory on the principal investigator’s credit card.
[4] To put this in context, most scientific papers are rarely cited. A paper with 100 citations may be considered a “citation classic,” and this does indicate the paper had a significant impact on related research.
[5] Grantsmanship (1961): The art of obtaining grants. As I mentioned in my previous poston why basic research is essential, “grantsmanship” has truly become a very important thing. There is even a Grantsmanship Training Program, ready and willing to help one become proficient in grant procurement; this is probably one of many. While I have had success in “procuring” grants, I confess to remaining clueless about what really matters the most in any given situation.
[6] Technicians and similar personnel are essential lab members but often have no continuing career interest in the research and are therefore unlikely to pay close attention to publications from the laboratory. In many laboratories, technicians are not expected to be coauthors, although this is changing. As a former research technician, I approve of this practice!
[7] A description of the current R01 awarded to Dr. Lesné is here. All current NIH funding for Dr. Lesné is here, and all NIH support for Dr. Lesné from 2008 through 2022 is here.
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I have no expertise with which to weigh up the claims made by Dr Marc Siegel on Tucker Carlson here, about how Viagra has in one study reduced AD in men by up to 69%. But even if that is twice the actual effect it is a firm (!) reason to consider taking it.
I passed that on to a cousin whose wife is a superfit mountaineer in her early 60s who scaled Kilimanjaro a few years ago as part of a group. She said that several of them experienced altitude sickness and were given Viagra to relieve symptoms. Apparently the results were startling. As were the selfies at the summit, presumably.
Viagra is the brand name for the boner-pill version of the drug. It is also sold for cardiovascular under another name. (Possibly with minor tweaks, but basically tomato tomahto)
Just as an aside, many years ago I did a thesis on decision making in the face of scientific uncertainty and I trawled through a lot of literature on scientific failure, and in particular those cases where entire scientific establishments managed to hold fast for decades onto theories or techniques despite overwhelming evidence that they were wrong. Many of these are of interest only to connoisseurs of bad ideas but we’ve seen plenty of examples recently where, quite literally, lives are at stake. Just this morning I saw a tweet from a senior medical scientist relating to Monkey Pox where, in criticizing a particular epidemiologists concerns about rising cases among children, she revealed that whatever her other qualifications as a scientist, she knows absolutely zero about how to apply risk analysis to known hazards. I would actually say less than zero, because the average person would probably immediately pick up on the very obvious flaw in her thinking, and yet her view is typical of many highly trained professionals (in short ‘we shouldn’t do anything until we have more data’). I could pick thousands of examples among scientists (and engineers too, but that’s another story).
Perhaps others can chip in, as I’m a long time away from academia, but when I was doing my research it seemed very clear that many scientists literally knew nothing about epistemology and practical techniques for assessing knowledge in the face of uncertainty. They were often highly rational and rigorous within their own field but had no tools whatever in applying their knowledge either to other fields (and every field has its own implicit and explicit rules for shifting through the mud to find ‘truth’), and often even less to applying their research to real world applications. Even worse, there was often overt hostility to others (especially in the humanities or applied sciences) who tried to analyse or theorize about scientific processes.
I’m not sure what the solution for this is, except for much better peer review and a greater openness to criticism (its amazing how prickly some specialists can be at even the mildest questions about underlying assumptions in their research), but we sure do have to find some answers quickly.
In your study of scientific failures, did you come across this doozy?
Poverty, the Thymus and Sudden Infant Death Syndrome
What would be some of those tools to assess knowledge in the face of uncertainty or to apply your knowledge to other fields? Sounds like a very interesting topic, like everything in your comment.
That’s just how life is in corporate science and engineering.
The Primary Directives are: “Never solve any problems one has not been specifically asked to solve by Management”, and “Never bring any problems in front of Management that one has not already solved”!
The ambitious people, very generally, take two distinct paths:
Create problems, which they know the solution to because they created them, let them ripen up for a bit, then come up with a clever project to make it all go away again. Like, create a hugely bureaucratic PLM system that drives everyone visibly nuts, then create an RPA-project (Robotic Process Automation) to drive it.
Skunkworks. Find a decent problem and secretly work on it on company time. As long as one sticks to the official project KPI’s, “embezzling hours” is quite manageable because most “knowledge” work in a large organization is performative. Then wait until someone asks about the problem, or more fun, there is an opportunity to present it to a forum where it is unstoppable, so ones venal management are forced to get in front of the thing with visibly faked enthusiasm. This is how Ericsson developed several key technologies.
The burned-out people, who no longer give a shit about anything, they will always ask for more data :)
I am a neuroscientist that has followed this story. Good overview here. There is rot at the core of modern science, and it mostly comes down to the influence of money and big pharma. The NIH has been completely taken over by people who’s only interests are IP associated with new drugs. Basic research is not funded to any significant degree. If you do not submit grant proposals on drug development, your chances of funding are extremely low. This started in the 1990s, and now it pervades all of what the NIH does. Aducanumab is a perfect example of IP for a drug that does not work. How much time and money was wasted on this? How much more would we know about AD if most of the money went into basic scientific research, rather than drug development? Who knows.
Thank you Bill Clinton.
Actually, Bob Dole left his fingerprints all over the patent system. I first noticed it with the Bayh-Dole Act (1980), which permits universities that receive federal funding, businesses, or non-profit organizations to pursue ownership of an invention rather than obligating inventors to assign inventions to the federal government. https://research.wisc.edu/bayhdole/
More basic research would be wonderful especially for those of us who have a parent with Alzheimers. If we knew what the real causes or triggers for Alzheimers were, we could probably delay onset or prevent it altogether. No money in that though.
Right now all the advice is around the general health guidelines you should be doing anyway.
My mother was diagnosed with AD in 2001. As a trained chemist, I read every book (and some of the scientific literature) on the subject.
One book impressed me most, it was written by a gerentologist with many years of experience and also a researcher in aging. He cited research that pointed to people with severe AD having normal brains and normal people having high amounts of plaques and tangles. He dismissed the plaque and tangle theory and wrote about the demise of the number of autopsies done as this is the source of much valuable information. Another negative result of the pharmo industrial complex, always looking for a drug eliminates the collection of other work.
Autopsies have decreased because it costs money to do them. Everyone from universities to hospitals to the law have an incentive to not do them or to do as quickly and incompletely as possible.
In 2017 I posted a paper titled “A Diet-Stress-Diathesis Model of Homosexuality” on psyarxiv.com. It has over 5000 downloads, but no citation. Because it is politically incorrect. Scientists are afraid to cite research they are using to further their knowledge. No grants were taken to write the paper and the author is unknown in the academia, thus helping the objectivity of the paper, but at the same time making it unwelcome for the establishment.
About the “super-vicious” hamsters: interestingly, the scientists CRISPR-CAS9-editing their genes were convinced that it would “reduce both aggression and social communication — but the opposite happened” resulting in “high levels of aggression towards other same-sex individuals”.
They concluded that “we don’t understand this system as well as we thought we did.”
I am afraid we will also face surprises when those bio-scientists tweak genes of plants and animals to make them supposedly resilient to climate change (creating super-weeds instead of super-crops?)
“I am afraid we will also face surprises when those bio-scientists tweak genes of plants and animals to make them supposedly resilient to climate change (creating super-weeds instead of super-crops?)”
I suspect such surprises as you suggest should be expected and carefully controlled. Given the rate at which the climate is changing and the slower rate at which many lifeforms are able to evolve, there may be cases where the choice is between extinction and attempts to artificially adapt a species. Part of the problem might reside in equating resilient to climate change with creating super-crops. To my ear super-crops rings of profits and economics, which I regard as poor motivations and worse judges for failure and success.
Note added in proof: Ab should be read as A-beta. Greek letter did not come through. Now I know ;-)
…and eliminated the following space. Made it a little harder to read, but still greatly appreciated your article.
I listened to a presentation (as an experienced med lab scientist) in the 90s explaining AD, amyloid and tangles, and came away a skeptic. Nothing since has diminished that skepticism.
As part of a late career PhD in health informatics, I came to grips with ontology, epistemology and Thomas Kuhn. I suspect that AD research may have a Kuhnian revolution to look forward to somewhere in its future.
Thanks again KLG for laying this out so clearly.
“Yet another manifestation of the Max Planck observation that science advances one funeral at a time.”
The USA is breaking the mold on that observation. With the fanatical faith in deregulation and rush to profit, I’m convinced there is no hesitation to advance one mass death event at a time.
Yes, and we’re well on our way, as US life expectancy continues to decline.
https://www.nytimes.com/2022/08/31/health/life-expectancy-covid-pandemic.html
I believe there was link or comment here on NC recently that said the main driver of reduced life expectancy in the US is opioid overdoses.
… another interpretation of the Max Planck observation is that science advances as the old guard dies off and the reigning dogma dissipates…
That is actually what he really meant. What I often heard from my German biochemistry professors is that “Theories are not refuted but die out”. Not sure who said it first or wether it is just another version of the Planck quote but the idea is the same.
The problem with technical reads is some of us aren’t experts, so we don’t understand all the terminology. No matter. I would like to know the difference between Alzheimers and senility?
Senility is an older non-medical term that refers to a loss of cognitive function in old people. Dementia is the current term for memory and cognitive impairment. It isn’t limited to old people. There are many causes of dementia including strokes and brain injuries, reactions to meds, and degenerative diseases. Alzheimers is a specific disease with a known pattern of symptoms and progression that mostly affects older people.
I’ve been watching it up close and personal for years now as my Mom “loses herself”.
To add: Alzheimer’s is not the only common type of dementia that is recognized as a disease. Lewy body dementia is another.
I read the bombshell expose about Dr. Lesne when it was published. I told all my friends and family about it. Really shocking stuff.
What interested me also was how Dr. Lesne’s colleagues piled on after the fraud was discovered. The pattern reminds me of something I read probably 20 years ago about witness statements. Let’s say a witness sees a man trying to get into a burning building to save his children. The police interview the witness on the scene, and the witness says that the man behaved as one would naturally expect a distraught father to. Later, however, after the police begin to suspect arson, the witness changes their story to fit the new narrative that the man is “bad”. They might say something like: “Oh, yes, well I’ve always thought he was suspicious. I once saw him slap his son! And he didn’t try hard enough to get into the house to save his children. He barely even cried!”
There’s a tendency to fit testimony to the narrative as the narrative changes. When Dr. Lesne’s a researcher in good standing, all his sketchy behaviors are kind of forgotten or brushed aside or kept discreet. Once the narrative begins to shift, suddenly what was subtext comes to the fore. I’m not saying the new testimony is wrong–as it often is when the witness changes their story to fit the narrative–but it demonstrates that the narrative of one’s career is sacrosanct and that there’s an unspoken agreement in the sciences not to “go after” one another publicly. However, when one’s career narrative is attacked in the press, all bets are off.
One wonders as well if this behavior, this tendency for fraud, is rather common and perhaps tolerated to the extent necessary to progress one’s scientific career. Why rat on a colleague when maybe one of your early papers has suspect material in it?
My suspicion is that Dr. Lesne’s the tip of the old iceberg, and there will be a strong tendency to make him out to be a mere bad apple when it’s clear that the field is dealing with some real institutional corruption that allowed Lesne to keep this up for so long.
Another example of the adage (usually attributed to Winston Churchill and typical of media habits), “At your feet or at your throat.”
Just from personal experience, I noticed that once my husband was diagnosed as having dementia shortly after surgery, everyone from doctors, professionals and family treated him as though he was not longer capable of thinking for himself. I noticed he watched all the information about this incurable disease on TV. He grew worse and worse. One day I told him that he shouldn’t believe what the experts said because I knew he was capable of much more. Gradually over a period of time he became functional again and began to enjoy life more. At the time of his death in his 80s, he was enjoying the company of friends again, going out regularly and leading a full life in spite of other health problems.
I also observed that often symptoms appeared when a person lost interest in life and their social circle shrank.
The thought occurs that national research foundations could improve the incentive structures by implementing an annual lottery to select previously funded and now published studies for “replication challenge” by government laboratories or carefully selected contracted private laboratories. Devotion of a few per cent of the annual research budget to this might have significant effects in terms of improving the reproducibility of the research funded by the rest of the budget.
The New Yorker had an article about this valuable study that basically debunks the idea the amyloid proteins are the cause of Alzheimers. My mother had the disease for 20 years. She was in a memory unit for 6 years . Anecdotally, alzheimers is an umbrella term for multiple causes. MIC always want a silver bullet to sell drugs. That article apparently has been removed from the internet but here is the summary.
https://sanescohealth.com/blog/nun-study-and-alzheimers/
Senility is an older non-medical term that refers to a loss of cognitive function in old people. Dementia is the current term for memory and cognitive impairment. It isn’t limited to old people. There are many causes of dementia including strokes and brain injuries, reactions to meds, and degenerative diseases. Alzheimers is a specific disease with a known pattern of symptoms and progression that mostly affects older people.
I’ve been watching it up close and personal for years now as my Mom “loses herself”.
So much said with so few words: “…grantsmanship at its finest.”
Perhaps science and education ensconced in a Neoliberal Market managed by Masters of Business applying best practices for maximizing return on investment … falls short of its promise.
“But public trust in scientists is indeed a trust. Once broken, it will be exceedingly difficult to regain, as we are reminded once more during a strange time.”
This close to the post is suggestive. We do indeed live during a strange time.
I would encourage people to consider getting their genome sequenced if they have a parent with Alzheimer’s. Contrary to what a quick google search may tell you, the risk is substantially genetic [1].
Someone might wonder, if the risk is mostly genetic, why get tested at all? But the single biggest common genetic risk factor is a single allele [2], so if your parent had only one copy, there’s a 50/50 chance you got it.
The good news is that a single copy of the allele in question (APOE4) still gives you “just” a 30% risk of Alzheimer’s… whether you will be in the 30% or 70% is substantially a matter of diet and exercise, so understanding your genetics may be an inducement to take better care of yourself.
Alternative theories have been emerging over the last decade, which may indicate that the culprit may be poorly regulated iron, and ferroptosis may play a role in the memory loss.
See-
https://www.nature.com/articles/s41418-020-00685-9#:~:text=Iron%20homeostasis%20disturbance%20has%20been,pathogenesis%20of%20AD%20remains%20elusive.
and
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000453/
This could well be one of the causative factors of AD, while the protein plaques could be a side phenomenon occurring at the same time as the damage from ferroptosis.
The fact that Cuba’s Regulatory Authority for Medicines, Equipment and Medical Devices recently approved the conditional sanitary registration of the Cuban product NeuroEPO, for patients with mild and moderate Alzheimer’s disease, is exciting news not only for the scientists involved in the creation of the drug, but also for the entire population, aware that this condition is the most common dementia in the country.
“This registration means a lot because it is a drug that can be in the Cuban therapeutic arsenal for the treatment of this disease, of which only the symptoms are treated because in Cuba we do not have access to the six drugs approved by the Food and Drug Administration (FDA), to treat this disease which, as we know, not only affects the patient, but also the whole family and especially the caregiver,” said Leslie Pérez Ruiz, a researcher at the Center for Molecular Immunology (CIM), who holds a master’s degree in Pharmacology and Health Economics.
The condition is valid for three years, which will make it possible to present the results of research that will enable a phase III study to be carried out during this period to obtain more information on the product’s efficacy, she explained.
He recalled that the research in the clinical part began at the end of 2017 and concluded in 2020, after which the final report was made and delivered in June last year with all possible requirements. Now the granting of the sanitary registration is received.
“We are happy, but not satisfied, because we have a long way to go. The registration was granted for three years, but it is conditional on another clinical trial that we have to carry out. In the completed study we obtained good efficacy compared against placebo, but in the new trial that is being designed, we will compare against an active control, that is, the efficacy of NeuroEPO will be compared against a drug approved to treat the disease. This study will give us more information on the efficacy of the Cuban product.
“In the Phase III study, patients will undergo molecular characterization, that is, we will have the possibility of diagnosing them not only from the clinical point of view, but also from the molecular point of view, by means of biomarkers approved for the diagnosis of the disease.
“Due to the logistics involved and its complex design, it will be carried out only in institutions in Havana. This research, as I said before, is in the protocol writing phase, which will have to be submitted for evaluation and approval by the regulatory agency Cecmed. We think it should begin in the second half of the year”, said Perez Ruiz.
The specialist emphasized that this is an achievement of many people, who were intensely committed due to the sensitivity of the subject, and that even in the middle of the pandemic, the process of treatment, evaluation and follow-up of the patients was not interrupted.
https://www.juventudrebelde.cu/suplementos/en-red/2022-03-26/neuroepo-un-paso-mas-cerca
A similar long standing failure has been the “cholesteral hypothesis” as a principle cause of heart disease. In this case this theory was gradually whittled away and many experts now regard cholesteral as a sympton, not a root cause. See the work by Malcom Kendrick (“The Great Cholesteral Con”) and others. Nevertheless cholesteral lowering drugs like statins are still big business, a classic case of inertia and deeply entrenched interests.