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  • Reply to: Dr. Oskar Fischer’s Mysterious Little Alzheimer’s Germ   2 months 1 day ago
  • Reply to: Several vaccines associated with reduced risk of Alzheimer’s disease in adults 65 and older   2 months 2 weeks ago

    Any data yet on the effect of Covid vaccinations (spike RNA vaccines) on the incidence of Alzheimer dementia?

  • Reply to: APOE4 genotype and risk of developing Alzheimer’s disease   2 months 3 weeks ago

    Apolipoprotein E gene allele 4 (APOE4) is not only “genetic”. APOE-ε4 alleles are known to show a distinct increase in tuberculosis [Taghi Naserpour Farivar., et al. “Apolipoprotein E Polymorphism in Tuberculosis Patients”. Journal of Applied Sciences 8.4 (2008): 719-722], Thank you.

  • Reply to: The Prion Hypothesis at Forty: Enlightening or Deceptive?   2 months 2 weeks ago

    CWD Tuberculosis Found in Spongiform Disease Formerly Attributed to Prions: Its Implication towards Mad Cow Disease, Scrapie and Alzheimer’s.

    Citation: Lysenko AP, Broxmeyer L MD, Vlasenko VV, et al. CWD Tuberculosis Found in Spongiform Disease Formerly Attributed to Prions: Its Implication towards Mad Cow, Disease, Scrapie and Alzheimer’s J Mol Path Epidemol. 2017, 3:2
    https://www.academia.edu/32910752/CWD_Tuberculosis_Found_in_Spongiform_Disease_Formerly_Attributed_to_Prions_Its_Implication_towards_Mad_Cow_Disease_Scrapie_and_Alzheimers

    Abstract

    The TSE’S or transmissible spongiform encephalopathies, include bovine spongiform encephalopathy (also called BSE or “mad cow disease”), Creutzfeldt–Jakob disease (CJD) in humans, and “scrapie” in sheep or goats (caprine spongiform encephalopathy). They remain a mystery, their cause still hotly debated. Current mad cow diagnosis lies solely in the detection of late appearing “prions”, an acronym for hypothesized, gene-less, misfolded proteins, somehow claimed to cause the disease. Yet laboratory preparations of prions contain other things, which could include unidentified bacteria or viruses. And the only real evidence that prion originator Stanley Prusiner had in his original paper that the disease agent behind “Scrapie” in sheep and goats was devoid of DNA or RNA– was based upon the fact that he couldn’t find any. Furthermore, the rigors of prion purification alone, might, in and of themselves, have killed any causative microorganism and Heino Dringer, who did pioneer work on their nature, candidly predicts “it will turn out that the prion concept is wrong.” Roels and Walravens as well as Hartly traced Mad Cow to Mycobacterium bovis. Moreover, epidemiologic maps of the origins and peak incidence of Mad Cow in the UK, suggestively match those of England’s areas of highest bovine tuberculosis, the Southwest. The neurotoxic potential of bovine tuberculosis has for some time been well known. By 1911 Alois Alzheimer called attention to “a characteristic condition of the cortical issue which Fischer referred to as ‘spongy cortical wasting” in Alzheimer’s disease (AD). But behind AD, Fischer suspected a microbe called Streptothrix which was constantly being mistaken and confused for tuberculosis. Our present investigation of the TSEs clearly shows cell-wall-deficient (CWD) tubercular mycobacteria present, verified by molecular analysis, ELISA, PCR and microscopy to cause spongiform encephalopathy.

    Keywords: Prions; Scrapie; The Spongiform Encephalopathies; Alzheimer’s disease;The eiology of Alzheimer’s Disease; Mycobacterium tuberculosis Complex

  • Reply to: The Prion Hypothesis at Forty: Enlightening or Deceptive?   2 months 2 weeks ago

    Even prion advocate Kane had to admit:

    Although there is little indication of chronic inflammation in the injected mice, the participation of an infectious microorganism in promoting the amyloidosis cannot yet be definitively ruled out.”

    ____________________________________

    Introduction  

    The theory surrounding neurologist Stanley Prusiner’s “prions”, a word which he himself coined for gene-less proteins that were infectious, was under a rightful cloud of suspicion from its onset. In fact, from the get go Prusiner’s prion theory was felt to be heretic, unorthodox, and contrary to accepted belief.

    And the only real evidence that discoverer Stanley B. Prusiner had in his original paper was that the disease agent behind “Scrapie” was devoid of DNA or RNA - was because he couldn’t find any. Nevertheless, fueled by U.S. National Institutes of Health grants which since 1975 fed him in excess of $56 million, Prusiner began his research — working, at first on obscure diseases thought to be caused by “slow viruses”.  Prusiner would in effect rename them. “Prion” said Prusiner, “is a terrific word. It’s snappy. It’s easy to pronounce. People like it. It isn’t easy to come up with a good word in biology. One hell of a lot of bad words people introduce get thrown away.” [1]

    The prion story is one that illustrates in particular how deep a role public relations can play in the scientific community. Prusiner launched the prion hypothesis in 1982, after realizing that he didn't have the necessary funding to do the meticulous and extensive experiments that might unambiguously identify the agents of these strange diseases. Eighteen years later, he still had yet to do the experiments that would offer compelling proof of the existence of prions. Perhaps Prusiner lost his motivation to do so once he started getting extraordinary amounts of press simply on the basis of his claim. (By 1986, The New York Times had seen fit to mention prions in 21 separate articles, and Reader's Digest had named prions "Killer Diseases from the Dawn of Time.") Why didn’t anyone else do the experiments? Because they remained frighteningly expensive and time-consuming—and because Prusiner got more than twice the funding of all the other U.S. researchers in the field combined.

    So by April, 1982 he announced that the real culprit behind such diseases as scrapie in sheep and goats, kuru in cannibals, Creutzfeldt–Jakob disease (CJD) in humans, and  chronic wasting  disease in deer and elk was either a virus—not yet isolated—or some rogue infectious protein-only “prion”, which unlike  anything yet known could multiply, and infect—without genes. Thus, right from the beginning, it was obvious that Prusiner’s plans for the eventual dominance of prion terminology would be based, in large part, on either/or ambiguity. Such vagueness did not go unnoticed or without the criticism of several investigators [2, 3]. Carp mentions in The Journal of General Virology that “The attempt to subsume within the single term, prion, both the 'protein only' and the 'protein with nucleic acid' concepts, has made it difficult to engage in precise dialogue about the term [PRION].” [4]

    Of course it did. That was exactly what was intended. The term prion was being fashioned by Prusiner to mean all things to all people. It you, for some reason, agreed with Prusiner’s protein-only hypothesis—you would be satisfied; and if you did not believe in Prusiner’s “snappy” prions—there was something in there for you as well. And if by chance you sat on the fence of uncertainty, Stanley had something for you as well. In the meantime the term’s credibility increased with each and every one of its utterances, making it harder to challenge with each passing day. Perhaps Manuelides best summed it up in Lancet as “the peculiarly American sport of betting on popular momentum.” [5]

    Furthermore, from the onset, Prusiner also had Alzheimer’s and Parkinsons in his sights. In his April, 1982 announcement, he staked his sweeping territorial claim:

    A knowledge of the molecular structure of prions may help identify the etiologies of some chronic degenerative diseases of humans. Development of sensitive probes for detecting prions in such diseases is needed. Diseases where prions might play an etiological role include Alzheimer's senile dementia, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, diabetes mellitus, rheumatoid arthritis, and lupus erythematosus, as well as a variety of neoplastic disorders

    That is if there really was such a thing as a PRION to begin with.

    A key strategy, according to colleague Dave Bolton, who worked with Prusiner was: “If we coin a new term for it [prion], and go out and tell people of the potential link to Alzheimer’s, we’re going to draw people’s attention to this. And we’re going to get money.” [1] Yet another postdoctoral researcher in Prusiner’s lab, Paul Bendheim said that Prusiner “rammed that word [prion] down the throats of everybody in that laboratory and in the world.” [1]

    All things considered, Prusiner’s idea wasn’t new. The thoughts of biologists in the 1930s who had incorrectly said that viruses were only proteins and that ‘slow viruses’ might be geneless had been proposed by and  discarded in Britain by Griffith as early as 1967 [6]. Prusiner’s rejected grant application from February 18, 1980 was for “Slow Viruses Causing Degenerative Diseases.”  Prion advocates, salvaging what remained from the experience, put forth that prions were way smaller than other viruses, without the capacity to carry genes. Yet, the biology of scrapie alone, because of its many strains, spoke for a cause with genes [7].

    At every twist and turn in discovery Prusiner and colleagues, showed chameleon-like properties, camouflaging their theory with endless color combinations to fit new findings. For example, when his colleagues identified the host protein involved in the diseases under implication, they named it prion protein or PrP, and the gene that codes for it—prion protein gene. Never mind that this gene did not agree with the original hypothesis—just use “snappy” prion lexicon to self-inoculate your theory from criticism, especially if buttressed with an overarching  system of classification that included “prion science”, “prion biology” and “prion diseases’. Such classification, implied authority, suggesting an aura of inevitability for the prion hypothesis.

    But in reality, “prions” were not, and never have been the only game in town.

    By 1984, Rower, at the National Institute of Health, showed that despite what prion advocates were claiming,  prions were the size of small viruses, with plenty of room for genetic material [8]. In the same study Rohwer attacked the prion purists supposition that prions were immortal, citing  agents of  potential damage to them. [ibid] Early prion  workers used a test called the “incubation-time assay” to judge prion purification, utilized cautiously in England since the 1960s. A modification had cut the time to score this assay from a year to a couple of months. Rohwer commented that this test was enormously less accurate than traditional methods and that purifications using it could be off by a factor of from 100 to 1000. Such knowledge kept mad cow’s viral and bacterial theories alive.

    The finding that prions were proteins normally found in the body, including the brain of healthy controls, also seemed to contradict the best evidence that they were infectious. The theory, like all questionable science, survived by finding a difference: prions from healthy animals, were quickly claimed to be “cellular” protein; those from scrapie were “scrapie” protein. Scrapie protein aggregated into rods while cellular protein did not. Another so-called “critical clue” [9]: scrapie protein survived  proteinase, while “cellular” did not. This still did not mean however that some virus or bacteria did not cause the change being attributed to prions to begin with. Cow tuberculosis [Mycobacterium bovis], for example, both by virtue of its cell-wall-deficient, virus-like forms, and that it shares  methyllysines with  other mycobacteria is also protease-resistant [10]. The amyloid proteins in Alzheimer’s, not at first linked to prions, were known at that time to be also protease resistant [11].

    Healthy “cellular” prions  also remained  a mystery, but they need  not have  been. Prions  are  amyloid  and  it  was common  knowledge way before the word prion ever existed that there is a soluble serum protein component [SAP] of amyloid in healthy blood, its purpose also unknown [12]. What was clear is that the role of deposited amyloid fibrils, once formed, is to disrupt, destroy, and compromise, whether in mad cow, JCD, Scrapie, Alzheimer’s or any of the  other amyloid provoked degenerative disorders.

    Prion theorists further elaborated that although proteins normally fold into three-dimensional states, protein prions sometimes ‘misfolded’, assuming an incorrect, infectious state, which somehow subsequently changed surrounding cellular protein into itself, setting off an infectious chain  reaction. And since the  damage done by prion protein seemed similar to the malfunctioning proteins in Alzheimer’s and even Parkinson’s—yes, these too  might  be caused by prions.

    Critics pointed out that despite the vast expenditure [13] on research geared to verify that prions cause mad cow and the spongiform encephalopathies,—to this point prions have not been established fully as the cause of any disease. Furthermore, it remained unclear how prions destroyed brain tissue. Also, experts  pointed out, prion investigators had not proven that  protein-only-prions—even if amplified over 100-fold from an infected brain—increased infectivity. Such criticism represents perhaps the  best kept  secret of prion  researchers [14, 15].

    Both CJD and scrapie can be transmitted without prions [16]. Also, brain  material from which prions and their antibodies have been removed, can still infect animals. Moreover, prions have been found in completely unrelated disease processes, such as Kawsaski syndrome and inclusion body myositis. Finally, although there were many strains of “prion”  diseases, there is no credible theory as  to  how  these strains  exist without genetic material. Aguzzi points out that abnormal prions  have  exactly the same amino acid structure as nonpathogenic prions, found  in everyone. How could  prion  proteins, then  be claimed to do what they are claimed to do [17]?

    By all logical estimates, the death-knell to the prion hypothesis should have occurred with Lasmezas’s 1997 interspecies  transmission of mad cow in which more than  half of injected mice had no detectable prions [16]. If this was not enough, then there was Manuelidis’s 2002 [18] study on infectious neurons (microglia) with low prion levels in otherwise highly infectious material, which only served to support the concept that pathologic prions were the result of infection rather than  being  the  actual infectious agent. To Manuelidis  this  was  likely to be  a  virus,  although she admitted the  fundamental mystery remained. In fact, to many dissenters, some other, not as yet identified  pathogen  such as a virus or bacteria [or a mycobacteria] caused “prions” to  misfold—thus damaging the brain.

    References
    [1]  Taubes G (1986) The game of the name is fame. But is it science? Discover 7, 28–52.
    [2]  Kinberlin RH (1982) Scrapie agent: Prions or virinos? Nature 297, 107-108.
    [3] Chesebro B (1998) BSE and prions: Uncertainties about the agent. Science 297, 42-43.
    [4] Carp RI, Merz PA, Kascsak RJ, Merz GS, Wisniewski HM (1985) Nature of the scrapie agent: current status of facts and hypotheses. J Gen Virol 66 (Pt 7), 1357-1368.
    [5] Manuelidis L (2000) The force of prions- Review of prion biology and diseases. Lancet 355, 2083.
    [6] Griffith JS (1967) Self-replication and scrapie. Nature 215, 1043-1044.
    [7] Dickenson AG, Frasor H (1975) Extraneural competition between different scrapie agents, leading   to  loss of infectivity. Nature 253, 556.
    [8] Rohwer RG (1984) Scrapie infectious agent is virus-like in size and susceptibility to inactivation. Nature 308, 658–662.
    [9] Prusiner SB (1995) The prion diseases. Sci Am 272, 48–51, 54–57.
    [10] Pethe K (2002) Bifani pablo mycobacterial heparin-binding hem agglutinin and laminin-binding protein share antigenic methyllysines that confer resistance to proteolysis. Proc Natl Acad Sci U S A 99, 10759–10764.
    [11] Tsubuki S, Takaki Y (2003) Dutch, Flemish, Italian and Arctic mutations of App and resistance of Abeta to physiologically relevant proteolytic degradation. Lancet 361, 1957–1958.
    [12] Wyngaarden JB, Smith LH (1992) Cecil textbook of medicine, 19th ed. W.B. Saunders, Philadelphia.
    [13]  Mitchell S (2003) Mad cow: prion research misguided. Medline Plus.
    [14] Manuelidis L (2003) Transmissible encephalopathies: speculations and realiaties. Viral Immunol 10, 123–139.
    [15] Saborio G, Permanne B (2001) Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411, 810–813.
    [16] Lasmezas CI, Deslys JP (1997) Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275, 402–405.
    [17]  Aguzzi A (2000) Prion diseases, blood and the immune system: concerns and reality. Haematologica 85, 3–10.
    [18]  Baker CA (2002) Microglia from Creutzfeld–Jakob disease-infected brains are infectious and  show specific mRNA activation profiles. J Virol 76, 10905–10915.

  • Reply to: What’s Leqembi got to do with Alzheimer’s dementia?   5 months 2 weeks ago

    RE: What’s Leqembi got to do with Alzheimer dementia? JAD blog by Markku Kurkinen, June 15, 2023

     

    Supplementary Information

     

    van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, Kanekiyo M, Li D, Reyderman L, Cohen S, Froelich L, Katayama S, Sabbagh M, Vellas B, Watson D, Dhadda S, Irizarry M, Kramer LD, Iwatsubo T (2023) Lecanemab in early Alzheimer’s disease. N Engl J Med 388, 9-21.

     

    RESULTS 

    A total of 1795 participants were enrolled, with 898 assigned to receive lecanemab and 897 to receive placebo. The mean CDR-SB score at baseline was approximately 3.2 in both groups. The adjusted least-squares mean change from baseline at 18 months was 1.21 with lecanemab and 1.66 with placebo (difference, −0.45; 95% confidence inter- val [CI], −0.67 to −0.23; P<0.001). emphasis added

     

    Fig. S1.B in Supplementary Appendix

     

               No. of Participants     Adjusted     Percent

                (placebo, lecanemab)   Mean          Slowing of

                                                     Change       Decline (%) 

    Female         446,441               -0.20           12

    Male             411,416               -0.73.          43

     

    CDR-SB measures cognition and function on a 0-18 points scale, higher scores indicating worse performance

              

    Calculemus

    x - y = z

    x = score with lecanemab

    y = score with placebo

    z = change

    z/y = % slowing 

     

    MEN (47.7%)

    x - y = - 0.73

    0.73/y = 0.43

    y = 1.70

    x = 0.97

     

    WOMEN (52.3%)

    x - y = - 0.20

    0.20/y = 0.12

    y = 1.67

    x = 1.47

     

    MEN + WOMEN (1734) weight adjusted mean change

    x = 0.477 x 0.97 + 0.523 x 1.47 = 1.23
    y = 0.477 x 1.70 + 0.523 x 1.67 = 1.68

    x - y = - 0.45

     

    Note also

    0.477 x (- 0.73) + 0.534 (- 0.20) = - 0.455

     

    -0.45, expressed as 27% (0.45/1.66), is often said to demonstrate lecanemab’s clinical benefit in slowing cognitive decline. This is a misleading miscalculation. We have said it before, and I say it again: what matters at the end of the 18-month trial with lecanemab are the CDR-SB scores in the lecanemab group (4.41) and the placebo group (4.86), including the 3.2 baseline. In the real world, lecanemab's 9.3% (0.45/4.86) benefit is unlikely to make any difference for people living with early Alzheimer dementia.

     

    Kurkinen, M, Fułek M, Fułek, K, Beszłej JA, Kurpas D, Leszek J. The Amyloid Cascade Hypothesis in Alzheimer’s Disease: Should We Change Our Thinking?  Biomolecules 2023, 13, 453. https://doi.org/10.3390/biom13030453

     

    Leibniz used to say: Gentlemen, let’s calculate

    and Wittgenstein:  What can be said at all can be said clearly, and what we can not talk about we must pass over in silence (Introduction to Tractatus).