Yves here. As KLG explains in detail below, received wisdom on Alzheimer\u2019s disease is a classic example of at least two very damaging yet widespread failures in what passes for scientific reasoning. The first is foundational myths, that persuasive-seeming early theories that become well accepted are remarkably difficult to dislodge. One classic example is ulcers. As recently as 20 years ago, a full 1\/3 of GI specialists were treating acid as the cause of ulcers, not bacteria, as had been established in 1982. The second is that correlation is not causation. Mind you, KLG has other items in his bill of particulars, such as bad incentives like greed. <\/p>\n
KLG\u2019s overview:<\/p>\n
Alzheimer\u2019s disease (AD) has remained refractory to meaningful intervention despite intensive research, especially during the past 30-40 years. It may be that no cure can be found to AD. But the almost total lack of success could be due to inadequate theories of AD and faulty assumptions that are embodied in the Amyloid Cascade Hypothesis (ACH), which can be viewed as the Central Dogma of Alzheimer\u2019s Disease. The foundation of the ACH was constructed more than a hundred years ago, shortly after Dr. Alois Alzheimer identified his eponymous plaques in the brain of his first patient after she died. The ACH has ruled modern research on AD since then. This history is deep in the archives of basic and clinical research on AD but is covered exceedingly well in How Not to Study a Disease: The Story of Alzheimer\u2019s (2022) by Karl Herrup of the University of Pittsburgh. In addition to showing where the research community went wrong on AD, this history is an object lesson in the perils of epistemic closure in any field. It also seems likely that these wrong turns have led to some of the more egregious failures of science that have recently come to light. There are also lessons here for the science and the political economy of science as emerging diseases cause ever more damage the world over. We, scientists and citizens alike, should heed them well.<\/p>\n
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<\/p>\n
We discussed Alzheimer\u2019s disease (AD) here two years ago and that led me to read much of the literature in the history of AD research.\u00a0 My questions were\u00a0 \u201cHow was the amyloid cascade hypothesis (ACH) developed, and why has it dominated research on AD for the past 30+ years despite leading to no interventions that are effective in preventing or arresting the horrific and inexorable course of AD?\u201d\u00a0 As treated at length in the very accessible How Not to Study a Disease: The Story of Alzheimer\u2019s [1] by Karl Herrup of the University of Pittsburgh, it turns out the ACH was baked into the cake in the first decade of the twentieth century, shortly Dr. Alois Alzheimer published the case report of his first patient with an odd form of dementia, Auguste D, in 1907: About a peculiar formation of the cerebral cortex.<\/p>\n
This case report is just that, a presentation based on one patient.\u00a0 Case reports are essential to modern medicine, but they are not \u201cproof\u201d of anything.\u00a0 Nevertheless, Alois Alzheimer had become a member of the scientific circle of Emil Kraepelin, in whose laboratory he identified plaques in postmortem samples from the brain of Auguste D after she died in 1906.\u00a0 Kraepelin was an early psychiatrist, probably the first, to put forth the theory that mental\/psychiatric illnesses are caused by biological changes in the brain of those so afflicted.\u00a0 His argument with Sigmund Freud about the nature of mental illness is a recurring theme in Mind the Science by Jonathan N. Stea, which was discussed here recently.\u00a0 Dr. Kraepelin subsequently included \u201cAlzheimer\u2019s Disease\u201d in the 1910 edition of Psychiatrie.\u00a0 As noted by Herrup, this was a \u201cbold and reckless\u201d choice by Kraepelin because once a disease is named in a textbook (or the DSM), it becomes much more real than a mere hypothesis in a case report or scientific paper.<\/p>\n
The clear implication from the beginning was that plaques cause AD.\u00a0 But, and this was not considered a hundred years ago and has barely been considered up to the present, something else could have caused both plaques and the disease.\u00a0 Yes, Alois Alzheimer identified his now eponymous plaques in the brains of several patients postmortem.\u00a0 However, he never did the control experiment, which would have been to examine the brains of the elderly who died without showing evidence of dementia (more on this below).<\/p>\n
According to Herrup, this demonstrates the differences between science and medicine.\u00a0 The response of medical establishment to AD goes something like this: \u201cWe have millions of people with AD.\u00a0 We must do something, now!\u00a0 So, let\u2019s start clinical trials based on what we know, and what we know is that amyloid plaques cause AD.\u201d\u00a0 On the other hand, a biomedical scientist would respond, \u201cYes, we should do what we can and closely watch what happens, but we know next to nothing about the biological causes of AD. \u00a0Therefore, while we could get lucky in the short term, we cannot begin to respond intelligently to this disease until we know a lot more.\u201d\u00a0 The biomedical scientist was ignored.<\/p>\n
But there were and are many potentially promising theories of AD other than the ACH.\u00a0 Over the past 25 years at least 30 genes have been linked to AD.\u00a0 One of them is similar to an ancient, evolutionarily conserved protein from amoebas to humans that has been the primary focus of my research for the past 25+ years. \u00a0The complex world of normal and pathological cell biology is a crowded space that is not generally acknowledged by clinician and layperson alike.\u00a0 These mechanisms include but are not limited to the following.<\/p>\n
Inflammation. A large subset of these AD-linked genes (I do not distinguish between a gene and its protein product here) are involved in the inflammatory response.\u00a0 It has been shown that microglial cells, which are the brain\u2019s version of the macrophages of the immune system that cause your skin to get red, swollen, and warm to the touch when your immune system is fighting off a bacterial infection, are altered in the brains of AD patients.\u00a0 People who have taken anti-inflammatory drugs long-term for other conditions are less likely to be diagnosed with AD.<\/p>\n
Lipid\/Cholesterol Metabolism.\u00a0 APOE (pronounced A-po-E, all long vowels) is an essential protein on the surface of the lipoprotein particles that transport lipids and cholesterol (essential nutrients and components of every membrane in every cell in the body) through the circulation.\u00a0 There are several APOE genes, and APOE4 is the number one risk factor for sporadic (i.e., non-familial) AD. [2]\u00a0 The connection between APOE4 and AD remains to be determined.\u00a0 Too much information, but a description is here (scroll down to Alzheimer Disease 2).<\/p>\n
Vesicle trafficking and Energy Metabolism.\u00a0 Cargoes are transported in our cells in membrane-bounded vesicles.\u00a0Several putative AD genes are involved in this process, which is ubiquitous in eukaryotic cells and particularly essential for neuronal function.\u00a0 Other cellular processes implicated in AD include energy metabolism.\u00a0 For example, mitochondria (the powerhouses of the cell, as we all learned in high school biology) are disrupted in the brains of AD patients.\u00a0 This could lead to an energy deficit and oxidative damage in specific areas of the brain, with inflammation to follow.<\/p>\n
Infection. \u00a0Bacteria or viruses may also be involved in the etiology and progression of AD.\u00a0 Early research was promising and a current review in an authoritative journal outlines the potential involvement of herpes viruses in AD.\u00a0 Viral infection would lead to neuroinflammation, and my gut feeling, for whatever it may be worth, is that an infectious agent is involved in early stages of AD in many if not all patients.<\/p>\n
Neurotransmission.\u00a0 And finally, data point to dysregulation of neurotransmission in AD.\u00a0 The AD drug Aricept (donepezil) increases the level of the neurotransmitter acetylcholine in the brain.\u00a0 Aricept improves cognition at the margin in some patients by some measures but does not prevent progression of disease.<\/p>\n
Thus, many biological mechanisms could contribute to the origin(s) and progression of AD.\u00a0 But concomitant with the development of modern molecular biology (i.e., gene cloning), the ACH<\/p>\n
\u00a0became dominant and virtually exclusive when the amyloid precursor protein (APP) was cloned in the mid-1980s.\u00a0 Here was a signal triumph of modern biomedical science, at a time when an analog of Kraepelin\u2019s thesis (i.e., mental illness is caused by a biological\/structural problem in the brain) became dominant: Disease is caused by mutant genes, and when we know the gene, we can find the cure in short order. [3] \u00a0Thus did the ACH become the Central Dogma of Alzheimer\u2019s Disease: APP makes amyloid makes Alzheimer\u2019s disease.\u00a0 The Central Dogma of Molecular Biology, dating to the late-1950s (Francis Crick), is DNA makes RNA makes Protein.\u00a0 With a minor modification for the existence of retroviruses such as HIV that integrate into the human genome (viral RNA makes DNA makes RNA makes Protein), this Central Dogma provided the theoretical basis for modern molecular biology and genetics.<\/p>\n
Scientific politics and institutional imperatives, but not scientific research, soon confirmed the Central Dogma of Alzheimer\u2019s Disease.\u00a0 The National Institute on Aging (NIA) was established in 1974.\u00a0 Since we all hope to grow up without growing too old and decrepit to enjoy maturity, NIA was a natural expansion of an NIH that now has 27 institutes and centers.\u00a0 Without going into the details, a marketing strategy to develop support for the NIA \u201crequired a new reshaping of the narrative.\u00a0 Alzheimer\u2019s disease needed to become recognized as the most common form of dementia.\u201d\u00a0 Yes, scientists market their brands, contrary to their self-image.\u00a0 This worked.\u00a0 In 2021, 70% of the NIA budget was devoted to AD research.\u00a0 Virtually all this funding was in support of the Central Dogma of Alzheimer\u2019s Disease. [4] \u00a0In Herrup\u2019s memorable formulation \u201cThe amyloid flea is wagging the Alzheimer\u2019s tail which is wagging the NIA dog\u2026This is not how you study a human disease.\u201d<\/p>\n
This is where Big Pharma comes into the picture.\u00a0 Aricept works at the margin for some patients but does not halt or reverse progression of AD.\u00a0 Aricept is a cheap chemical, not a blockbuster drug.\u00a0 On the other hand, a cure for AD would be worth billions.\u00a0 And this explains why over the past 25 years a series of expensive Phase III clinical trials have failed to make any substantial progress in confirming the Central Dogma of Alzheimer\u2019s Disease.<\/p>\n
A brief narrative would include the following: \u00a0Soon after amyloid was identified a mouse model that expressed human amyloid was constructed.\u00a0 A \u201cvaccine\u201d against this amyloid resolved the plaques.\u00a0 This was tried in human subjects.\u00a0 Those who were successfully immunized against amyloid nevertheless continued to decline at a rate virtually indistinguishable from patients who were not immunized.\u00a0 This intervention was clearly not working in humans as it did in mice.\u00a0 In other models, mice do not exhibit the progressive loss of function like that in humans. \u00a0They have defects but they do not get worse as the mice age.\u00a0 If these model mice are vaccinated against amyloid these defects go away.\u00a0 It goes without saying, but this is apparently not appreciated, that if these triumphs of modern molecular genetics were a good model of human AD, even the best result would not restore function that had been lost.\u00a0 AD progression in humans is inexorable and irreversible.<\/p>\n
So, why has Big Pharma persisted up to now?\u00a0 Herrup proposes three reasons that are not mutually exclusive: (1) Stubbornness \u2013 associated with the myth of the omniscient (and very rich) CEO of the modern transnational Big Pharma firm, (2) Greed \u2013 \u00a0throwing good money after bad will lead to that billion-dollar breakthrough, and (3) Bad advice \u2013 in this Herrup is direct to the point of rudeness.\u00a0 But I have been following AD research closely for about 25 years, since I worked with colleagues who were very good scientists enthralled with the ACH.\u00a0 One was a physical biochemist whose research was far beyond my ken.\u00a0 He could expound at length on the structure of soluble (inconsequential) versus insoluble (pathognomic) amyloid but almost nothing about the disease itself.\u00a0 Here is Herrup\u2019s take on bad advice to Big Pharma:<\/p>\n
What began as maneuvers of academic politics \u2013 inflation of the meaning of Alzheimer\u2019s disease and the suppression of nonamyloid research \u2013 ended up creating a bevy of inbred (Ouch!) experts who were repeatedly and exclusively called upon as advisors to the industry.\u00a0 So certain were these experts if their own models of Alzheimer\u2019s disease that they repeatedly reassured the CEOs they were on exactly the right course.<\/p>\n
This is the magical thinking leading to Aduhelm (aducanamab), the brand (keyword) that did not work, despite the wishes of Biogen (one of the first Biotech companies, established in 1978 before biotech even existed; founders Walter Gilbert and Philip Sharp were awarded Nobel Prizes) and the Food and Drug Administration of the United States.<\/p>\n
What is the current state of the ACH\/Central Dogma of Alzheimer\u2019s Disease?\u00a0 Remember the controls that Alois Alzheimer did not do?\u00a0 They have been done.\u00a0 Upon postmortem examination of brains of healthy people who died in old age but showed no signs of even mild cognitive impairment or dementia, up to one-third of these brains have enough amyloid plaques to support a diagnosis of Alzheimer\u2019s disease they did not have.\u00a0 Therefore, plaques (and Tau tangles, ignored here but no more likely than amyloid plaques to cause AD) are not the cause of AD.\u00a0 In the mouse model of familial AD, which is probably what the 51-year-old patient zero Auguste D had, the mouse disease does not resemble human disease.\u00a0 These mice develop plaques but have few other health problems.\u00a0 They are also hard to distinguish from the wild-type controls in their behavior (grooming, feeding, social activity).\u00a0 Contrast this with human patients in memory care units with their contemporaries who do not have AD.\u00a0 Moreover, when AD mice are successfully vaccinated against amyloid, they are restored to \u201cnormal\u201d within days.\u00a0 Contrast this with any AD treatment to date in human patients.\u00a0 Aricept may marginally slow cognitive decline in AD patients, but it does not reverse it.<\/p>\n
The Central Dogma of Alzheimer\u2019s Disease was only that, dogma.\u00a0 It has been an intuitive cul de sac.\u00a0 Unfounded dogma leads nowhere.\u00a0 It is past time, 100+ years after the first description of Alzheimer\u2019s disease, for an approach that focuses on the basic biological mechanisms (plural) of AD.\u00a0 This is the only way forward.\u00a0 Before the biological bases of cancer and metastasis were understood, largely based on research within the last 50 years and accelerating in the past 25 years, clinical oncology was also limited to what may be called intuitive approaches such as the radical mastectomy\u2013 cut it all out \u2013 first performed by William Stewart Halstead (one of the four physicians who founded Johns Hopkins Hospital) in 1882.\u00a0 The operation became even more radical in time, even after realization that it often did not prevent recurrence at a secondary site (metastasis) while mutilating the patient.\u00a0 All of us have had friends or relatives treated in this wayb.\u00a0 All of us also have friends whose breast cancer has been cured by modern, biologically based clinical oncology.<\/p>\n
Alzheimer\u2019s is a brain disease of aging.\u00a0 Thus, the answer(s) to AD are likely to come from a deeper understanding of the biology of aging and the local and systemic effects of aging on the brain.\u00a0 This will require a complete rebalancing of the research portfolio of the National Institutes of Health and other funding agencies so that the molecular, cellular, and organismal understanding of aging in the brain reach the levels of the extensive (but still sometimes insufficient and sometimes misdirected) knowledge we have of heart disease and cancer.\u00a0 This rebalancing can be done only if the rewards of research are changed, and the Central Dogma of Alzheimer\u2019s Disease is displaced as the ruling paradigm of AD research.<\/p>\n
Basic biomedical research takes time and patience.\u00a0 It is tedious and incremental and not amenable to fads such as the Central Dogma of Alzheimer\u2019s Disease.\u00a0 Very few useful scientific advances can be rushed.\u00a0 Nevertheless, the tenure clock ticks inexorably for the young scientist in a research university or medical school or NIH, so one must go with the flow to be successful in a dogfight that often turns nasty.\u00a0 This is one major reason that biomedical research can lead to dogmatic dead ends, some of which are filled with untoward behavior (covered here before). \u00a0And this recently revealed outrage involving research on Alzheimer\u2019s and Parkinson\u2019s disease, which is unbelievable but probably true! [5]<\/p>\n
Finally, as Karl Herrup puts it toward the end of his book, with authority:<\/p>\n
It is precisely because we have relied so heavily on this hurry-up-and-do-something approach that we are in the situation we find ourselves in today \u2013 no cure and few clues\u2026We must do something\u2026(but)..there is nothing ethical about endlessly repeating expensive trials based on old, unreliable disease models such as the amyloid cascade hypothesis.<\/p>\n
The \u201churry-up-and-do-something approach\u201d in biological research has a dismal history, one that most recently has failed to lead to any real solution to a worldwide pandemic. [6] \u00a0That particular dogma was \u201cvaccination is the one true path to success for one novel disease.\u201d \u00a0Yes, vaccines are an essential tool in the control of infectious disease.\u00a0 But not always, and especially not recently.\u00a0 This was known regarding coronaviruses as early as the 1950s.\u00a0 Unfortunately, the importance of vaccination in preventing infectious disease has been called into question by the institutional and political responses to COVID-19.\u00a0 This has the makings of catastrophe.\u00a0 Dogma can be deleterious.<\/p>\n
The Amyloid Cascade Hypothesis told us that the definition of Alzheimer\u2019s disease is the presence of amyloid plaques in the brain. \u00a0This is not true. \u00a0Many of us of a certain age have enough plaques in our brains to support a diagnosis of AD but without dementia or even mild cognitive impairment.\u00a0 Going forward the definition of Alzheimer\u2019s disease must be based on the clinical symptoms of the patient, not on protein deposits and tangles remaining after cells die in the patient\u2019s brain.\u00a0 The symptoms of AD cannot be understood until research on AD is based on a biological model of the disease.\u00a0 The health and wellbeing of millions depend on this.\u00a0 The likely paths (not path) have been outlined above.\u00a0 Other candidates will emerge, perhaps from a completely unexpected direction, which would include the function of APP itself.<\/p>\n
This is how you study a human disease.<\/p>\n
Notes<\/p>\n
[1] Much of what follows is based on this book, which is an astonishing read that illustrates everything that must not be done when studying a human disease.\u00a0 I recommend it highly, as a good read and a source for those who want to dig deeper.\u00a0 I can also imagine responses from the usual suspects to this book, which I have not read but plan to get to soon in another context.<\/p>\n
[2] Sporadic, i.e., non-familial, disease.\u00a0 Familial AD accounts for relatively few cases of AD.\u00a0 It was thought originally that cleavage of Amyloid Precursor Protein (APP) to produce amyloid plaques would reveal the secret of AD.\u00a0 This research has revealed much about amyloidogenic fragments but less about the disease itself.\u00a0 Similarly, Familial Amyotrophic Lateral Sclerosis (FALS) is associated with the enzyme superoxide dismutase (SOD1), which converts the highly reactive superoxide anion to hydrogen peroxide, which is then split by the enzyme catalase to produce water.\u00a0 FALS represents only 5% of ALS cases.\u00a0 The connections between SOD1 and ALS remain obscure, but the courses of disease of familial and sporadic ALS are similar.<\/p>\n
[3] I was a research laboratory technician\/coordinator when the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) was cloned in 1989.\u00a0 A drug combination has recently shown promise in treating the most common form of cystic fibrosis.\u00a0 It was essential to know the gene\/protein associated with CF to reach this point, but these drugs are simple and expensive compounds that help misfolded mutant CFTR find its way to the cell membrane of cells in many tissues other than the lung and function properly when it arrives. \u00a0Molecular genetics per se has nothing to do with this and there is no prospect of gene therapy for cystic fibrosis.<\/p>\n
[5] To cut to the chase: \u201cAfter Science brought initial concerns about (Eliezer) Masliah\u2019s work to their (University of California-San Diego and NIA) attention\u2026a 300-page dossier\u2026revealed\u2026a steady stream of suspect images between 1997 and 2023 in 132 of his published research papers.\u201d\u00a0 The analysts, who were not paid by Science noted \u201cIn our opinion, this pattern of anomalous data raises a credible concern for research misconduct and calls into question a remarkably large body of scientific work.\u201d\u00a0 As illustrated in the table in the news article, Masliah is among the world\u2019s top 10 scientists in certain subfields, including mouse models of AD.\u00a0 Scientists at the end of the piece \u201cworry about (this apparent catastrophe) giving science a further black eye, just as the public\u2019s confidence in science is sinking to new depths.\u201d\u00a0 My reaction is unprintable.\u00a0 Another link is here if the Science link is paywalled.<\/p>\n
[6] A comparative analysis of our collective responses to Alzheimer\u2019s disease, AIDS, and COVID-19 will provide useful lessons for the future, but only if the entire research community is reorganized for biomedical science instead of \u201cBioscience\u201d that could make a lot of money.\u00a0 The scientists and the infrastructure are in place and can be repurposed to the benefit of all.\u00a0 We need only the wit and the will to discard Neoliberalism \u2013 \u201cThe market is the measure of all things, even those that cannot be measured.\u201d<\/p>\n
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