The brain, Alzheimer ’ second researchers patiently explain, is hard — hard than the heart, harder even than cancer. While that may be true, it is increasingly apparent that there is another, more distressing reason for the tragic miss of progress : The most influential researchers have long believed so dogmatically in one theory of Alzheimer ’ s that they systematically thwarted alternate approaches. several scientists described those who controlled the Alzheimer ’ s agenda as “ a conspire. ”
In more than two twelve interviews, scientists whose ideas fell outside the dogma recounted how, for decades, believers in the dominant allele guess suppressed research on alternative ideas : They influenced what studies got published in crown journals, which scientists got funded, who got tenure, and who got speaking slots at reputation-buffing scientific conferences .
This suppression of competing ideas, say a growing number of scholars, is a big rationality why there is no treatment for Alzheimer ’ randomness. ( The four approved drugs have no effect on the disease, providing entirely a irregular memory hike. )
The scientists described the torment, evening career-ending, obstacles that they confronted in pursuing their research. A top diary told one that it would not publish her paper because others hadn ’ thyroxine. Another got whispered advice to at least make-believe that the research for which she was seeking fund was related to the leading estimate — that a protein fragment called beta-amyloid accumulates in the brain, creating neuron-killing clumps that are both the induce of Alzheimer ’ s and the key to treating it. Others could not get speaking slots at important meetings, a samara case for research results. respective who tried to start companies to develop Alzheimer ’ second cures were told again and again by speculation das kapital firms and major biopharma companies that they would back merely an amyloid approach .
“ The amyloid hypothesis has been one of the most tragic stories [ in ] disease research, ” said neurobiologist Rachael Neve of Massachusetts General Hospital .
Despite being described as a “ conspiracy, ” the starchlike camp was neither organized nor nefarious. Those who championed the amyloid guess sincerely believed it, and thought that focusing money and attention on it rather than competing ideas was the surest way to an effective drug .
It has not worked out that way. Research focused on amyloid, and the development and testing of experimental drugs targeting it, have sucked up billions of dollars in government, basis, and drug company fund with nothing to show for it. While targeting starchlike may or may not be necessary to treat Alzheimer ’ mho, it is not sufficient, and the extra steps about surely include those that were ignored, even censored. credibly the most shattering turn came in March, when Biogen halted the study of what proponents called the most promise Alzheimer ’ randomness drug in years — an amyloid-targeting antibody .
For all her regrets about the amyloid hegemony, Neve is an unlikely critic : She co-led the 1987 discovery of mutations in a gene called APP that increases starchlike levels and causes Alzheimer ’ south in middle age, supporting the then-emerging orthodoxy. Yet she believes that one reason Alzheimer ’ mho remains incurable and untreatable is that the starchlike camp “ dominated the field, ” she said. Its followers were influential “ to the extent that they persuaded the National Institute of Neurological Disorders and Stroke [ region of the National Institutes of Health ] that it was a waste of money to fund any Alzheimer ’ s-related grants that didn ’ metric ton center around amyloid. ”
To be certain, NIH did fund some Alzheimer ’ s research that did not focus on amyloid. In a ocean of amyloid-focused grants, there are bantam islands of research on oxidative stress, neuroinflammation, and, particularly, a protein called tau. But Neve ’ mho NINDS program officeholder, she said, “ told me that I should at least collaborate with the starchlike people or I wouldn ’ thymine get any more NINDS grants. ” ( She hoped to study how neurons die. )
A ten after her APP discovery, a disillusioned Neve left Alzheimer ’ s research, building a distinguished career in gene edit. nowadays, she said, she is “ pale about the millions of people who have needlessly died from ” the disease .
Dr. Daniel Alkon, a longtime NIH neuroscientist who started a caller to develop an Alzheimer ’ south treatment, is even more emphatic : “ If it weren ’ thyroxine for the near-total dominance of the idea that starchlike is the only appropriate drug target, ” he said, “ we would be 10 or 15 years ahead of where we are now. ”
Making it worse is that the empirical digest for the amyloid hypothesis has constantly been precarious. There were numerous red flags over the decades that targeting amyloid entirely might not slow or reverse Alzheimer ’ second .
“ tied at the time the amyloid hypothesis emerged, 30 years ago, there was business about putting all our eggs into one basket, particularly the idea that ridding the brain of amyloid would lead to a successful treatment, ” said neurobiologist Susan Fitzpatrick, president of the united states of the James S. McDonnell Foundation. But research pointing out shortcomings of the hypothesis was relegated to second-tier journals, at best, a bespeak to other scientists and drug companies that the criticisms needn ’ metric ton be taken besides seriously .
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Zaven khachaturian exhausted years at NIH overseeing its early Alzheimer ’ s financing. Amyloid partisans, he said, “ came to permeate drug companies, journals, and NIH study sections, ” the groups of largely outdoor academics who decide what research NIH should fund. “ Things shifted from a scientific inquiry into an about religious belief system, where people stopped being disbelieving or even questioning. ”
That would be tragic enough in any area of biomedical research, but it ’ randomness particularly so in Alzheimer ’ s. today, 5.8 million people in the U.S. have the disease, including 1 in 10 of those 65 and complete, estimates the Alzheimer ’ s Association. It is the fifth leading cause of death in that age group. For many patients and their families, that ’ s a minor mercifulness : Robbed of their memories, unable to recognize those they loved, much suffering from psychosis, they lose their thinker and their identity farseeing before their life .
Scientists close associated with the amyloid model argue that if alternate ideas received little fund defend, it was because NIH ’ s Alzheimer ’ s budget was deplorably insufficient ( $ 425 million in 2012, $ 2.4 billion in 2019 ). “ It ’ s our responsibility to choose studies that are the most promise, and I think we have been doing that, ” said Dr. Paul Aisen of the University of Southern California, a leading amyloid advocate. “ I would reject the idea that we would have been further along if there had been more receptiveness to other ideas. ”
Dr. Dennis Selkoe of Harvard Medical School, besides a big amyloid research worker, international relations and security network ’ thyroxine therefore sure. He, excessively, says low NIH fund for Alzheimer ’ mho from the 1980s through the 2000s is to blame for option ideas languishing. “ But society has the right to ask, why haven ’ thyroxine we made more progress ? ” he said. “ I have no doubt that if we had done broader research we would be more advance now. ”
“ I don ’ deoxythymidine monophosphate think there was a purposeful try to scuttle other approaches, ” Selkoe added. Or as Aisen put it last week on the sidelines of the Aspen Ideas Festival, “ I don ’ triiodothyronine think I ’ m separate of a conspire. ”
Ruth Itzhaki Courtesy University of Manchester Ruth Itzhaki much felt like she was in a house of mirrors. A molecular neurobiologist at England ’ s University of Manchester, in 1991 she discovered pathogens — herpes simplex virus type 1 — in the brains of aged people who had died with Alzheimer ’ s and carried the most coarse gene for the disease. It was the first indication that infectious agents might play a function in Alzheimer ’ mho, raising the hypothesis that eliminating them ( and the resulting immune reception, including inflammation ) might stop or even reverse it .
closely half a twelve journals rejected Itzhaki ’ south newspaper before it was accepted by the Journal of Medical Virology, not a bad daybook but not a leading one. A frequent reason top journals declined to publish her papers, as they did those of early amyloid skeptics, was former rejections. As one peer commentator wrote about a fund proposal Itzhaki submitted in 2010, “ very few [ of your ] papers have appeared in the most highly see journals. ”
“ And here I thought research should be judged on its own merits, ” Itzhaki said .
Like other doubters, Itzhaki wasn ’ metric ton dismissing the idea that amyloid has a character in Alzheimer ’ south ; she was questioning whether it was the lawsuit, and therefore a good drug target. She saw it as a consequence of the true lawsuit — making amyloid the gravestones of genius neurons killed by something else and not their assassins. In that case, targeting amyloid would no more revive dead neurons than removing headstones would resurrect bodies in a cemetery .
Funders did not beat a path to her lab door. When Itzhaki was an adviser on a proposed clinical trial of an antiviral drug for Alzheimer ’ second, one scientist who assessed it for a private foundation wrote, “ The bangle of this approach appears to be quite lacking, ” according to documents she shared with STAT. To which Itzhaki wondered, the thousands of clinical trials based on eliminating starchlike, which keep getting funded, are novel ?
The Alzheimer ’ s Association awards its Zenith Fellowships to scientists “ on the edit edge ” of research, acknowledging that their studies “ may not conform to current conventional scientific wisdom of solomon or may challenge the predominate orthodoxy. ” Itzhaki thought that described her function to a T, so in 2004 she applied for fund for a study on the role of herpes simplex virus in Alzheimer ’ south .
The know was that of an impala asking a pride of lions for support. One of the four reviewers gave her scores of “ poor people ” ( 3 on a 10-point scale ) on key criteria, arguing that because “ there is no conclusive attest for a major role of this pathogen in Alzheimer ’ s disease, ” the research “ will not have an affect on advancing the field of dementia research. ” A moment reviewer called the function of pathogens in Alzheimer ’ s “ a fringe topic. ” Although one gave Itzhaki scores of 10 ( “ outstanding ” ), the two dismissive reviews sank her chances .
It was another demonstration of the power of the amyloid clique. even when some reviewers were open to option ideas, fund and publish are then competitive, a single slam mean failure .
Itzhaki fared small better getting speaking slots at the field ’ s most important annual gather. In 2004, a colleague, neuroscientist George Perry of the University of Texas at San Antonio, talked the organizers of the Alzheimer ’ s Association International Conference into giving Itzhaki 10 minutes, something, he recalled, that “ took a lot of persuading. ”
That was the only meter she “ was allowed to give a talk, ” Itzhaki said, “ though I applied every class. They never included viruses in the list of meeting topics, and I was allowed only a poster. No one influential ever even came to see it. ”
For all the obstacles thrown in her direction, in 2009 Itzhaki showed that herpes simplex virus character 1 is a strong gamble factor for Alzheimer ’ second, and in 2007 that beta-amyloid accumulates in mouse brains that are infected with it. Studying mouse brains and patients ’ brains, she found tell “ that this virus is a major cause of amyloid plaques and hence probably a significant [ causative ] factor in Alzheimer ’ south disease. ”
last year, two studies by teams at Mount Sinai and Harvard tied infectious agents to Alzheimer ’ s more powerfully than any former inquiry had, supporting the mind that targeting pathogens and not the response to pathogens ( starchlike plaques ) might prevent or slow Alzheimer ’ s. In fact, a little-noticed report in Taiwan, besides published final year, found that people diagnosed with herpes infections were 2.6 times american samoa probably to develop dementia as herpes-free individuals, but that antiviral drugs cut the risk 90 percentage. In 2017 the first clinical trial investigating antiviral drugs in people with meek to moderate Alzheimer ’ sulfur got afoot at Columbia University .
“ I just wonder if we ’ five hundred be far along if those of us studying the function of pathogens in Alzheimer ’ sulfur had gotten the sanction of journals and meetings that the starchlike people did, ” Itzhaki said .
In comeliness, the truthful believers had attest implicating amyloid in Alzheimer ’ sulfur disease .
Auguste Deter, the first person to be diagnosed with Alzheimer ’ s disease, died in 1906. Public domain In 1906, when german neuropathologist Dr. Alois Alzheimer examined the brain of a 51-year-old woman who had died from what he called presenile dementia, he identified muggy plaques between neurons and tangles of filamentous proteins within them. Plaques in particular, and tangles secondarily, have been the disease ’ s defining characteristics ever since.
Flash forward to 1984 : Scientists determined the weight, length, and precise molecular sequence of the protein fragment, or peptide, that makes up the brain plaques. It has come to be known as beta-amyloid .
Hard on the heels of the 1987 discovery by Neve and her colleagues of one amyloid-related gene came several more, all linking mutations in genes called PS1, PS2, and APP to early-onset Alzheimer ’ randomness, which accounts for about 5 % of cases. The 1991 discovery of one APP mutant ( there are many ) was the most-cited wallpaper in all of biomedicine that year. The mutations all raise starchlike levels, and people with them develop Alzheimer ’ mho before age 65 .
In an era capture of genes “ for ” this or that disease, it was an article of faith that genetics would produce cures. “ When the genetics discoveries came out, it all pointed to amyloid having a critical role, ” said UT ’ south Perry, a longtime critic of the starchlike model .
By the mid-1990s, a now-defunct San Francisco biotechnology ship’s company, Athena Neurosciences, created the first genetically engineered mouse with a mutated, amyloid-producing homo gene. The animals ’ brains filled with amyloid plaques, and their memories were destroyed. The shiner were hailed as a “ model for testing therapeutic [ Alzheimer ’ s ] drugs ” and rodents that “ shook the earth ” : Eliminating the amyloid in their brains at least partially reversed their memory loss and other cognitive deficits .
“ If you stopped the starchlike, the mouse got better, ” said Alkon, the early NIH neuroscientist. “ Everyone said, this must be the means to treat Alzheimer ’ mho. ”
And indeed they tried. The biopharma giants Pfizer and Eli Lilly and Merck and Biogen, the now-defunct Elan ( which acquired Athena in 1996 ), and hundreds of academic researchers each crafted a vaccine or antibody or humble atom to prevent the geological formation of amyloid plaques, to remove soluble ( pre-plaque ) starchlike, or to destroy the plaques .
“ You had a whole industry going after starchlike, hundreds of clinical trials targeting it in unlike ways, ” Alkon said. Despite success in millions of shiner, “ none of it worked in patients. ”
Amyloid plaques have long been the suspect induce of cognitive decline experienced by Alzheimer ’ randomness patients. drug companies have spent billions of dollars creating amyloid-targeting drugs, so far they ’ ve all failed. STAT ’ mho Damian Garde explains why .
Scientists who raised doubts about the amyloid model suspected why. amyloid deposits, they thought, are a reply to the on-key cause of Alzheimer ’ mho and therefore a marker of the disease — again, the gravestones of neurons and synapses, not the killers .
The testify ? For one thing, although the brains of aged Alzheimer ’ south patients had amyloid plaques, so did the brains of people the lapp age who died with no signs of dementia, a diagnostician discovered in 1991. Why didn ’ thymine amyloid rob them of their memories ? For another, mouse engineered with human genes for early on Alzheimer ’ sulfur developed both amyloid plaques and dementia, but there was no proof that the much more common, late-onset class of Alzheimer ’ mho worked the lapp way. And yes, amyloid plaques destroy synapses ( the basis of memory and every other brain function ) in sneak brains, but there is no correlation coefficient between the degree of cognitive impairment in humans and the amyloid charge in the memory-forming hippocampus or the higher-thought frontal lens cortex .
“ There were so many clues, ” said neuroscientist Nikolaos Robakis of the Icahn School of Medicine at Mount Sinai, who besides discovered a mutation for early-onset Alzheimer ’ sulfur. “ Somehow the playing field believed all the studies supporting it, but not those raising doubts, which were identical impregnable. The many weaknesses in the theory were ignored. ”
Reluctance “ to admit that possibly we have it wrong, ” as the McDonnell Foundation ’ s Fitzpatrick put it, made it unmanageable for researchers who, mindful of those loss flags, wanted to explore ways to understand, prevent, and treat Alzheimer ’ s that didn ’ t orb around starchlike. alternative ideas ranged from infectious microbes and ignition as causes, to blood flow and synapse restoration as treatments. today, therapies based on all of those ideas, and more, are being tested in people, testify of their promise .
But many of the scientists with alternative ideas “ became roadkill on the highway to nowhere, ” Perry said, their careers stalled or worse. Perry fared better, rising to become dean of the College of Sciences at UT San Antonio, but saw many of his NIH grant proposals rejected by NIH study sections. A ally on one “ told me my NIH accord was sacked due to my anti-amyloid stance, ” Perry said. “ The sacker came up to me at a meet a few weeks later and asked why I wrote articles questioning amyloid. ”
not every young scientist has the stomach for the Alzheimer ’ mho wars. Neurophysiologist Malú Tansey of Emory University has focused on neuroinflammation for closely two decades, convinced that this hyped-up immune answer kills synapses and neurons and explains many early discoveries about Alzheimer ’ randomness brains .
If that ’ south right, “ it suggests a function for non-amyloid drug targets, ” she said .
But this was no subject for a young scientist trying to gain a bridgehead in the field. In her first gear university speak as a junior faculty extremity, in 2002, Tansey described her research. “ A senior staff extremity stood up and said neuroinflammation has nothing to do with Alzheimer ’ second, ” she recalled. “ It was intimidating. ”
She has since focused on Parkinson ’ mho disease, but hush has two grants to study neuroinflammation in Alzheimer ’ s .
similarly, at Mount Sinai, one of Robakis ’ s postdoctoral fellows witnessed Robakis ’ s NIH grant proposals to study things like neural survival ( without a function for amyloid ) getting such a abject score that the study section didn ’ t even discuss it .
“ He left Alzheimer ’ second to study something dependable, the blood-brain barrier, ” Robakis said. “ That happened all the clock. ”
For youthful academics, biotechnology administrator Dr. Raymond Tesi said, “ it ’ s unmanageable to break into a field with so many firm voices supporting a single target. Alzheimer ’ south has egos and superstars and big personas unlike anything I ’ ve seen elsewhere. ”
Tesi was persuaded enough by the neuroinflammation explanation of Alzheimer ’ s that he vowed to found a company to develop a discussion based on it. Starting about a decade ago, he said, “ I talked to everyone : Lilly and Novartis, venture capitalists, arguing that neuroinflammation was the core pathology of Alzheimer ’ sulfur. We couldn ’ metric ton get past the front doorway. If you weren ’ deoxythymidine monophosphate doing amyloid, you could barely get a meet. ”
He called it an example of “ the groupthink that occurs in biopharma. Every company goes to key opinion leaders in academia and asks, ‘ What should we do ? ’ ” Since starchlike had a lock on such leaders, from Harvard to the University of Southern California and in between, the answer was always the same : eliminate amyloid .
In 2015, Tesi and others finally scraped together enough confirm, including a $ 1 million grant from the Alzheimer ’ randomness Association, to found INmune Bio and develop a compound to quell neuroinflammation. That year, he estimated, 90 % of NIH, diligence, and private foundation spending on Alzheimer ’ s research and drug development was premised on the idea that eliminating or reducing starchlike was the road to success .
INmune launched a Phase 1 clinical trial this calendar month of its anti-inflammatory agent XPro1595. It may well fail, but INmune is targeting people with balmy to moderate Alzheimer ’ mho, whom virtually every big biopharma has given up on. If an anti-inflammatory helps such patients, that could have been discovered millions of harry minds ago. “ We credibly lost five years, ” said Tesi, the company ’ south chief executive .
Alkon said he lost at least that many. During three decades at NIH, he did groundbreaking work on the cellular and molecular basis of memory, rose to the position of lab director, published hundreds of scientific papers … and never cured anyone of anything. But in 1999, he felt, he merely might .
He consequently resigned from NIH to head a cure-focused, neurological establish founded by the Rockefeller family, studying an odd intensify called bryostatin-1 ( made by sea mosses, of all things ) and its noteworthy ability to increase synapse-boosting molecules. Hoping to turn bryostatin into an Alzheimer ’ sulfur drug, Alkon co-founded Neurotrope BioScience in 2012, and soon tried to interest a leading pharmaceutical company in collaborating to develop bryostatin faster than a little inauguration could alone .
In a meet at the drug godhead ’ mho headquarter, Alkon ran through the data. In homo neurons growing in lab dishes, bryostatin provided protection against amyloid and preserve synapses. In mouse, it improved eruditeness and memory even when amyloid levels remained high. It not only continue synapses, it besides sopped up amyloid molecules, the protein fragments whose clumping into awkward plaques between brain neurons is considered the authentication of the disease. And in earlier studies, when tested against cancer, bryostatin was highly safe .
Cool, great, the executives said. There was barely one thing .
“ The alone way they would consider bryostatin was if we could show it was superb at stopping amyloid, ” Alkon recalled. “ They were merely interested in that, not its impression on synapses, ” whose personnel casualty causes the memory and other cognitive decay of Alzheimer ’ second patients and which Alkon believes is the key to treating the disease .
The company ( which he declined to name so as not to jeopardize future collaborations ) passed. It had better ways to eliminate starchlike, it decided, and didn ’ metric ton much care about restoring synapses. The future companies Alkon approached said much the lapp thing : It was all amyloid, all the meter. “ There weren ’ t many I didn ’ thyroxine lecture to, ” he said .
No one claims that if deep-pocketed drug company had gotten behind bryostatin seven years ago there would be a treatment for Alzheimer ’ mho today. The experimental drug produced acceptably results in a modest clinical trial, according to data published in January in the Journal of Alzheimer ’ sulfur Disease, though it improved cognitive function adequate in some patients that Neurotrope is running a larger study, convinced the improvement is substantial .
For three years, Jeff Borghoff was a patient in Biogen ’ s Alzheimer ’ s drug test. Its holocene failure has left him and his family diffident of his following discussion options .
The failure of every amyloid-based experimental compound has, ultimately, triggered soul searching about how it all went so wrong that, in 2019, there is nothing for people who develop Alzheimer ’ mho and likely nothing for many more years. What happened ?
“ People who said, wait, it might not be then simple as eliminating amyloid, they were not able to go against the wave, ” said Mount Sinai ’ s Robakis. “ critical thinking gave way to dogma. What you believe can be influenced by what is in and what is out. How else do you explain the widespread acceptance of a theory despite its weaknesses ? ”
Robakis has been continually funded by NIH ( including for studies unrelated to Alzheimer ’ mho ), so his criticism international relations and security network ’ t sour grapes. Yet he began to feel that the amyloid clique saw him as a “ traitor, ” the more he pointed out flaws in the theory. “ I decidedly lost grants, ” he said. “ If starchlike wasn ’ thymine in the grant proposal, it was an uphill struggle. There were very big egos involved and they couldn ’ deoxythymidine monophosphate stand to be improper. It wasn ’ thymine skill anymore. ”
He paused. “ We should have known better, ” he continued. “ You can ’ t say what would have happened if things had been unlike, but possibly if there had been more back for option ideas, we would be better off [ in terms of Alzheimer ’ mho treatments ] than we are. ”
It isn ’ t unvoiced to understand why hundreds of academics lined up behind the amyloid model over the years, Fitzpatrick said. “ Once a field commits to a particular hypothesis, the inquiry resources — fund, experimental models, and training — all get in line, ” she wrote in a 2018 analysis. That brings backers of the dominant theme accolades, awards, lucrative confer deals, and well-paid academician appointments. Admitting doubt, let alone mistake, would be not only be a blow to the ego but besides a terror to support .
Academics who took part in clinical trials of amyloid-premised drugs greeted each failure with “ some lame excuse, ” said Jack de la Torre of the University of Texas, Austin, who studies the estimate that reduced rake flow within the genius is a key contributor to Alzheimer ’ sulfur. “ This direction, the money from big drug company would mercifully not dry up. ”
Harder to understand is why drug companies embraced the dogma even after the repeat failures of experimental drugs based on it, which has cost them billions of dollars. A longtime drug company scientist who recently joined a biotechnology inauguration offered one explanation : If company executives greenlight the growth of an amyloid drug and it fails, they don ’ t lose their jobs because “ the smartest guys in the room, meaning academia, said this was the way to go, ” he said. “ But if you greenlighted a different kind of Alzheimer ’ south therapy, and it failed, dependable fortune with your career. ”
While there is growing recognition that there could have been more advance if non-amyloid ideas had received greater accompaniment early on, those alternatives are nowadays being explored in both basic research and clinical trials. The NIH, for exemplify, is funding the 130-patient study of whether an antiviral can help Alzheimer ’ south patients ; Columbia ’ s Dr. Davangere Devanand, who is leading it, expects results in three years .
The increasing diversity of approaches might finally bring help to the millions of people already suffering from Alzheimer ’ mho and the tens of millions more who will develop it. “ The tragedy is, ” said UT ’ mho Perry, “ we could have gotten to this point many, many years oklahoman. ”