In the wake of disappointing results this week for yet another experimental Alzheimer’s drug, scientists who have toiled for decades to understand the devastating disease expressed frustration and even anger that their field has not made more progress toward a cure.

“Our field desperately needs new therapies,” Dr. David Knopman, an Alzheimer’s expert at the Mayo Clinic, said at the Alzheimer’s Association International Conference in Toronto, where biotech company TauRx reported the failure of its drug candidate. “In defense, our field is still young,” Knopman added — a justification that dismayed some of his colleagues.

To a growing number of scientists, the problem isn’t that there’s been too little time to make meaningful progress against a hugely complicated disease that strikes an organ unrivaled for its complexity. It’s that the field has made many missteps, that its leaders stifled research that deviated from the dominant theory of what caused Alzheimer’s, and that it was too easy to count as progress journal papers rather than advances that help patients.

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“People got into a certain mindset, had a certain set of expectations, and then proceeded on those expectations for 35 years,” said Dr. Daniel Alkon, a 30-year veteran of the National Institutes of Health and now scientific director of the Blanchette Rockefeller Neurosciences Institute in West Virginia. “It was the expectation that amyloid plaques and tau tangles kill brain synapses and neurons,” and that eliminating them will stop the disease, he said. “There were a lot of clues that wasn’t true, but because of their mindset, people didn’t see those clues.”

The idea that Alzheimer’s is caused by sticky clumps of protein called amyloid plaques, which destroy the synapses between brain neurons, dates to the 1980s, and key genetic mutations that cause early-onset forms of it were discovered in the 1980s and 1990s. The discovery that a protein called tau forms “neurofibrillary tangles” that are toxic to neurons dates to 1986, but for decades was overshadowed by the amyloid idea. The animosity between the two camps grew as bitter as a religious war, earning it the name “tauists vs. baptists” (the “ba-” stands for beta-amyloid, the formal name of the protein).

Way back in 1991, however, a study of the autopsied brains of Alzheimer’s patients found that tau tangles and amyloid plaques hardly correlated with the severity of dementia. Loss of synapses did. “But people were blinded by the mindset that amyloid plaques not only must cause Alzheimer’s but be the best target for treating it,” Alkon said, and didn’t entertain the possibility that restoring synapses should be the goal of an Alzheimer’s drug.

In 2008, another team of scientists studied the autopsied brains of Alzheimer’s patients who had been in a study of an experimental Elan drug, an antibody that removed amyloid plaques. They found that a number of the brains had completely cleared amyloid; the antibody worked. But those patients had shown no cognitive improvement.

At minimum, that suggested that by the time amyloid plaques appeared, a brain was too far gone to be rescued with an anti-amyloid drug. But it also raised the possibility that the plaques are markers of cell death, not causes of it, since many people have plaques but not loss of synapses or Alzheimer’s. If so, then destroying amyloid plaques — as many drugs in company pipelines still aim to do and as virtually all the failed drugs did — would not treat the disease. The same might be true of tau tangles, the deadly filaments that form inside neurons and the target of the compound that had disappointing results this week.

The disconnect between plaques and Alzheimer’s “should also have been a wake-up call to everyone that new approaches to Alzheimer’s disease are needed, as almost everyone recognizes now,” Alkon said.

One group that realizes that is the foundation started by Microsoft cofounder Paul Allen. Last year, it awarded $7 million to Alzheimer’s research — on the condition that at least one leader of each of the five teams not be an Alzheimer’s researcher. “We wanted to bring in people and perspectives from outside the field,” Judy Lytle, the former director of the foundation’s program, told STAT at the time.

To be sure, in the last few years both NIH and other funders have opened their wallets to non-amyloid, non-tau approaches to treating Alzheimer’s. Scientists are studying everything from the role of inflammation and microglia, the brain’s immune cells, to that of leakiness in the blood-brain barrier.

“There is no doubt that we have to start looking at things other than amyloid” for drugs to target, Dr. Howard Fillit, executive of the Alzheimer’s Drug Discovery Foundation, which funds many non-amyloid, non-tau research on potential treatments, said recently.

Fillit recalled that when he was a young neurologist in the 1980s, he met with NIH leaders and discussed how “there is immunoglobulin in plaques, there is copper in plaques, there is an inflammatory response,” and more than 400 proteins other than amyloid in plaques. “They basically kicked me out of Bethesda,” uninterested in any Alzheimer’s research other than that on amyloid, he said.

That doesn’t surprise Alkon. “The way the system works at my alma mater [NIH]” is that the outside scientists who advise the agency “tend to fund things they know about and have been working on,” he said. “It’s very conservative, and the system discourages innovation. Advancement in the academic hierarchy depends on conforming, not breaking the rules.”

Another reason for the slow progress toward an Alzheimer’s drug is that “we don’t have great animal models,” said Mayo’s Knopman, vice-chair of the Alzheimer’s Association’s medical and scientific advisory council. “They haven’t been very good at predicting a drug’s effect, and none of them is appropriate for late-onset Alzheimer’s” as opposed to the uncommon early-onset form that results from rare genetic mutations.

Yet scientists kept using the animal models, which yielded publishable studies — the coin of the realm in academia. “The field has known for over 10 years, probably 15 years, that the models were not Alzheimer’s disease and could not predict therapeutic efficacy,” said neurobiologist George Perry, dean of the College of Sciences at the University of Texas at San Antonio. “The models are, at best, models for amyloid and tau deposition, and even that is questionable. These mice never really develop Alzheimer’s.”

It’s not clear where the “other approaches” that Alkon calls for will come from, given the enduring legacy of the amyloid hypothesis on funding decisions. Alkon, working primarily with Rockefeller funding and industry support, focuses on the core pathology of Alzheimer’s — loss of synapses and death of neurons — and has developed a drug called bryostatin. It is being tested in a mid-stage clinical trial sponsored by Neurotrope Bioscience. (Some patients are also receiving it through the “compassionate use” exemption that regulators allow for drugs that have not yet received Food and Drug Administration approval.)

In a paper to be published next week, Alkon and his colleagues describe the molecular steps by which bryostatin increases the production of two key molecules to stimulate the creation of new synapses. “That’s what you need, something that gets at the underlying disease,” said Alkon. “None of the other experimental therapeutics restores lost synapses and prevents neuronal death.”

For now and, it seems, years to come, Alzheimer’s patients will therefore be stuck with the four existing drugs, which have no effect on the disease’s inexorable toll and improve symptoms, such as memory loss, only a little and only temporarily.

“I have to live with [the failure of experimental drugs] every day,” Knopman said, “when I have to tell my patients, ‘This one didn’t work either.’”

Glimmers of hope with non-amyloid, non-tau drugs such as bryostatin suggest that it is not the youth of the Alzheimer’s field that explains why there are no effective treatments.

“I think,” said Fillit, “that with the controversy about the amyloid hypothesis over so many decades, a more balanced approach would have yielded more progress.”

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  • Sorry but only glanced over, looking for natural, from the Earth’s vast vegetation type research & saw nothing.
    Should I reread this article or are researchers really just trying to use valuable research time (perhaps using ‘old/failed’ research platforms to start another) throwing together 4 (un)cures for this (new-ish*) disease?
    *Did it exist 100-150 years ago (except, maybe, idk, in some of the ppl who worked in highly caustic fields) & what’s changed since then…?
    BESIDES: fluoridated H2O, vaccinations with chemicals that have absolutely NO reason to be in our bodies, chemicals just to improve the appearance of foods & marathon shelf lives, aluminum etc. in the air we breathe, resent/current radioactive runoff into Earth’s oceans & into fish we eat(*see below), pesticides that kill pests that eat our crops that we, then, eat, ‘normal/assumed safe’ everyday items we use just after bathing, canning goods with pop-tops lined with chemicals, medications in our H2O supplies from EVERYthing from ppl flushing them, chemicals leaching into the H2O supplies from fracking, & environmental pollutions. I could go on, but y’all get my gist.
    (*)No matter what is done, no1 can separate contaminated water molecules from uncontaminated water) In other words, oceans everywhere will eventually have atomic radiation in it).
    In a nutshell, we’re trying to make cures for the devastating effects of our current way of life, that are, sadly, making man-made diseases & furthering others.

    PS I’m not unsympathetic to frustrated researchers & ppl affected by this disease. I lost someone to it as well.

  • Why is the Salk Institute finding of THC from marijuana eliminating amyloid beta and inflammation from human neurons not part of this discussion? Why isn’t our endocannabinoiod system being considered as a potential cure? Is it because marijuana is such a taboo subject due to the decades of negative publicity from the DEA and NIDA? http://www.salk.edu/cannabinoids

    • I agree completely. My mother with AD just started taking some high CBD tincture and the positive response she has had is unbelievable!

  • Ok, so everyone (including and especially pharmaceutical companies) should have some kind of a conscience in avoiding stating that they “treat” Alzheimer’s disease.
    I get very furious when medications state they have been “approved” for “the treatment of Alzheimer’s disease” and then as you keep reading the fine print, it says “there is no evidence that it neither prevents nor slows the disease process of Alzheimer’s disease. Alzheimer’s drugs are NOT effective in decreasing the protein plaques or inflammation or increasing spatial memory. Their mechanisms of actions are also “guesses”. They are basically listed as “cognitive performance enhancers,” and they TEND to not even do that for most Alzheimer’s patients. And, yes the side-effects tend to outweigh the potential benefits. Drugs tend to be given because, you have to try something. This is where most people start with alternative remedies. Most alternative recommendations find some study that they reduce inflammation in the body, and then jump to great conclusions that they “treat” the underlying problem.

    Here is what we HAVE KNOWN for a long time (beginning in the late 1940’s).
    Physical Activity increases spatial memory, increases cerebral blood flow, decreases cerebral inflammation, decreases protein plaque deposits in the brain, slows the aging process of the brain (and can even actually reverse the aging of the brain up to 2 years). Physical Activity is NOT a cure, but is by far the BEST chance we have today of potential prevention, slowing, and even reversing the progression. The problem is…how do we get an end-stage patient to exercise? Well, we HAVE an answer.

    If you have not seen our video footage of the first case review ever on Aquatic Therapy & Alzheimer’s Disease, please watch below. It is regarding an end-stage, non-responsive patient that had an unbelievable response.

    https://www.youtube.com/watch?v=aQP1p8lWQys

    Several facilities are now coming on board & creating aquatic programs for their LTC & dementia patients w/ breathtaking results! I’m now working on a 2nd case-review (plan for publication release @ the end of the year) of another end-stage patient that had behavioral outbursts, & the aquatic environment proved an amazing tool to reduce those episodes, and to increase communication & physical initiative.

    From what I have seen, Teepa Snow’s educational clips on how a caregiver can ‘deal’ with the complications with a dementia patient are UNSURPASSED! Thank you to the whole Teepa team. I hope to one day be able to present our upcoming research to your team!

    Please do not hesitate to contact me for more information at
    beyondrelief@msn.com

    You can access the PDF of the mentioned case review at http://www.inertiatherapy.com

    • Institutions of long term care will not put in a pool as it would greatly increase their liability insurance costs.

  • I told you over and over that plaques and tangles ain’t the cause of Alzheimer’s disease. Most likely, a consequence of the degenerative process.

    And yet, countless “brilliant” careers have been conveniently made and millions keep being invested in biotechs pursuing those targets. While different points of view have been ostracized and marginalized, and a few careers shattered, like mine for instance

  • I gave my relative egg whites fried in coconut oil (which is NOT BAD for you!) because, in Alzheimer’s, the Brain doesn’t metabolize Glucose well. The CBD and THC components of marijuana must also be studied. Microglia are MOTHERS! The Glioblastoma is the Deadliest Brain Tumor, and Also has No Cure. Bryotstatin, BTW, is an antiangiogenic cancer drug that has Not been proven to work.

  • No mention of the Anavex 2-73 trial described at AAIC that has 31 week data showing the AD progression on average is halted, even though a number of the patients the dosage was not at the just determined MTD.

  • A drug approach to this condition is like me learning to play the piano that has one key.

    A multifaceted condition like this needs an approach that os the same: multifaceted.

    Inflammation is key but what triggers inflammation? Must identify all causes and reduce.

    Xenobiotics
    Heavy metals
    Stress
    ROS > antioxidants
    Fatty acid imbalance
    Methylation dysfunction
    NOS uncoupling

    Give a fraction of that money to my research team and we’ll lay out an integrated theoretical approach based on known research findings.

    Tired if the model:
    Problem – Drug

    It’s failing worldwide for all chronic disease.

    Change the thinking.

    • The psychiatrists call it catastrophizing. This is irrational thought that something is far worse that really is. Abetted by the media, the “Dementia Industry” has scared people into believing that every slight memory lapse must mean that Alzheimers is right around the corner. If anything has been learned is that their are no predictive models and hence no drugs that work. I work in pharma and don’t believe there is a drug for everything. We focus only on the aspect that involves cognitive decline. The reality is that with proper care and attention to needs, most Alzheimer’s patients retain their emotional life intact. Its the NON PATIENTS who get alarmed when when granny forgets that she has just buttered her toast when she asks if another helping of Country Crock.

  • What are these dudes crying about? These academics have scored some nice cash for their coffers while at the same time dishing up flawed hypotheses that have caused the pharmaceutical industry to waste billions of dollars chasing those “expectation” down a rat hole. Seething? Methinks a bit hyperbolic since these guys have already made their money leading us Pharma guys down one blind alley after another.

  • Great perspective to include context for this latest failure. One caveat re the current drugs–they “work” in a minority of people, up to 20% very optimistically. Thanks for this! (I’m a geri psychiatrist, formerly in charge of AD research at NIA; worked for couple summers in Alkon’s lab, & write for Health News Review)

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