The idea that sticky brain plaques cause Alzheimer’s disease began as an interesting hypothesis and eventually became drug industry dogma. Now, after a string of clinical trial failures, that hypothesis looks less credible than ever.

But how did nearly two decades of failure not convince the brightest minds in pharma that it was time to move on?

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  • Amyloid was so visible it was logical to study it first. But microbes have been implicated as causative ever since Oskar Fischer, a contemporary of Alois Alzheimer. However, few grants were ever approved to investigate them. Some new funding for this is now offered by NIA and IDSA. Perhaps amyloid will turn out to be like pus in staph furuncles, bloody sputum in TB, and watery stools in cholera–the result of a causative infectious agent.

  • Low-dose lithium has long been known to be highly neuroprotective, to thicken grey matter, and to clear amyloid and tau from the hippocampus. “Expert” researchers have ignored this treatment, hiding in plain sight, while chasing Big Pharma and government funding. If those who treat Alzheimer’s had been paying attention, millions would have been saved from dementia, starting in the 90s.

  • There is a very strong connection between stress/anxiety and the development of Alzheimer’s – see the articles below:

    Gimson, A., Schlosser, M., Huntley, J. D., & Marchant, N. L. (2018). Support for midlife anxiety diagnosis as an independent risk factor for dementia: a systematic review. BMJ open, 8(4), e019399.

    Justice, N. J. (2018). The relationship between stress and Alzheimer’s disease. Neurobiology of stress, 8, 127-133.

  • Perhaps we aren’t looking for a drug at all. The Nuns Study and other studies as well suggest that keeping the brain active is key. Recent studies at MIT and at the University of Toronto suggest that a signature of Demetria is the absence of gamma waves, ie the slowing of brainwave activity. This can be addressed with neurofeedback

    • The MIT study used an exaggerated mouse model and mostly judged by the reduction of amyloid aggregates in those mouse brain. So, in essence, it is still based on the amyloid hypothesis. BTW, most of those failed drugs are probably more effective than light and sound in terms of reducing amyloid aggregates.

  • All amyloid trials on symptomatic patients have failed and will fail to improve cognition NOT because amyloid is the wrong target – genetics shows it is causative. But, because it must be targeted 10 or more years BEFORE symptoms of cognitive impairment. This is documented by brain imaging data going back to 2009.

    Yet, pharma tries and tries again to improve cognition by targeting beta-amyloid. And with each new failure, the press, predictably cries “no more amyloid”. The truth always lies in the details.

    Hitting amyloid in symptomatic patients is like giving a person who just had a heart attack, with congestive heart failure, lipitor (or some other statin), and then expecting their heart to get better. In both cases, inflammation has ALREADY caused the bulk of organ damage. Treating the cause of disease that occurred a decade or more before organ failure, e.g. cholesterol in heart disease and beta-amyloid in Alzheimer’s disease, will NOT make those organs better or improve the symptoms resulting from organ failure and dysfunction.

    If you want to help a patient with symptomatic Alzheimer’s dementia, you need to stop neuroinflammation–this is what is killing the bulk of brain nerve cells. Amyloid triggers tangles, which kills nerve cells, and spreads. This eventually triggers a brain immune response – neuroinflammation, which kills 10-100 times more nerve cells than the original tangles. And, this is what ultimately leads to dementia.

    If you want to nip Alzheimer’s disease in the bud and stop the brain from degenerating, you need to detect amyloid deposition early (brain imaging and eventually a blood test), and treat it early.

    There may be up to 40 million people in the USA who need this early preventative treatment against beta-amyloid, now. So, the drug that will be used for early (pre-symptomatic) prevention of amyloid will need to be relatively inexpensive (immunotherapy is expensive!) and, also, safe (since it may have to be taken for up to 40 years).

    My lab is working on two such drug candidates for hitting beta-amyloid early, often and safely, and another that targets neuroinflammation, for those patients already suffering.

    We are hoping for the best, for the sake of all of those suffering from this hideous disease.

    Dr. Rudolph E. Tanzi
    Joseph. P. and Rose F. Kennedy Professor of Neurology
    Harvard Medical School
    Vice-Chair, Neurology
    Director, Genetics and Aging Research Unit
    Co-Director, McCance Center for Brain Health
    Co-Director, MassGeneral Institute for Neurodegenerative Disease
    Massachusetts General Hospital
    114 16th Street
    Charlestown, MA, 02129

    • The just failed Biogen drug trail targetting potential AD patient in early stage. The genetic evidence for amyloid hypothesis is from familial AD, not the 95% or more sporadic AD. In fact, no genetic evidence from the latter case directly support the amyloid hypothesis.

    • The neuroinflammation approach has a big assumption: current drugs such as Donepezil and Galantamine do not inhibit neuroinflammation, which is not true.

    • The genetic arguments that amyloid is the cause of Alzheimer’s disease is based on the assumption that these mutations do not lead to something else. That something else is nitro-oxidative stress. Misfolded amyloid and tau proteins are both a result and a cause of nitro-oxidative stress, but dozens of other factors cause this stress including environmental toxins, various chronic bacterial, viral, and fungal infections, a diet high is sugar and other carbohydrates, salt, and high fructose corn syrup, and psychological stress.

      Mice designed to develop Alzheimer’s disease have basically only one of these triggering factors–amyloid, so removing amyloid from mice helps to restore cognitive function, but in humans removing amyloid only slightly slows the progression of the disease if at all.

      Even in genetic cases of early onset Alzheimer’s disease, other factors play a role. Families with a particular presenilin-1 gene mutation develop Alzheimer’s disease nearly a decade earlier on average than a family in Japan with the exact presenilin-1 gene mutation. The family members in Colombia are exposed to some of the highest levels of mercury contamination in the world due to mining operations whereas the family members in Japan have a diet high in antioxidants including rice bran oil and green tea.

      What can be said of amyloid can also be said of neuroinflammation–it is both a result and cause of nitro-oxidative stress. Caspase-3 activation (via peroxynitrite) leads to neuorinflammation (and to the death of neurons) and neuroinflammation leads to more caspase-3 activation.

      The focus then should not be on amyloid (or even on neuroinflammation), but on scavenging and reversing the damage done by peroxynitrite and by inhibiting caspase-3 activation. Antioxidant compounds found in plants such as CBD oil, various essential oils via aromatherapy, panax ginseng, and various Chinese herbs have led to improvements in certain forms of cognition and behavior that have been sustained over long periods of time.

  • Listen, It’s not just the brightest minds in pharma chasing amyloid hypothesis. Most of Alzheimer’s academics also still believe in it and they are advising pharma. Pharma would not chase this without support from research field. Analysts and media like to tell pharma how stupid they are for continuing to chase the target, but would you rather listen to top scientists and physicians or bankers and reporters?

  • It’s not just the brightest minds in pharma chasing amyloid hypothesis. Most of Alzheimer’s academics also still believe in it and they are advising pharma. Analysts and media like to tell pharma how stupid they are for continuing to chase the target, but would you rather listen to top scientists and physicians or bankers and reporters?

  • Perhaps now they’ll give histones the attention they deserve. The manner in which AD is growing should be an indication that epigenetic factors may be involved, and that includes microbial.

  • The amyloid hypothesis has kept center stage for so long, because that critical mass of scientists, working on it in the 90’s, have benefited both career-wise and economically from such hypothesis. And once they achieved leading positions in both academy and industry, they had a vested interest in keeping such hypothesis alive, and thwarting any other approach in the process. And they will keep doing so, as long as they will have the opportunity.

    • Thanks for the fresh view.

      Pharm companies have moved into new therapies through new drug development to deactivate the oxidant stress and to introduce other novel approaches, early results look good. The main trend in academia remains unchanged except for few cases.

    • It is true. The loudest voices reign in updating the DSM-IV – only their research is published or their graduate researchers gratuitous reports support a hypothesis that is so easily questioned and disproved by the unpublished research. Basically, like all things, it is who you know and not what is actually happening. Why we are so behind our European colleagues.

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