s I read the findings about drugs targeting beta amyloid proteins that were released during the annual Clinical Trials in Alzheimer’s Disease conference in Boston earlier this month, I thought of a favorite old quote, “99 percent of success is built on failure.” But that only holds true if we are learning from our mistakes.

Trials of drugs targeting beta amyloid — which makes up the plaques common in the brains of people with Alzheimer’s — continue to get the lion’s share of attention and funding, even though many such trials have failed in recent years. But rather than pivot to other targets, many companies are choosing to try again with the same drugs, testing them at higher doses or in patients at earlier stages of the disease. It’s time to devote at least the same amount of attention to other approaches that could slow, prevent, or even reverse Alzheimer’s.

Bill Gates announced this week a $100 million investment in Alzheimer’s research and outlined an agenda for it. “We need more approaches to stopping the disease,” he wrote. Gates went on to acknowledge that most investments have focused on beta amyloid and tau, another toxic protein that comprises tangles. “A more diverse drug pipeline increases our odds of discovering a breakthrough,” he concluded.


A recent analysis published in Nature Reviews Drug Discovery also raises questions about continuing to pursue drugs that target beta amyloid, particularly at the expense of other approaches. The authors reviewed 10,107 unique drugs that were in development for a variety of diseases between 1996 and 2016. They determined the number of drugs that were successful or discontinued for specific approaches to treating diseases. (Drugs may be discontinued for many reasons, including lack of effectiveness, safety issues, and strategic or business considerations.)

The authors found that 83 percent of treatment approaches were abandoned after just a single program was discontinued. Among disease targets that never resulted in an FDA-approved drug, only 2 percent had five or more clinical trial attempts. But that picture looks very different for Alzheimer’s disease: Four of the top five targets with the most discontinued drug trials — but which are still being tried in ongoing trials — are all beta amyloid drugs. Together, these beta amyloid targets have been discontinued 93 times. Despite this, beta amyloid remains the most common drug target in Alzheimer’s clinical trials, representing about 25 percent of the current clinical pipeline in Alzheimer’s, according to a recent report from my organization, the Alzheimer’s Drug Discovery Foundation.

I couldn’t agree more with Gates or with the authors of the Nature Reviews Drug Discovery analysis, who argued that reducing the odds of more trial failures will require more and better drug targets.

And such targets do exist. Alzheimer’s drugs aimed at neuroinflammation, genetics and epigenetics, neuroprotection, and metabolic and mitochondrial dysfunction are now in clinical trials or nearly there. We need to pursue all of these targets, and look for new ones. That’s why our foundation funds a diverse pipeline of drug targets beyond beta amyloid.

Alzheimer’s is a complex disease with multiple, interrelated causes. An effective treatment will likely involve taking several drugs that target more than one of its causes. This approach is already the standard of care in diseases such as diabetes, HIV/AIDS, and high blood pressure. Alzheimer’s researchers can and should follow these examples.

Everyone in the field hopes that the search for an Alzheimer’s drug will be successful in the next few years. If it’s a beta amyloid drug, we will all rejoice. But even if that happens, to effectively treat Alzheimer’s, we will still need other drugs that target other causes. To get there, we must invest in more diverse drug targets now.

Howard M. Fillit, M.D., is the founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation. He also serves as a clinical professor of geriatric medicine and palliative care, medicine, and neuroscience at the Icahn School of Medicine at Mount Sinai.

Editor’s note: The author did not initially disclose having received payments for consulting work in pharmacoeconomics for Hoffmann-La Roche; Genentech; Eli Lilly; Otsuka; Lundbeck; and Merck Sharp & Dohme.

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  • Any alternative hypothesis as to the cause of AD must explain why every single one of the genetic mutations that cause early-onset AD affect either the amyloid precursor protein or the enzymes which process APP. Many anti-amyloid mechanisms have been tried, but not nearly every possibility. Being on the other side of the BBB is a big difficulty in any new therapy for AD. Just because we’ve seen many failures is no reason to give up. There were decades of failures in the development of heavier-than-air flight, and those helped build the knowledge base that led to the Wright brothers success. We may indeed see more decades of failures in anti-amyloid drug trials. We don’t even have a clear understanding of what the various products of APP processing do in the normal brain. It’s far too early to throw in the towel on anti-amyloid strategies. That would be like giving up on heavier-than-air flight in 1890.

    The notion that Borrelia has anything to do with AD is absurd. If it did cause AD, the incidence of AD would be concentrated in the New England states. It’s not. The incidence is slightly higher in the Deep South, where there is no Lyme disease. (The map of AD incidence in the U.S. roughly corresponds to the map for obesity, and studies do show a significant association between AD and type 2 diabetes.) This wrong hypothesis has been propagated by “Lyme-literate doctors”, i.e. despicable quacks hoping to enlarge their scope of victims.

    • A bacterial infection kills cells and hence can cause gene mutations as the cell dies. Borrelia and oral pathogens have been cultured from Amyloid plaques. Borrelia has been added to human nerve cells in Vitro and produced TAU and TDP-43 protein debris from dead cells.
      Having been in contact with thousands of ALS patients and Neurodegenerative diseases similar to AD has indicated to me that the BBB does not function when an inflammation exists in the brain. GABA works very well to reduce hypertonic muscle symptoms

      There are several incorrect concepts about Borrelia. One is that it only causes LD which is only one manifestation of a Borrelia infection.
      Another is that Borrelia is endemic and transmitted only by ticks. It is trans mitted by sand fleas, mosquitoes and bed lice and probably other vectors. Also since it is a spirochete there is a high probability that it is trans placenta.
      One can be inoculated with Borrelia but not be clinically infected. The host immune system holds-the pathogen in check. So the endemic research is at a minimal questionable.
      Commensal bacteria secrete cytokines which stimulate the immune system to attack the Borrelia suppressing it clinically. Then a concomitant factor either suppresses the host immune system or substances that enhance the growth of the Borrelia allow it to overcome commensal bacteria. killing enough host cells to become symptomatic.
      The problem is the laboratories do not test for enough antibodies to detect the Borrelia. WE don’t even know what antibodies to test for. So B/c we can’t document an infection we say the body is attacking itself. We create auto immune diseases.
      Patients with MS, PD, AD, ALS have tested positive for Borrelia and been treated with antibiotics. Another problem is co-infections and biofilms which until now have not been addressed in treating these ND, hence research failure and erroneous conclusions.
      Another point is that Borrelia does not exist in circulation and cause the usual responses to infections. It has a flagellum and is mobile we have EM pictures of it in the extracellular space in soft tissues. It only enters the cell every 28 days to reproduce and only then is it susceptible to antibiotics. It is pleomorphic and can change its protein membrane configuration. WE have not identified all the sp. Borrelia much less the strains in each species. The protein configuration on the cell membrane differs among strains. Further Borrelia is compartmentalized with predilection for certain tissues this could be species or strain specific. Hence the diverse clinical pictures.
      The research up to now has been in the wrong direction and this has caused millions of patients to die terrible deaths and wasted much money. Much of what I have stated is hypothesis but borne out by clinical responses and investigating the literature since 2007 and putting the pieces together. I am certain of one thing that the protein aggregations found in ND are cell debris and not the cause of the disease.
      Now it is time to prove me wrong and spend some money on what has been stated above.

    • It is not up to us to prove you wrong. It is up to the despicable quacks to prove their hypotheses right. Which will never happen, because they are so far wrong.

    • At the moment, the same can be said for the plaque proponents, and they have been trying to prove their hypothesis for a long time now and have failed.

      BTW, your analogy about flight is poor. We thought we could fly just as we think we can beat AD…that’s probably both true (we’ve done the flight now we have AD to overcome). However, when we were trying to fly we started off by running off piers, hillsides, etc, with rudimentary wing designs and composition. However, after a lot of trial error, adapting the designs, materials used, etc, we learnt to fly. Problem with AD, as far as I can tell, is that there is not much learning gong on and still hitting the plaque hypothesis. I know there are people looking at alternatives and this will probably be where the breakthrough comes, but I could be wrong (I’m an immunologist so this isn’t my field).

    • The plaque hypothesis has been dead for over a decade. The current version of the amyloid cascade hypothesis concerns amyloid-beta oligomers, not plaques. Accumulation of amyloid-beta occurs early in AD, while plaques and tau-protein tangles occur late in the disease.

    • That’s good to know. I did do a quick 5 min search after my last comment and I thought the stuff about the potential role of copper and zinc in the APP/amyloid process seemed interesting, but no idea on the robustness of the research, especially since some of the papers I saw are already 10+ years old and there appears to be some contradiction among the research.

    • Could you post a little more about the role of copper and zinc, or drop the interesting links as little breadcrumbs? BTW there is also research showing exposure to mercury makes similar nerve damage and tangles. Multiple things are likely triggers, worse when a synergistic genetic, exposure and metabolic cascade starts.

  • I posted this on twitter @LonSchneiderMD but ran out of space:
    In pharma, academe, and at NIH — especially the study sections — you don’t get fired for making the same mistakes over again; but you do get fired for making new ones. Older amyloid-beta approaches are incentivized at the expense of expanding new approaches. “We just didn’t go early enough, long enough, with high enough doses, in large enough trials, and use the right ultra-sensitive clinical rating scales…we need more funding.”
    Despite Gates’ aspiration and big-hearted commitment, much of his investment appears destined toward incremental, derivative drug development, old methods, and the servicing of current or ‘yesterday’s’ clinical trials.
    Hopefully, Fillit’s and Lauder’s ADDF really will stretch beyond amyloid-beta — maybe even see dementia in old-age as the set of dystrophic complex metabolic processes that it is — and support the rational, scientific drug/target discovery that he cites from the Nature Drug Discovery paper.
    The ADDF and Gates might also consider — as Molchan writes below — that mitigating environmental and behavioral risk for old-age dementia could decrease its prevalence by 35%. That’s a much greater effect than we can imagine for any current drug in development.

  • My candidate for a search is (or are) Mycoplasma. Size, refractive index and difficult to culture. Has tissue from affected hippocampus ever been studied? Loves cholesterol so there is a possibility mitochondrial and cell membranes could be disrupted. Once calcium channels are affected so will ATP and acetyl coA and acetylcholine synthesis be interfered with.

  • It’s unfortunate that only drugs are mentioned in the article (multiple times) as considerable evidence has accumulated of the importance of lifestyle/public health factors on dementia risk,including evidence from randomized controlled trials. http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(17)31363-6.pdf Most people with dementia are in their 80s . . . how many more drugs can we really sock then with (and presumably starting decades earlier)? Even if it were so simple as to swallow a couple of pills, who is going to pay for these the way drug prices are going?
    As another commenter noted, as long as the academics and those in industry continue to egg each other on & the $$$ keep flowing, they will continue to hawk the false hope of drugs.

  • “It’s time to devote at least the same amount of attention to other approaches that could slow, prevent, or even reverse Alzheimer’s.”
    A search for the actual cause and measures to prevent the disease is where we should be going but these do not fit into the pharmaceutical financial model.

  • Thank you for this article, and your broader perspective: “Alzheimer’s drugs aimed at neuroinflammation, genetics and epigenetics, neuroprotection, and metabolic and mitochondrial dysfunction are now in clinical trials or nearly there.” This is one significant step for man/woman.

    One giant leap for humankind would be to flip the lab, and instead of mostly looking for drugs for different targets, research the multiple different synergistic and overlapping causes of these degenerative processes, develop cheaper diagnostic screenings, and remediate them.

    As you wisely note, it is combination of various genetic susceptibilities, synergistic exposures, and disease processes that cause Alzheimer’s and other dementias. We have learned much about the permeability of the blood brain barrier, the Vagus nerve, oral/gut/brain and microbiome/immune/inflammation interactions, and more.

    A related question: Are we building realistic mouse models? We need more than those genetically predisposed to Beta amyloid, tangles, tau, plaques, folded proteins, etc. Realistic mouse models would then subject the mice to different classes of common, everyday, human exposures: e.g. Lyme disease, mold exposure, common chemicals and pesticides, dental amalgams and root canals, tiny metal and plastic medical devices, bacterial and viral infections, sugar-laden liquids, artificial sweeteners, and the standard American diet. See which hasten decline, alone and in combination. Then screen for and remediate them.

    Also consider therapeutic use of focused ultrasound and microcurrents to reopen and reboot nerve and brain pathways. Since ultrasound was found to clear plaque and restore memory in 75% of plaque and memory-impaired mice in Australia as reported in 2015: http://stm.sciencemag.org/content/7/278/278ra33, there have been rapid advances. Ultrasound was used to open the BBB to deliver an anti-tau antibody into mouse brains in Australia: https://www.theguardian.com/society/2017/apr/05/alzheimers-ultrasound-safely-delivers-drugs-to-damaged-brains-of-mice. The first clinical trial of using focused ultrasound in humans began in Canada earlier this year: https://www.fusfoundation.org/news/129-press-room/1924-first-alzheimers-trial-with-focused-ultrasound-begins.

    Let many flowers bloom regarding treatment, and no stones go unturned regarding causative factors, diagnosis and remediation.

    • Most interesting… the removal of this plaque.
      1. Plaque on the pineal gland stops the melantonin process that disrupts sleep.
      2. Plaque on the pineal gland affects the circadian rythms of when Humans, Plant life and insects, animals eat and feed and sleep.
      3. Circadian Rhythms and Life
      Circadian rhythms are not unique to humans—they are also found in plants, animals, fungi, and even bacteria. External signals, such as light, trigger the cyclical release of chemicals that signal when to start and stop different actions. Circadian rhythms govern all types of activities: feeding times in bees, leaf movement in plants, and DNA replication in fungus, among others. In humans, circadian rhythms are best known for governing our sleep schedules.https://www.acs.org/content/acs/en/education/resources/highschool/chemmatters/past-issues/archive-2014-2015/the-science-of-sleep.html
      3. The honey bee here when exposed to Tau- Fluvalinate a pesticide to kill of the Varroa mite …. Tau-Fluvalinate when heated produces hydrogen flouride.
      3. flouride has been shown to cover the pineal gland … in the US we have been using this flouride for years to cover our teeth … while covering this important center of the brain. The US has the highest rate of this disease and spends the most monies to treat. Harvard has documented the study of this cause of flouride on our brains and shows it impairs cognitive learning functions.

      4. Here the bee exposed to this Tau- Fluvalinate :
      Effects of fluvalinate on honey bee learning, memory, responsiveness to sucrose, and survival.

      Frost EH1, Shutler D, Hillier NK.
      Author information
      Contaminants can affect organisms’ behaviour and, as a consequence, survival. Tau-fluvalinate (hereafter fluvalinate) is the active ingredient in a pesticide commonly used in North America to control Varroa destructor mites in honey bee (Apis mellifera) colonies. Fluvalinate’s effects on honey bees are not well known. Honey bee cognitive and neural function can be assessed using the proboscis extension reflex (PER), which applies Pavlovian conditioning techniques. This study used PER to evaluate effects of fluvalinate on honey bee acquisition learning, (long-term) memory recall, responsiveness to sucrose, and mortality. We also evaluated how exclusion criteria for honey bees that did not exhibit PER during training and memory trials affected interpretation of results. Fluvalinate was administered both orally and dermally at high and low doses to mimic routes by which honey bees are exposed. We found negative effects of fluvalinate on honey bee learning, memory, responsiveness to sucrose, and survival, especially in high oral doses. We also found significant consequences to interpretation of results using different exclusion criteria. For example, almost 50% of individuals that failed to show evidence of learning subsequently showed evidence of memory. The latter results have important implications regarding traditional assessment of PER-based learning and memory; the former results suggest that evaluation of honey bee exposure to fluvalinate and attendant consequences warrants further investigation.

      4. It is one thing when a bee forgets to pollinate and eat at the time when a plant opens … as all things in nature go by this circadian rhythm … It is another when your loved one loses its memory and thus decides to stay awake at the time when the caretakers are going to bed.
      5. Not sure of the study on the brain of the honey bee and how they are like the human brain. Their brains are smaller but are smart. And are affected like humans by these man made chemicals. As shown above.
      6. Not sure if even if the plaque is removed that the tangles of these Taus and the damage done can be repaired to restore these humans cognitive functions and sleep patterns to avoid the sundowner’s syndrome.
      7. In the meantime Laura you mentioned remediation… which is important .
      It is also important that the treatment of these patients and its costs may not be doing the trick. If the circadian pattern of the humans brain has been askewed to a different time…. then no amount of drugs are going to alter this. Of course we want, we need to adhere to our sleep patterns work and take care of our loved one. The long term care model is based on these normal working hours ….. everything is based on the fact that we wake with the sun and sleep when its night.
      These patients can’t … so drugs are introduced. To coerce the body to do something it just is never going to do.
      8. A new model needs to adhere to their new rhythm … again we want them to be awake and function during our rhythm and this study and program shows they are awake during all hours of the night at least living a fruitful existence…. http://www.wbur.org/hereandnow/2015/03/02/night-program-dementia-alzheimers
      9. Not sure again of the brain of the honeybee and what lies in its Central Complex. But surely their jobs and functions are more complex than that of a mouse. In ensuring they again pollinate our food sources and remember how to get back to their hives. If their circadian rhythms are again not in stereo due to again due to this pesticide has anyone every studied if plaque is built on their brains like the mice you mentioned?
      10. It is one thing for a honey bee to wander at night and get lost …. it is another for your loved one to go out venturing at night and be put at harm.
      11. I felt encouraged by your words of letting many flowers bloom… which reminded me of the honey bee…. and even if this is a little stone …. hopefully someone can look into it.

  • If you add Borrelia to human nerve cells you get TAU and TDp -43. Borrelia has been cultured from amyloid. Do you think these protein tangles might be cellular debris? Should we not start looking at bacteria causing Alzheimer’s and other Neurodegenerative diseases?

  • It will be looked beyond beta amyloid, only once the establishment in both academia and industry, that made careers and money with it, will retire.

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