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Alzheimer's Disease

Merck’s BACE-Inhibitor Alzheimer’s Wipeout

I mentioned last year that Merck’s BACE inhibitor trial for Alzheimer’s had been stopped for futility. Now here’s the full writeup in NEJM, and futility appears to have been le mot juste. There were two treatment groups (12 mg and 40 mg), and in neither one did the ADAS-cog or ADAS-ADL scores (scales for degree of dementia and ability to function) improve whatsoever. There was no difference in the people who had been scored at the start with milder Alzheimer’s, and no difference related to APOE4 status. The placebo group in general declined at a normal Alzheimer’s rate, so that’s not the explanation.

There were many other markers examined, and in every case treatment did nothing at all or did things that are hard to interpret, such as decreasing hippocampal volume (which has been noted in other anti-amyloid studies, and whose significance is actually not well understood). And all this was while cerebrospinal fluid measurements showed that all the amyloid species assayed decreased sharply in the treatment groups. This compound lowered 1-40 amyloid-beta, it lowered 1-42, it lowered APP-beta, all by like 70% and more, decreased brain amyloid itself (by PET imaging) and nothing happened. An intelligent space alien with no history in human Alzheimer’s research would examine these results and conclude that the hypothesis that reducing cerebral amyloid is beneficial is wrong. The paper comes out and states as much.

Past the efficacy data, or lack of same, the adverse events with drug treatment were notably higher, and in a dose-responsive manner. These included falls, weight loss, sleep disturbance, change in hair color, and suicidal ideation (that last one technically mild, but definitely real). So not only was there no benefit, there was some actual harm, which makes halting the trial absolutely the correct decision to make. But there are still BACE clinical trials going on, and if you weren’t pessimistic about them before this trial, you should be now.

68 comments on “Merck’s BACE-Inhibitor Alzheimer’s Wipeout”

  1. Some idiot says:

    Right. Time for plan B (or C, or D, or….)

    1. Mol Biologist says:

      Right! Plan A. To make ti profitable we must add B or something which is already have some profit . Since the compound already lowered amyloid peptide by 70% and PET imaging showed same we can try some statins.
      Plan B. To make it profitable we must add C or something which have to be profitable in our desire. What is about PSK9 antibody?
      Plan C. Past the efficacy data or, lack of same, adverse effects? We have to do it more personalized according to FDA guidance:
      Plan D. If you don’t know where you’re going, any road will get you there. – Lewis Carroll,
      IMO it is high priority to overcome these routes but not other ways around such as A, B, C, D, E….

  2. Anon says:

    Boom, boom, boom, another one bites the dust. And another one’s down, and another one’s down, another one bites the dust.

    But let’s give it another go, shall we? /sarcasm

    1. Oh yeah says:

      What are you talking about……its all the grad students faults. If they could have worked real hard like i did in school for my PI most of these drugs would be working. Or maybe we are finally figuring out that a big boy in a high chair isnt enough to figure out the science of medicine. I flatly refused to write a “mentorship” recommendation for my PI requested by my school I suggest you all do the same until they do something with their life.

      1. Anothercorporateschmo says:

        Whats that sound?
        The distinctive sound of an axe being ground that has absolutely nothing to do with the article

  3. johnnyboy says:

    Looking at those adverse effects, the space alien might also conclude that cerebral amyloid is actually beneficial…

  4. luysii says:

    Have a look at Proc. Natl. Acad. Sci. vol. 115 pp. 4661 – 4665 ’18 for an example of the aggregated form of a protein (SOD1) being protective for a neurologic disease (ALS) and the soluble trimer being the toxic form. Similar considerations may apply to the aBeta42 aggregates of Alzheimer’s disease.

    1. arcya says:

      No. Companies have knocked down specifically aggregated Abeta, oligomerized Abeta, TOTAL Abeta, all types of Abeta. None of it helps. This is not a new idea. Abeta is not a good AD target and I think we all need to accept it.

      That SOD1 paper is also not a new idea, researchers have been saying aggregates might be protective for decades now but no evidence has ever backed that up in the clinic.

      1. luysii says:

        The paper does contain data supporting their claim. They mutated various residues in SOD1 stabilizing the SOD1 trimer, or promoting the aggregate, and the trimer was found to be more toxic to neurons than the amyloid-like aggregate. Have a look at the data, it seemed pretty convincing to me.

        1. arcya says:

          I have read the paper, I worked on protein aggregation in ALS for many years and still keep up with the literature. There are also as many SOD1 papers are there are possible protein aggregation hypotheses. The paper presents some biochemical data and some unconvincing in vitro images, like nearly every other protein aggregation paper out there. Which is fine! Their hypothesis might even be correct.

          But the idea that large protein aggregates are protective is not new, and every few months a paper like this comes out for every other protein that is capable of aggregation. It’s fine, whatever. But none of that data has ever been well-supported by evidence *in the clinic*, meaning in actual patients who have diseases featuring protein aggregation.

          1. luysii says:

            Fair enough, as a researcher you were frustrated by the lack of progress. As a clinician running a muscular dystrophy clinic for 15 years and seeing ALS patients (the clinics essentially covered anyone with any form of neuromuscular disease) so was I. Mutations are all over SOD1 and we still don’t know how they are related to ALS, although related they are.

            Actually Derek’s note does contain some ‘clinical evidence’ that the aggregates are protective.

            “all this was while cerebrospinal fluid measurements showed that all the amyloid species assayed decreased sharply in the treatment groups. This compound lowered 1-40 amyloid-beta, it lowered 1-42, it lowered APP-beta, all by like 70% and more, decreased brain amyloid itself (by PET imaging)”

            Here’s the clinical evidence

            “Past the efficacy data, or lack of same, the adverse events with drug treatment were notably higher, and in a dose-responsive manner.” “Past the efficacy data, or lack of same, the adverse events with drug treatment were notably higher, and in a dose-responsive manner.”

          2. Ian Malone says:

            In reply to luysii’s suggestion that the study shows aggregates are protective, not exactly, at least not on what’s been quoted: lowering of amyloid markers and dose-dependent increase in adverse events. The first objection is is just the normal correlation is not causation, and quite simply the treatment may be removing plaques and causing adverse effects through other mechanisms. It’s also not quite the same to say that aggregates are protective against neurodegeneration in Alzheimers as to say removing them couldn’t cause problems of its own (e.g. oedema due to damaged blood vessels that have had a lining of plaque removed) or the mechanism of removal is causing problems (immunotherapies are after all encouraging immune activity within the brain). You could rule out the former by looking at relationships between biomarker changes and adverse events within the stratified treatment group, but you can’t tackle the second problem so easily.

  5. MALLAM says:

    And another one bites the dust. The general public and many of our current lot of politicians in DC should be educated about the number of such studies that fail and the huge cost in manpower, time and funds that bring no profit back to the sponsor.

    1. NMH says:

      I dont think that excuses Medicare to be able to negotiate prices for drugs, like every other government does.

  6. John says:

    Biogen has to be soooo unsettled right now….

    1. blank says:

      and Lilly. They have a lot invested in the clinic in this hypothesis.

  7. Brian says:

    interesting interpretations and one knows when the disease is Abeta dependent. All these studies were designed, if successful, to register a drug. To do that you need a simple diagnosis and reasonable treatment period but the disease may not cooperate. If you are interested in real science you need a longitudinal study that may require many years and many dollars. For instance, once you are diagnosed with a high plaque load and cognitive decline how many neurons do you have left and are they still declining for secondary or tertiary reasons?..perhaps you have AD while cognitive normal and no plaque load as dimers tetramers of the Abeta peptide are the unseen culprit..the main clues are that those who genetically over produce or under clear Abeta get the disease quite early those that genetically under produce Abeta don’t get the disease ever …in any case what new hypotheses are waiting in the wings with no funding? Lets talk about those before we plan to go to Mars or better before we go to another war…

  8. steve says:

    I’ve said this before but what the heck, I’ll try again. These trials are predicated on the idea that amyloid is both necessary and sufficient for pathogenesis. But what if it’s sufficient but not necessary? There may be two pathways going on simultaneously and knocking out one just is not enough to reverse disease. I say this because eventually people will give up on amyloid and move to something else but if both path A and path B are sufficient but not necessary then the only way you’ll reverse disease is to knock them both out. Otherwise, people will abandon amyloid despite the huge body of evidence that it plays an important role and everyone will focus on (for example) tau and the same dynamic will play out again if you need to knock out two things to reverse the pathology.

    1. Eric says:

      True, but couldn’t the same be said for most any multifactorial disease, whether it’s diabetes, osteoporosis, or cardiovascular disease? The approved therapies help slow the progression, but they don’t stop it. Trying to run combination trials is extraordinarily difficult and expensive in a disease like AD where you don’t even have a hint of activity with single therapies. I’m not proposing we ignore the idea, but it adds an additional level of complexity to what’s already one of the most challenging fields in the industry. It’s likely to be cost prohibitive for even big pharma.

      1. steve says:

        I’m proposing something different than just complex, multifactorial disease. I’m saying that the reason there is no effect – none, nada, zippo – of inhibiting amyloid is perhaps because there’s a second pathway that can have the same effect. In this scenario you’ll never get a therapeutic effect unless you knock them both out. From my reading there are just too much data supporting a role for amyloid for it to play no role; as a result, there needs to be a hypothesis on why amyloid interventions have yielded no positive signals whatsoever.

        1. Lane Simonian says:

          Amyloid oligomers likely cause oxidative stress through the over-activation of g protein-coupled receptors (as do several other factors). In other cases Alzheimer’s disease may result from the over-activation of receptor tyrosine kinases. And it is possible that ionotropic receptors in addition to NMDA receptors may some times play a role in the onset and early progression of Alzheimer’s disease.

          If you inhibit calcium release, you inhibit the formation of amyloid and limit oxidative stress early in the disease (Aricept, for instance). If you combine compounds that inhibit intracellular calcium release with antioxidant compounds you likely produce sustained improvements in cognition and activities of daily living in early stage Alzheimer’s patients (as another example, Anavex 2-73 inhibits intracellular calcium release and may be a direct antioxidant).

 (p. 29).

          Since there are many sources of oxidative stress, removing amyloid oligomers is not sufficient to prevent the onset or the progression of Alzheimer’s disease. Removing amyloid oligomers and the removal of other sources of oxidative stress in combination with anitoixidants may be of some value in the treatment of Alzheimer’s disease during it early stages.

        2. Chris Phoenix says:

          Would every person have both pathways with equal strength? If not, then one would expect treatment of one pathway to produce at least some improvement in the people where that pathway was stronger.

        3. Paul Panzerfahrer says:

          If it was an actual “pathway” we would see some results. At least some! I rather think it’s more of a downstream effect of disease. Probably some weird kind of reaction to the inflammatory state. I would not be suprised if cancelling out the true cause also would stop amyloid beta aggregation at least in most cases.

          1. Jerry Smith says:

            Dr. Mark Smith, an AD researcher at Case Western, and a bit of a non-conformist, was quoted 8 to 10 years ago in a Business Week(?) story on AD regarding whether amyloid was the cause of AD: “It’s as if the fire engines arrive at the site of a house that has burned to the ground, find a pile of ashes and the firemen declare: “Ashes cause fires.” Sadly, Smith died way too young (as I recall he was killed in a traffic accident in suburban Cleveland). Good guy! I knew him through an investment I had made in an early stage AD company.

          2. Lane Simonian says:

            Dr. Mark Smith was one of the best both as an Alzheimer’s researcher and as a person. His students and colleagues liked and respected him.


  9. Mark Thorson says:

    Interesting that Amyloid Cascade Hypothesis 2.0 continues to drive billions of dollars into a bottomless rathole. (1.0 was it was the amyloid plaques which caused AD, and 2.0 was it is the oligomers which are the poisonous species. I suppose 3.0 is that we just didn’t catch it early enough, and PET imaging with florbetapir is the way to detect pre-symptomatic AD and treat it before the wildfire takes off.) What’s the next great AD hypothesis? I still think it is endothelial dysfunction caused by oxidative stress. And yes, the p-word we dare not utter is part of the mechanism but not causative. Tetrahydrobiopterin and its deficiency in the vascular endothelium leads to uncoupled eNOS, resulting in p-word being generated rather than nitric oxide. This is the Endothelial Dysfunction Cascade Hypothesis — more p-word destroying more BH4, resulting in more p-word being generated by uncoupled eNOS. This also explains the small vessel disease associated with AD and the strong association between AD and type 2 diabetes, which is also strongly associated with endothelial dysfunction. If this is correct, then the therapeutic approach should be boosting BH4 for example by administering sapropterin.

  10. JB says:

    It’s a metabolic disease. AB, tau, etc. are all resultant from dysregulated metabolism.

  11. Lane Simonian says:

    Excessive amounts of the amyloid precursor protein and amyloid oligomers contribute to nitro-oxidative stress in Alzheimer’s disease but so too do dozens of other factors. Mice models of Alzheimer’s disease only expose mice to one trigger for nitro-oxidative stress–amyloid–or perhaps two (psychological stress). If you have the mouse chain smoking, exposed to air pollutants, pesticides, industrial solvents, mercury, etc. and feed it a diet high in sugar, carbohydrates, and high fructose corn syrup then you would have a model closer to actual Alzheimer’s disease in human beings. Remove only one source of nitro-oxidative stress and you at best barely slow down the progression of the disease and then just early on.

    The damage done by nitro-oxidants goes well beyond endothelial dysfunction. Cysteine oxidation and tyrosine nitration inhibit the synthesis and release of neurotransmitters needed for the retrieval of short-term memory, sleep, mood, social recognition, and alertness, increase inflammation early in the disease, prevent the regeneration of neurons, and contribute to neuronal cell death.

    The pathways leading to amyloid formation and peroxynitrite (the p-word, of course) overlap.
    Protein kinase C activation leads to the secretion of the amyloid precursor protein, intracellular calcium release leads to the first cut in the amyloid precursor protein (the gamma secretase cut), and caspase 3 leads to the second cut in the amyloid precursor protein. Protein kinase C activation also leads (via NMDA receptors) to peroxynitrite formation, the depletion of glutathione, DNA damage, inflammation, inhibition of neurotransmission via misfolded tau proteins, synaptic dysfunction, and mitochondrial dysfunction (see following chart

    The following thus almost perfectly encapsulates the disease.

    Pathological hallmarks of Alzheimer’s disease include:

    increased formation and aggregation of amyloid-beta peptide (Abeta) derived from amyloid precursor protein (APP)
    formation of intracellular neurofibrillary tangles (NFT)
    lesions of cholinergic neurons
    synaptic alterations in cerebral cortex, hippocampus, and other brain regions essential for cognitive function
    loss of neurons and synapses in the cerebral cortex and certain subcortical regions in the brain

    After many years of study, researchers have now accepted that dementia and Alzheimer’s disease are caused by a combination of multiple factors, such as:

    dysfunctional apoptosis
    oxidative stress
    nitrosative stress
    disturbance of energy metabolism homeostasis
    mitochondrial dysfunction
    inflammatory responses

    The only treatments that have ever lead to initial improvements in cognition that were sustained for two years in early stage Alzheimer’s disease and slowed down the progression of the disease in moderate Alzheimer’s disease have involved substances containing multipe peroxynitrite scavenging compounds.

  12. Paul Panzerfahrer says:

    If the cause of a disese isn’t known it’s absoultely sure that the “oxidative stress”-crackpots will show up. It’s kind of a disease in itself…
    At the moment the viral hypothesis is the giant elephant in the room and most everybody in the field knows that while trying to ignore it as good as possible.

    1. Lane Simonian says:

      What is the viral hypothesis but another case of the oxidative hypothesis for Alzheimer’s disease?

      “Redox Imbalance and Viral Infections in Neurodegenerative Diseases”

      Alzheimer’s disease is a multi-factorial disease but it all funnels to the same end.

      1. Paul Panzerfahrer says:


      2. tangent says:

        The fact that you can immediately turn anything into no more and no less than one more cause of oxidative stress, does this make you conscious of what a closed system you’ve built?

        Lane, I could be wrong, but I don’t think you used to operate quite like this. Step back and take a breath?

        1. Lane Simonian says:

          Maybe not a closed system, but at least a circular system. Most of the factors that increase the risk of Alzheimer’s disease initially increase the production of protein kinase C. Protein kinase C activation then increases both amyloid production and nitro-oxidative stress (and other features of Alzheimer’s disease). Amyloid oligomers early in Alzheimer’s disease further increase protein kinase C activation exacerbating already existing problems: nitro-oxidative stress, inflammation, mitochondrial dysfunction, DNA damage, glutathione depletion, energy deprivation, synaptic failure, and loss of neurons. Unless amyloid oligomers are the only or primary cause of protein kinase C activation then removing them or blocking their production is going to make very little difference. On the other, if you inhibit protein kinase C activity early in the disease (although not so much as to negatively effect learning and memory) and NMDA receptors especially later in the disease (again not so much as to negatively effect learning and memory), then at least you have a shot at slowing down the disease. And if you reverse or partially reverse oxidation and nitration you have a chance to partially reverse the disease at least in the hippocampus where neurons can be regenerated.

          Here is the initial circle involving protein kinase C (perhaps several different isoforms):

          “We found that overexpression of PKCy in cultured cells, as well as
          in vitro incubation of PKCy without heat or chemical denaturants, causes amyloid-like fibril formation of this protein.”

          “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

          “In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle.”

          And also part of the cycle:

          “We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.”

          I look for new information on Alzheimer’s disease every day and I incorporate new findings along with supporting information from old findings. It is all right to express personal distaste for my doggedness and lack of scientific training (other than some background in biology), but remember you are also arguing against some well-respected Alzheimer’s researchers and against hundreds of studies. We may all be wrong, but at least we are trying to provide an alternative explanation for the disease that provides a better explanation for the observed data than provided by the current amyloid/tau paradigm.

  13. Matthew K says:

    The fallacious rejection of the amyloid hypothesis on the basis that amyloid removal post deposition doesn’t fix cognitive symptoms, drives me mad. It’s like saying that putting out a fire in a library doesn’t restore the contents of the books, so the fire can’t be the cause of the loss of information.
    The counterargument is very simple.
    – connectivity in the cortex is the physical encoding of experience and learning, and cognition and memory depend on this physical encoding.
    – the process of amyloid deposition destroys connectivity and eventually kills the neurons themselves
    – cognition fails because the connectivity / physical encoding has broken down, so the network no longer functions properly
    – removal of amyloid by whatever means, does nothing to restore the broken connectivity
    – thus cognition does not improve because the only way the connectivity can be re-established is on the basis of experience and learning
    – the window of cortical plasticity on this large a scale closes during the early 20s
    – thus removal of pathology does not magically restore cognition
    Why is this so hard to accept? What would be the basis of cognitive failure in AD *other* than by disrupting cortical connectivity? Why on earth would the removal of amyloid be expected to restore connectivity which was made over the course of six decades of acquisition and refinement?
    Tossing aside the amyloid hypothesis leaves the enormous roadblock contradiction that APP and PS1 mutations trigger early onset AD, every time. How do you account for that if the hypothesis is invalid?
    Drives me mad. Apologies for the rant.

    1. Paul Panzerfahrer says:

      If the cognitive defects were a downstream effect of amyloid deposition we actually WOULD see a slower progression of disease in trials and we didn’t do a SINGLE time. Not being able to realize that is what drives ME mad!

    2. Lane Simonian says:

      If you cannot restore cognition or even substantially slow down the “loss” of cognition, then how is removing amyloid or blocking its formation an effective treatment for Alzheimer’s disease?

      The problem with the genetic argument is that it assumes that the overproduction of amyloid is the only result of genetic mutations. Excess amounts of the amyloid precursor protein increase oxidative stress by over-activating g proteins. Cerebral amyloidosis increases oxidative stress through oxygen and glucose deprivation. Presenilin 1 gene mutations increase oxidative stress by inhibiting the activation of the phosphatidyinositol 3 kinase. Presenilin 2 gene mutations increase oxidative stress by increasing intracellular calcium release.

      With early onset Alzheimer’s disease due to these genetic mutations you develop the disease earlier if other oxidative stress factors are present and perhaps decrease it with the use of antioxidants. On average family members with a specific presenilin 1 gene develop Alzheimer’s disease around 10 years earlier than family members with the exact same gene in Japan (in both cases the gene appears to have been brought by the Spanish). The family members in Colombia are exposed to some of the highest mercury concentrations in the world due to mining operations. The family members in Japan have a high antioxidant diet (green tea and rice brain, for instance). These are among the factors that potentially account for differences in the age of onset.

      Without oxidative stress amyloid does no damage to the brain (in Alzheimer’s disease oxidative stress usually begins with the activation of protein kinase C).

      “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

      Finally nitro-oxidative stress lowers levels of acetylcholine which is needed for the retrieval of memory. It is like a library where none of the books have call numbers. All the books are still there, but without the call numbers you cannot find them.

      “Alzheimer’s patients could recover ‘lost’ memories, scientists say
      Research on mice suggests disease does not wipe memories, but makes them harder to access”

      Nitro-oxidative stress inhibits the transport of choline, limits acetycholinesterase activity, and damages muscarinic acetylcholine receptors which lessens the release of acetycholine. Reverse part of this damage with specific antioxidants and certain types of memory can be retrieved again (object recognition, spatial recognition, facial recognition, repetitive memory–numbers, the alphabet, phrases, etc.). These memories seem tied to the hippocampus. As the disease progresses the damage increases in the prefrontal cortex. Memories connected to the prefrontal cortex are more difficult to repair (memory of events and the ability to sort out information into some logical order). Neurons can be regenerated in the hippocampus but apparently not in the prefrontal cortex. This may explain both the different patterns of memory restoration or non-restoration and why certain antioxidant treatments are less effective when started later.

      1. Matthew K says:

        I know better than to reply, but you know, Lane, I used to occasionally think to myself wouldn’t it be something if there was the germ of truth in the stuff that guy says. But to take an argument about connectivity and cognition and try to recast it as “but where is the oxidative stress coming from???!?” is just crank behaviour. Literally everyone who reads this column interested in AD has read your arguments a dozen or more times, at higher and higher rates of elision when they realise you say exactly the same thing regardless of context. Any hypothesis of merit is a testable tool to be used in various arguments about the phenomenon, but you never do that, you just use a weak linking sentence and then dump the exact same idea, slightly reworded, regardless of whether someone is talking about behaviour or biochemistry or genetics or …
        Either contribute a useful perspective based on your hypothesis or take it somewhere else, huh?

        1. Mark Thorson says:

          Wastes your time and annoys the pig.

        2. franko says:

          Matthew, how about, instead of asking him to take it elsewhere, you don’t read his comments if you don’t want to, and let leave them be for the people who are interested in them?

          Lane, thank you for your comments.

          1. Mch4 says:

            Oxidative Stress is inherent in mitochondrial quality control and fission-fusion subpopulations. But that’s what is missing in these AD arguments- any discussion of the mitochondrial dynamics and their inherent modulations in aging and AD.

            Keep talking Lane! Maybe one of these days it’ll sink in with the mono-target crowd and their lemming-stubborn money-burning ways!

            Any scientist that thinks AD is treatable using only one drug should think about another line of work.

          2. Matthew K says:

            Fair enough, franko, on reflection it’s pretty unethical to try to shut someone up. I had just hoped for a more constructive reply.

    3. Ian Malone says:

      This is why Alzheimer’s trials measure change in cognition longitudinally against an untreated control group. Nobody (or hardly anyone) expects to restore lost cognition with a treatment targetted at the disease mechanism, but we do hope to slow progression.

      The current hope for treatments based on the amyloid hypothesis is the idea that by the time there is noticeable cognitive change sufficient damage has been done that other neurodegenerative mechanisms come into play and it’s like trying to put out a fire by turning off the gas supply; it might be a good idea, and it might have helped earlier, but it’s no longer enough. People are starting to look at earlier treatment in genetic cohorts and screening with CSF or PET amyloid markers (which has the advantage of more specificity, you don’t want people with vascular dementia or other non-Alzheimer’s pathologies in your study). But given the lack of success of amyloid antibody therapies so far it’s a good idea to be looking at other things too, and there are a few different efforts out there now.

  14. Ron Louie, MD says:

    Merck might have a winner after all! Read the FDA’s Feb 2018 draft guidance for Alzheimer Disease (AD) Accelerated Approvals: if this drug, and some of the antibodies that have measurable biomarker effects, were tested in pre-symptomatic individuals (FDA Stage 1, perhaps defined as AD by the new NIA-AA Research Framework, Apr 2018), and certain unspecified FDA “persuasive” criteria were met (links below), we could have new agents at hand! How patients, caregivers and payers might assess such agents might be different than the FDA (comment to appear 05/08/18 on KevinMD website).

    1. Ron Louie MD says:

      Whoops! The KevinMD blog editors had me believe they were publishing my comments on the Feb 2018 FDA draft guidance for AD (before they might appear in the Fed Register) but they chose to reprint a piece of mine from last year, about what I see as a lack of clinical leadership and direction in AD research:

      Hoping my FDA piece appears there soon, it uses Avastin for GBM as an example of FDA Accelerated Approval. Avastin is a med I’ve prescribed, useful sometimes, but far from a “cure”, and I’m guessing the new draft guidance might provide similiar agents for AD.

  15. Barry says:

    This ^

  16. Gradscooltips says:

    Just remember, everything your mentor says is false, a contradiction meant to ” teach you a lesson”, possibly for your own good but often against your interest. Its a wash. It cannot be easily determined. You are best off ignorant of their advice. Trust me– i made the mistake if buying into the advice and i paid the ultimate price.

    1. DrOcto says:

      Do you mean that you died?

  17. Dolph Dümpling says:

    What I don’t get is why nobody is aggressively searching for interesting propionic acid derivates. We don’t understand the mechanism but they reduce the incidence of AD by about 50% in each and every trial. It seems crazy to actually have an effective preventive treatment available and ignoring it completely. CRAZY!

    1. Lane Simonian says:

      Due to this post, my day just got a lot better. As for mechanism:

      Development of indole-3-propionic acid (OXIGON) for Alzheimer’s disease.

      “The accumulation of amyloid-beta and concomitant oxidative stress are major pathogenic events in Alzheimer’s disease. Indole-3-propionic acid (IPA, OXIGON) is a potent anti-oxidant devoid of pro-oxidant activity. IPA has been demonstrated to be an inhibitor of beta-amyloid fibril formation and to be a potent neuroprotectant against a variety of oxidotoxins. This review will summarize the known properties of IPA and outline the rationale behind its selection as a potential disease-modifying therapy for Alzheimer’s disease.”

      Just looking at its structure, propionic acid appears to be a methoxyphenol and methoxyphenols are among the best antioxidants because they are excellent hydrogen donors. Curcumin, eugenol, vanillin, sinapic acid, guaiacol are all methoxyphenols that at various levels have shown potential in the treatment of Alzheimer’s disease.

      As to Me’s comments, g-protein coupled receptor inhibitors (montelukast, for instance) and receptor tyrosine kinase inhibitors (nilotinib) are already being studied for Alzheimer’s disease, but I don’t expect great results. First you would have to figure out which group of receptor was involved for each individual and then you would have to likely target specific receptors within that class. That is too much precision medicine, for me. Better in this case to work downstream.

      And to follow up on one more post: Dr. Mark Smith was a tireless advocate for the peroxynitrite hypothesis of Alzheimer’s disease:

      J Neurosci. 1997 Apr 15;17(8):2653-7.
      Widespread peroxynitrite-mediated damage in Alzheimer’s disease.
      Smith MA1, Richey Harris PL, Sayre LM, Beckman JS, Perry G.

      “the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs [neurofibrillary tangles], but instead reflects a generalized oxidative stress that is important in disease pathogenesis.”

      Dr. Mark Smith used to say that people liked to poke a lot of sticks in his eyes over his hypothesis, but he told them instead to prove his hypothesis wrong but not one ever did. I suppose that is the same type of arrogance that I have developed after 14 years of studying this disease (not through experimentation but by reading the work of others). I appreciate all positive comments and try not to let the snarky ones bother me (although admittedly I have a thin skin). Most of all I appreciate all the scientific writers who allow me to post my ideas on their sites, even though they strongly disagree with me and despite repeated calls for censorship.

      1. Dolph Dümpling says:

        You are easily the morst retarded crank ever…

      2. b says:

        “Just looking at its structure, propionic acid appears to be a methoxyphenol”

        Just no. Propionic acid is acetic acid (vinegar) with its carbon backbone extended by one. Please don’t pretend to be a chemist. There is absolutely nothing about propionic acid that makes it appear to be a methoxyphenol.

      3. c says:

        Nor is there anything about indole-3-propionic acid that contains a methoxy phenol

      4. Me says:

        Nobody tries to ‘censor’ you – instead they try to educate you, but to no avail.

        ‘Propionic acid’ = a methoxy phenyl. How come? does it have a methoxy group? No… it is a metabolite of tryptophan.

        And re: which GCPR/which TKI = precision medicine. No – it’s basic drug discovery. I’ve personally put hundreds of GCPR and TK inhibitors into AD models and studies. If it’s too much work for you to get into that level of detail then it shows the limitations of your knowledge.

      5. Derek Lowe says:

        Lane. LANE. I’m about to do something I don’t think I’ve ever done on this blog. You have been showing up here for years and years now, every time the topic of Alzheimer’s is mentioned. You say the same things every time, about the same topic. I am asking you, politely, to stop. Please, start your own blog. Talk about your Alzheimer’s theories on it every day of the week. But (and this is still a polite request), stop using this site as your relentless, inevitable, soapbox for your views. Everyone who has looked at more than one Alzheimer’s post here has heard them, and as this comments thread shows, you have gotten to the point of just adding to the noise.

        I realize that this will not be easy for you. You seem compelled to show up and deliver paragraph after paragraph about your pet theory, over and over again. I am not asking you to stop believing in it. I am not asking you to stop talking about it. I am, though, asking you to talk about it somewhere else.

      6. Nick K says:

        Lane Simonian: Your assertion than propionic acid “looks like” methoxyphenol is ludicrous. You clearly know nothing about Chemistry.

  18. Me says:


    Well now we know. I wonder what this means for amyloid ppl now?

    When I worked in an AD dept, I tried to push some non-amyloid programs. Not because I thought the amyloid hypothesis was a pile of garbage, but simply because we had alot of programs in that area anyway. I looked at mitochondrial dysfunction and ‘Type III Diabetes’ (ie metabolic) programs. I didn’t see anything to suggest these were better (or worse) ideas than ABeta, they all had a similar ‘chicken&egg’ argument to them.

    Hats off to Merck for funding the study. I probably wouldn’t fund any more ABeta programs after this if it were my money on the line. But hey, we can work on ‘tyrosine kinase’ and ‘G-protein Coupled Receptor’ inhibitors to target peroxynitrites now can’t we?!?

  19. John Wayne says:

    I’m disappointed in the overall tone of the comments in this usually well mannered blog. The real story here is how this is a huge setback for patients. Most of you just want to argue about who was right. Science is not about being correct, it is about becoming correct.

  20. luysii says:

    Ian Malone — my response was to arcya asking for evidence ” *in the clinic*, meaning in actual patients who have diseases featuring protein aggregation”. My response was found in Derek’s post — “Past the efficacy data, or lack of same, the adverse events with drug treatment were notably higher, and in a dose-responsive manner.” This, unfortunately, is how most clinical evidence is (aside from studies like Merck’s), correlation only, not causation. Your points are well taken, and I didn’t mean to imply causation.

  21. Tom says:

    Does anyone here have an informed opinion on Dr Bredesen’s research and recent book on his approach to treating Alzheimer’s disease? I read his book and recognize many of the features of the disease which he describes from having read this blog for the last few years. However, I don’t know enough to have a strong opinion one way or another.

    1. Dolph Dümpling says:

      My “informed opinion” is that as a money making scheme it’s certainly excellent. Otherwise it’s at least completely useless and bad quackery to say the least. Mr. Bredesen has a financial interest labeling as many people as having Alzheimer’s and then “curing” them as possible. So if I were you I wouldn’t panic and see a doctor for diagnostic procedures. Relax!

      1. Me says:


        Not much of an informed opinion is needed to spot quackery. I managed about 2 lines of text before my spidey-sense started to tingle. Got through a couple more pages before giving up.

        Bottom line is if his ideas were any good, he’s be pitching them to venture capitalists and investors and starting a business and opening studies, not publishing websites that give high readings on the quack-ter scale.

  22. Tom says:

    When my knowledge of the field is insufficient to guide my opinion as to whether or not someone is offering “quackery”, I usually rely upon checking their claims about their history. His CV and his book both claim an association with UCLA. I did find a press release about one of his studies from UCLA. He claims over 200 published articles and papers. I did not check all of these, but I noticed three of them were supposedly in Nature. I went to the Nature website and yes, he has had papers published in Nature (and the subjects such as Cell death in the nervous system) fit with his claim to be an active researcher for many years in neurology. Normally, I don’t see a history like this in someone pushing quackery. He might be wrong, but he doesn’t fit my idea of a quack. I don’t know if I am tempted to buy access to the 2006 article in Nature, but I might.

    1. Me says:

      All true. And with that background he should have no trouble getting venture capital to start a program that would lead to mass uptake of the program and incorporation into an SOC for AD. but for reasons unknown, he has chosen to open a ‘nutraceuticals’ website and only benefit patients that come to him directly and pay out of pocket.

      If the program was a slam dunk, health insurers would pay for it.

      Most of the papers related to the method are to be found in the journal ‘Aging’ as freeware.

      1. Lane Simonian says:

        It is indeed very hard for me to do. I enjoy reading this blog. Some of the subjects are not of interest to me and some I do not understand, but many are of interest to me and I can understand. I write almost exclusively about Alzheimer’s disease because that is where I feel I can contribute something of use (but not here I suppose).

        I thank you for your patience, Derek. This will be my last post until or unless there is a major breakthrough in Alzheimer’s disease.

        I am neither a prophet, nor a retarded crank, idiot, or complete imbecile. I have studied nearly daily Alzheimer’s disease for fourteen years first to help my aunt, cousin, and mother with Alzheimer’s disease and then to try to help those I still know who have the disease. I am certainly not a chemist, my knowledge of chemistry is almost completely limited to biochemistry. My posts are a combination of old and new findings–only the hypothesis remains constant.

        I long ago warned that the focus on amyloid was unwise long before it became en vogue to do so. People excoriated me for that as well.

        I did want to say that Dr. Bredesen is not a quack. He has identified more that 40 risk factors for Alzheimer’s disease adding to the realization that there is not a single factor that causes the disease and that its treatment requires many different approaches which may include a healthy diet, exercise, meditation, antioxidant supplements, and removal or decreased exposure to environmental toxins. In some people with early Alzheimer’s disease, this multi-pronged approach may have some effect.

        Calling people quacks or other names, dismissing studies that show cognitive and/or behavioral improvements in Alzheimer’s disease as worthless, and continuing to cleave to old paradigms and narratives is not going to get anyone closer to effectively treating this disease. We have to do better and be better than that.

        1. Derek Lowe says:

          Lane, I appreciate that. And thanks very much. I just think that you’re beyond helping your cause in the comments section here – I hope you can find a more effective way to advance it.

          You are, of course, welcome any time. Just not on the subject of Alzheimer’s, where your point has been thoroughly made.

          1. Dolph Dümpling says:

            Phew… That has been overdue for sure!!!

      2. Tom says:

        I wanted to point out what appears to be an error in your characterization of Bredesen’s business. It appears he does not require patients to come to him directly. He has “trained” other doctors in his protocol (I think he says 650 worldwide in his book) and a patient would go to one of these practitioners. Moreover, he spells out enough details of the testing he performs and the results he is looking for (as well as the treatments) that it seems that someone could always go to any willing doctor and get some variation on this protocol even without Bredesen’s approval. I also came across a forum dedicated to APOE4 whose members include some of his patients. That was interesting reading. I was hoping that someone on this blog would be able to point out errors in his research or else confirm it. I don’t suppose it matters, though. If there really are that many Dr’s carrying out his treatment, eventually either he’ll be proven right or he’ll be shown to be mistaken.
        I’ll go back to lurking. Oh, did anyone else see that Rutgers is re-issuing “Ignition!” around the end of May? I can hardly wait.

        1. Me says:

          Not sure what research you mean: he’s conducted no clinical trials into any of it (try searching

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