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Alzheimer's Disease

More Rough Alzheimer’s News

Man, Alzheimer’s.

That’s my reaction to yesterday’s news in the field. Merck started things off with news of their last-ditch attempt to see if their beta-secretase (BACE) inhibitor verubecestat (MK-8931) could be useful. I’ve been writing about that one for a while – here’s 2012, when they announced that the compound would move into Phase III, and here’s an update in 2016, making the case that if any beta-secretase inhibitor was going to do something, this would probably be the one. Last February, though, I wrote about that first Phase III trial ended up being stopped for futility: nothing was happening, and nothing ever looked like it was going to happen, either. Here’s a quick look back at that 2012 post:

. . .the headlines are. . .well, they’re mostly just not realistic. “Hope for Alzheimer’s”, “Merck Becomes Bigger Alzheimer’s Player”, and so on. My two (least) favorites are “Merck Races to Beat Lilly Debut” and “Effective Alzheimer’s Drug May Be Just Three Years Away.” Let me throw the bucket of cold water here: that first headline is extremely unlikely, and the second one is insane.

Yeah, that about sums it up. But Merck kept pitching. The usual resort in failed Alzheimer’s trials is the hypothesis that the disease wasn’t being treated early enough. That has never worked, but it’s not a stupid idea, either, and Merck gave it a try in “prodromal” patients, the earliest population you can pick without just calling it a preventative trial and giving it to healthy people. But an interim review of the clinical data apparently was discouraging enough to call a halt to the whole effort. There are a number of other beta-secretase efforts still going on in the clinic, and good luck to them, but these results have to lower their chances of success even further.

Then later on yesterday, Biogen came out with the news that they’re adding more patients to their Phase III trial of their antibody aducanumab. Remember that one? Back in early 2015, there was a rush of enthusiasm for it based on some Phase I data (yeah, Phase I). By July of that year, less compelling data had come out, but the company went straight to Phase III to see if there was something really there. So why are they adding patients? “Variability”, says the company, and it’s easy to assume that they mean “There’s so much noise in the data, because there’s hardly any effect, that we’re going to have to get a bigger N to have any hope of seeing anything at all”. What else? Investors did not take the news well.

I have the same worries about this that I had about Lilly’s failed amyloid-antibody efforts. Back in 2012, while the company was in the process of spending another mountain of cash to make absolutely sure their drug didn’t work, I wondered if we’d all be worse off if they did manage to achieve some sort of statistical significance. I think that the FDA would be under huge pressure to approve anything that reached some sort of endpoint, regardless of whether it actually affected the course of the disease much (or at all). There’s just so much demand for an Alzheimer’s drug – patients and families are desperate, and the first new drug that gets approved will bring in billions upon billions of dollars of revenue, whether it does a damned thing in the real world or not. The moral hazard for drug companies and regulators is the temptation to advance something that only looks as if it’s helping, but really isn’t. So far, the failures have all been definitive enough that this hasn’t been an issue, but it’s waiting for its turn.

What else was in the Alzheimer’s news yesterday? Why, talk of “reversing” the disease itself! Headline after headline used that verb, with only some of them using the word “mice” as well. The paper underlying all this coverage was indeed in an engineered mouse model, and showed regression of amyloid plaques on modulation of the activity of. . .beta-secretase. The same target that Merck had just dropped for futility in human trials again that morning. Even the Daily Mail noted the contrast; that’s how blatant things got.

The study (from a group at the Cleveland Clinic) says that its objective was “To better understand how BACE1 inhibition in adults will benefit AD patients“, but the mass of evidence is that such inhibition does not benefit AD patients in the slightest. Of course, the paper’s abstract starts out by saying that “BACE1 initiates the generation of the β-amyloid peptide, which likely causes Alzheimer’s disease (AD) when accumulated abnormally“, and you know what? I’m pretty sure that I don’t buy that last part any more, either. Not at this point.

67 comments on “More Rough Alzheimer’s News”

  1. Chad Irby says:

    Does anyone wonder if amyloid plaques are just a symptom of Alzheimer’s instead of the cause? It sure would explain a lot of these failures…

    “which likely causes Alzheimer’s disease”

    Are they really that sure, or is it another “stress causes ulcers” situation, where everyone sort of started assuming something that really wasn’t proven, and turned out to be mostly wrong?

    1. luysii says:

      It’s even worse — the inclusions might be protective. Here’s one example

      A fascinating recent paper [ Neuron vol. 97 pp. 3 – 4, 108 – 124 ’18 ] gives strong evidence that some inclusions can be defensive rather than toxic. It contains the following;

      “In these studies, we found that formation of large inclusions was correlated with protection from a-synuclein toxicity”

      For more detail see —

    2. dearieme says:

      “everyone sort of started assuming something that really wasn’t proven, and turned out to be mostly wrong”: that’s a pretty fair description of tracts of ‘medical science’.

      1. Grace's Acolyte says:

        “that’s a pretty fair description of tracts of ‘medical science’.”

        You can strike the word “medical” and it still applies. Every strand of science has its phlogiston.

    3. Ian Malone says:

      I think we all wonder from time to time, but the genetic evidence in humans, autosomal dominant forms; increased risk from APOE-e4 and protective effect of APOE-e2, implicates the amyloid protein as having a causative role in the disease. You can then go on to wonder if familial Alzheimer’s is the same as sporadic Alzheimer’s (it looks very like it, but reviewers will still shoot you down if you are incautious about extrapolating results) or whether the amyloid protein instead has some protective effect which is being overwhelmed (mouse models say it’s causative, but, of course, that’s in mouse models).

    4. Paul Hopkins says:

      One of the things that *rationally* keeps the amyloid hypothesis alive is the fact that the autosomal dominant mutations in the Amyloid Precursor Protein are all clustered in the sequence that corresponds to amyloid, those that do not are just outside (e.g. the “Swedish” mutation).

      Perhaps if one day someone finds another reason for this clustering then the amyloid hypothesis will finally die.

    5. Me says:

      No problems with your hypothesis at all – problem is all of the pathways looked at you could say the same about.

      Cue Lane Simonian….

      1. Lane Simonian says:

        I will take this cue as another opportunity. All of the pathways that lead to amyloid also lead to inflammation, oxidative stress, metabolic dysfunction, DNA damage, and mitochondrial dysfunction (and they are all interconnected). Here is one example for the damaging vascular events that occur in some cases of Alzheimer’s disease.

        Amyloid oligomers are often the only factor that contributes to oxidative stress in mice genetically-designed to have an Alzheimer’s like-disease whereas it may be one of many factors that contribute to oxidative stress in human beings. Thus preventing the formation of amyloid oligomers (bace inhibitors for example) or removing amyloid oligomers may in essence cure mice with “engineered” Alzheimer’s disease but largely fail to help human beings with actual Alzheimer’s disease.

        Amyloid itself does no damage itself unless via protein kinase C activation and NMDA receptor activation it leads to inflammation and oxidative stress.

        “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.”

        Although it is not as simple a matter as strongly inhibiting protein kinase C alpha as some protein kinase C alpha activation is also needed for memory and learning. Nor as trial after trial is showing, it is not as simple a matter as preventing the formation or removing amyloid oligomers. Alzheimer’s is not a mono-causal disease. One can either go the Bredesen protocol route early on and try to identify the forty or more factors that can cause Alzheimer’s disease and try to remove those factors or one can try to use compounds that inhibit the pathways that lead to Alzheimer’s disease, remove nitro-oxidants and reverse part of their damage to the brain (to be fair the Bredesen protocol also employs some antioxidants). Both strategies may in some cases stop the progression of early-stage Alzheimer’s disease and slow down the progression of moderate Alzheimer’s disease.

    6. Foodscientist says:

      The approach to curing “normal” old age Alzheimer’s may be fundamentally flawed. It’s entirely possible this is a normal human thing that will happen to all of us, if we live long enough. Something will kill all of us(or be a factor). Non-pharmacological treatments like caregivers seeing a psychologist or a classes on strategies for dealing with it would likely be thousands of times more beneficial than any small molecule discovered in the next 20 years.

      Hey Derek, interested in writing any articles on the failures in a lot of quality of life analysis during trials or difficulties getting patients to follow through with preemptive treatments(changes in diet, exercise, substance use, consistently taking an expensive medication; before any negative symptoms of a disease)?

  2. Imaging guy says:

    Genentech claims that intracerebroventricular (i.c.v.) infusion of anti beta-secretase (BACE) antibody inhibits beta secretase enzyme and reduce amyloid load in cynomolgus monkeys.

    “Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates” , Br J Pharmacol. 2017 Nov;174(22):4173-4185. doi: 10.1111/bph.14021

    1. Hap says:

      But that doesn’t help if reducing the amyloid load doesn’t do anything for Alzheimer’s. It assumes the amyloid hypothesis, and follows the logic; if the initial assumption is wrong , though, it doesn’t help.

  3. yeap... says:

    I used to work for CNS pharma company (but I think a lot of company operate in a similar fashion). One thing that was striking was although everyone knew that the assay and animal model were meaningless at best, we were (had to) behaving in a very bias way; any positive data that support product development could not be questioned (the animal model works, and the data does not need to be reproduced) and all the negative data that show your favourite molecule was doing nothing were always dismissed by saying the animal model is limited… Basically nothing could kill the project as long as there were no accute tox.
    When data on Bapineuzumab and solanezumab came out, it was dismissed by senior director sclaiming that those antibody were not good and could not be compared with our own approach on B-amyloid that we hope will be better (somehow)…
    I bet even now with the bad news from Merck, that company will ignore those data and move forward regardless hoping somehow that the result will be different…

    I am wondering how much waste in R&D is caused by this kind of attitude toward research

    1. tlp says:

      Same happens in academia, even when there IS acute tox – just don’t publish those data. We’ll figure out that later down the road!

      1. CR says:

        Excellent non sequitor.

        1. Tlp says:

          Why, did the influx of amyloid-targeting nanoparticles decrease recently?

          1. CR says:

            Again, excellent non sequitor. The comment had nothing to do with your obvious bias (disdain?) for academic scientists, but you wanted to make it known. Nice job. This comment section is usually more informative on topic.

        2. tlp says:

          Nice straw man, covering up with perceived bias (disdain) the fact that there is common subject in comments, which is wasted resources due to ignoring negative B-amyloid data.

  4. Hap says:

    This doesn’t come off well at all:

    At what point do you decide to cut bait on a hypothesis? On one hand, I have to assume that he knows more than I do about this, but on the other hand there have been an awful lot of shots on goal for amyloid, and at a high enough level of commitment (P3) that it’s unlikely that they all were deficient in some way. It’s always something else wrong with the trial, and it’s past the point when such explanations start coming off as special pleading. Perhaps it’s time to ask what data would be required to conclude that amyloid doesn’t cause Alzheimers.

    1. Adam says:

      I definitely agree. I would add (from having worked in basic neuroscience for a while now) that a fair amount of the AD (and PD) fields seem to be corrupted by “eminence-based” rather than “evidence-based” hypotheses.

      As scientists, we like to pretend that the field is “data-driven”. But more often than not, people defer to a few big-names and traditional thinking, rather than scrutinizing the data. The actual Aducanumab efficacy data (Sevigny 2015 Nature) is worth a read in this regard.

      1. johnnyboy says:

        “Eminence-based” – I love it ! So true. Sadly not a flaw of only scientists, but basically every human. Blindly following the designated ’eminences’ is much easier than making the effort to establish the necessary competence to review the data yourself – basically a shortcut for lazy minds, which basically describes 99.9% of people. Looking at pharma/biotech news outlets like Endpoint News and such, about 90% of the ‘news’ is about personalities – which eminent Executive got promoted to which eminent Company position and received money from which eminent VC… Like any of this is actually meaningful for results.

    2. yeap... says:

      I couldn’t agree more with you…
      The guy from your link says :” I fully believe in the amyloid hypothesis”
      If you look for the definition of “to believe in a dictionary is says: “accept that (something) is true, especially without proof.”
      My personal opinion when you have a molecule in your pipeline it becomes an asset then you have to back it up. You only have enough data to cut the bait when you have failed your own pivotal study.

      1. Anon says:

        Believing in a hypothesis when every experiment has turned out negative is not science, it’s called religion.

        But perhaps the problem is the way people view these experiments, as failing to prove the hypothesis, rather than successfully disproving it. Either way, you have to wonder at what point some so-called scientists will pay any attention to the data rather than their own beliefs.

        1. Isidore says:

          “Believing in a hypothesis when every experiment has turned out negative is not science, it’s called religion.”

          Actually it’s called delusion and if it continues it develops into insanity. Religion is believing in a hypothesis in the absence of data, positive or negative.

      2. anon says:

        Morgan Sheng, your comments sound like hyperbole to justify your million dollar salary.

      3. Matt says:

        You can’t BELIEVE in a hypothesis can you? You posit a hypothesis, test it, and a well-performed study (like these clinical trials) uphold or refute it.

        It has been refuted. There are lots of data that support the hypothesis, but it hasn’t been supported by experimental data. Time for a new hypothesis.

  5. Kent G. Budge says:

    This is unsurprising for such high-stakes research. Alzheimer’s is a terrible disease; it is a fairly common disease; we currently have pretty much no useful treatment for it. The company that finds a safe and at least moderately effective drug will not only be rolling in profits, but will be rolling in profits while being lauded for doing something positive to fix something terrible. You’re going to grasp a lot of straws groping for that huge a reward.

    Which is probably as it should be, as long as the trials get honest scrutiny to weed out the stuff that really doesn’t work. Which so far, alas, is pretty much everything.

  6. luysii says:

    It’s even worse — the inclusions in any neurologic disease might be protective. Here’s one example

    A fascinating recent paper [ Neuron vol. 97 pp. 3 – 4, 108 – 124 ’18 ] gives strong evidence that some inclusions can be defensive rather than toxic. It contains the following;

    “In these studies, we found that formation of large inclusions was correlated with protection from a-synuclein toxicity”

    For more detail see —

  7. BG says:

    I worked it the Alzheimer’s drug discovery field for quite a few years seeing nothing but failure after failure. I have long thought that the true cause of Alzheimer’s disease is upstream from amyloid plaques or tau tangles. Has anyone every thought to correlate cognitive decline with a “plaque score”? I would be willing to bet that there is no correlation and that some people with very high plaque scores would be cognitively intact (relatively).

    The other option is that it’s a multifaceted disease with several biological processes going awry resulting in plaques and cognitive decline.

    1. Lane Simonian says:

      Here is one of the best articles on the subject.

      1. Lane Simonian says:

        Just to highlight a couple of philosophy of science points in the above article.

        “Whenever a theory appears to you as the only possible one, take this as a sign that you have neither understood the theory nor the problem which it was intended to solve.”

        Karl Popper

        (I understand the irony of that quote for me, too).

        “The primary point of our review is to suggest it is inappropriate to ignore equally valid interpretations of data. There are many thousands of papers on Alzheimer’s disease, and many of these papers can be interpreted in alternative ways, while still more are contradictory to, and/or inconsistent with, the amyloid hypothesis. There are also many thousands more investigating mechanisms driving synapse function and dysfunction that could be linked to AD literature, given synapse dysfunction is a key early event and accurate correlate of AD progression. We conclude by suggesting the students, post-docs and young faculty who will determine the course of AD research in the next decade, must spend time reading this literature extensively, and thinking deeply, and thus become the next generation of leaders that, at the expense of time away from the lab bench, determine the best pathway forward.”

  8. Lane Simonian says:

    Mice designed to have an Alzheimer’s-like disease have fewer cognitive deficits than human beings with the disease. In addition, they basically have only have one source of oxidative stress (amyloid oligomers), so if you prevent the oligomers from forming with a beta secretase inhibitor, you may be able to “reverse” the disease in mice.

    The genetics threw the amyloidist off-track. Yes, excessive amounts of the amyloid precursor protein and mutations that lead to the formation of plaques in the walls of blood vessels lead to the death of neurons and to early onset Alzheimer’s disease, but they do so by increasing oxidative stress. A particular presenlin gene 1 mutation, which also increases oxidative stress, leads to the early onset of Alzheimer’s disease in some families in a region in Colombia around the age of 50, but the exact same gene in Japan leads to the early onset of Alzheimer’s disease about ten years later. The difference is that the families with Alzheimer’s in Colombia were exposed to high levels of mercury contamination.

    Diffuse core plaques can be found in children exposed to high levels of air pollution in Mexico City. They are a sign of less extensive oxidative stress. Dense core plaques are more closely associated with Alzheimer’s disease but as a a consequence not as a cause of the disease. Oligomers contribute to oxidative stress but they are only one of several factors that do so (others include mercury exposure, various air pollutants, several pesticides, psychological stress, chronic bacterial, viral, and fungal infections, a diet high in sugar, carbohydrates, high fructose corn syrup, and salt, and the ApoE4 gene). Remove amyloid oligomers and you are only removing one factor that contributes to Alzheimer’s disease. At best, you only slightly slow down the progression of early Alzheimer’s disease.

    The combination of Aricept/donepezil which slows down oxidative stress by limiting the release of intracellular calcium (incidentally, the stimulus for the gamma secretase) and herbs containing antioxidants appear to stop the progression of early Alzheimer’s disease and slow down the progression of moderate Alzheimer’s disease.

    The hypothesis has to change before the disease can be altered.

    1. Johannes Høher-Larsen says:

      I think heavy metal pollution is really worth looking into since mercury can stay as insoluble complexes for up to 100 years in the human brain.

  9. dearieme says:

    “Even the Daily Mail noted the contrast; that’s how blatant things got.”

    There is no excuse for that cruel sarcasm directed at the the Old England Journal of Medicine.

  10. kjk says:

    Maybe one of the best ways to convert $ into curing Alzheimer’s is better lab automation. When we are so far away from the finish line it makes sense to invest in building a car rather than trying to walk thousands of miles.

    1. tlp says:

      the speed is not an issue if you don’t know in which direction the finish line lies

    2. tt says:

      What’s the point of getting faster and using automation if you cannot characterize the disease, don’t have a good biomarker/model, or even an understanding of the biology of it. The last thing we need is a machine cranking out more molecules to readout in an irrelevant assay(s).

  11. Wavefunction says:

    Laura Manuelidis from Yale has been pushing a viral theory of AD for decades. My guess is that amyloid could have been a protective response to infection in old times (presumably its degenerative effects did not matter because they manifested after childbearing age). I know there was some research a few years ago pointing to a bacterial membrane-disrupting effect of the Aß peptide.

    1. Calvin says:

      Ruth Itzhaki at Manchester has done similar work. She has seen HSV RNA in the plaques of AD patients with ApoE4 and so her hypothesis is that HSV plays a kep role in driving Alzheimers. I used to be very skeptical of this, but given the massive failure on the amyloid approaches surely this is worth a look. The interesting thing is that Ruth (despite a lot of ridicule) has never been dogmatic about her work; if you speak to her it’s clear that she wants to test a hypothesis based on reasonable preclinical data; a proper scientist.

      1. Wavefunction says:

        Interesting. I think both of them should be commended for pursuing an unlikely but interesting path in the face of massive resistance from the establishment (I know Manuelidis had a longstanding and acrimonious dispute with the testy Stanley Prusiner about this).

    2. BigSky says:

      The thing that I don’t really understand about the Manuelidis lab’s papers is that they start a walk towards a conclusion… and then end. There seem to be some not-too complex experiments to do but in the intervening years between papers the lab publishes none of them and then moves in another direction. Is that because they tried and got negative results looking at nucleic acid incorporation in the particles or something else? In 2007 they described a virion-like particle capable of encapsulating nucleic acid (based on the size). I’m still waiting for the FPLC > cloning results. A decade ago I thought she might really be on to something. And she might well be. But I can’t tell. Bummer.

  12. anon says:

    “The usual resort in failed Alzheimer’s trials is the hypothesis that the disease wasn’t being treated early enough.”
    After so many failed attempts to cure it, one does start to wonder if there is any hope at all of being able to come up with a drug that would reverse or stall AD. Maybe it really is a case of aging, neuronal death by a thousand cuts, and when we can diagnose it, it is already much too late. Maybe some of the gazillion proposed treatments could have worked, if only the subjects started taking them at the age of 40 or 50.
    I wonder if there is a genetic link, maybe if you took DNA samples from 10 000 random ppl at the age of 50, did whole genome sequencing for all, then waited 30 years and looked for statistically significant genetic diffs between those who developed AD and those that did not, maybe then you could find it.

  13. Chris says:

    FDA also just updated guidance on AD clin trials that seems more accepting of biomarkers as endpoints

    1. Eric says:

      The FDA is accepting of biomarkers for early stage trials, but they pretty clearly state that “the effects on biomarkers in AD are not sufficiently well understood to provide evidence of a persistent effect on disease course”.
      It’s difficult to demonstrate a biomarker is useful before you have any therapies that alter disease progression. Otherwise it might just be correlative (perhaps like amyloid plaques?)

  14. Eric says:

    A lot of these comments imply that pursuing the amyloid hypothesis was a foolish idea. In hind sight that’s easy to say. Merck started these trials several years ago before seeing all of Lilly’s data and I commend them (and Lilly) for taking the aggressive approach. This is what I’d like to see big pharma do – take the big risks to address real unmet medical need. The amyloid hypothesis had a lot of good data supporting it, but it appears to be wrong. I’m still glad they tested it rather than trying for Viagra version 2.0

    1. Hap says:

      It doesn’t seem like that to me – it just seems like people are holding on to the amyloid hypothesis as a main driver for Alzheimer’s drug development when the evidence to support it isn’t there. (The second Lilly trial, though, seemed like a bad idea to a fair number of people when it was started.)

      Persistence sometimes looks really foolish and can be hard to distinguish from immunity to evidence.

      1. Eric says:

        That’s a fair point. It’s just easy to forget that some of the decisions to initiate these trials were made years ago before we had as much negative data.

        1. Hap says:

          No shorter-term models and no good biomarkers means every trial is a really expensive, uncertain bet. Boy, drug development and investment sounds fun!

  15. luysii says:

    The lack of therapeutic progress certainly isn’t due to an absence of research on the causes and possible treatments . A monster review in Neuron vol. 97 pp. 32 – 58 ’18 — contained references to over 400 research articles half of them published since January 2013.

    Still I found it quite depressing. Tons of work and tons of findings, and yet no coherent path to the cause (or causes); something absolutely necessary for a rational treatment, unless we somehow stumble into a therapy.

    In a way it’s like cancer. The cancer genome atlas intensively studied the genome of various cancers, looking for ‘the’ or ‘the set of’ causative mutations. They found way too much. The average colon and breast cancer had an average of 93 mutated genes, of which 11 were thought to be cancer promoting. Not only that, but the same 11 were not consistent from tumor to tumor.

    So it is with this epic review. Which of the myriad findings described are causative of the disease and which are responses of the nervous system to the ’cause’ (or causes).

    1. Barry says:

      We have a lot of evidence that “cancer” is not a single disease at all. I’m not aware of evidence that Alzheimer’s is more than one disease. Some cancers can be treated very satisfactorily. I’m not aware of any subset of AD for which anyone can seriously claim that.

    2. MTK says:

      Concur with the cancer analogy.

      All of these hypotheses regarding AD, and none of them, may all turn out to be “right”.

      AD may end up being a host of different diseases from a molecular standpoint that all exhibit a common phenotype. If that’s the case then treatments have to match the disease in order to have a reasonable chance at success.

  16. Ron Louie says:

    As a physician, clinical investigator and Alz caregiver, I hate the disproportionate attention given to any animal model: mouse, rat, even poor C. elegans! Someone sent me the Newsweek feed about the BACE1 mouse model results, and it seems so disingenuous, especially the quotes by clinicians in the field, given that Merck’s BACE1 failure was months ago. Isn’t this what they call FAKE NEWS?

  17. Helptherace says:

    How about a positive spin “A fantastic molecule provides strong evidence that inhibiting BACE1, and therefore the generation of the β-amyloid peptide, provides no benefit to patients suffering from Alzheimer’s disease. I hope, that as a result of this amazing effort, the scientific community can divert their efforts and funding toward other avenues for understanding and treating this disease, with the ultimate goal of improving the lives of patients and those close to them.”

  18. Scott says:

    Whatever happened to the tests with that big extended family from South America, where virtually all the males get aggressive, early-onset Alzheimers?

    1. Lambchops says:

      Still ongoing:

      Some relatively recent news:

      It’s not due to complete until 2022. One would suspect if it’s a failure then anyone suggesting that “we’re just not treating the patients early enough” will get short shrift.

    2. anon says:

      Not just males–it’s an autosomal dominant trait.

  19. Henry Porter says:

    A UK company, AB-Polyblok Ltd, has restored plasticity in the rat via IV after AB42 Tau and A Syn insult. Very low API values. So it’s not all for naught.

  20. DanielT says:

    Is there any evidence that any of the current beta-amaloid treatments actually having any significant impact on the level of beta-amaloid in the brains of humans?

    1. Lane Simonian says:

      Yes, but the degree to which they do so varies from drug to drug. Biogen’s Aducanumab has been reported to remove both plaques and oligomers: in significant amounts

      “In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner…Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.”

      There are now three red flags against this drug. First, the 3mg dose appeared to significantly reduce the rate of cognitive decline in early-stage Alzheimer’s disease patients but the 6mg dose did not. Second, the 10mg dose produced a series of adverse effects that primarily affected those with the ApoE4 gene. Since individuals with the ApoE4 gene advance more rapidly during the early stages of Alzheimer’s disease, these dropouts made it look like the highest dose of the drug was performing better than it actually was. And now, they are adding more trial subjects because they are apparently not seeing any clear-cut, positive results with the numbers they have.

      Antibodies against amyloid oligomers may delay the onset of Alzheimer’ s disease by a few years and slightly slow down its early progression, but these antibodies are probably not going to prevent Alzheimer’s disease nor stop its ultimate progression. At best amyloid oligomers are a contributor to Alzheimer’s disease and not the cause.

      1. DanielT says:

        Thanks Lane. The PIII results from this should be very interesting. It would be good to know how the patients in the PIb trial are tracking now.

  21. Diver Dude says:

    “It doesn’t matter how beautiful your theory is, it doesn’t matter how smart you are. If it doesn’t agree with experiment, it’s wrong.”

    Richard P. Feynman

    I’m worried that FDA just “updated” it’s AD biomarker guidance with no apparent recognition that amyloid (and tau) might not the whole AD story. Or any of the story.

  22. PorkPieHat says:

    Alzheimer’s disease: the new Sepsis. . . graveyard of experimental drugs.

  23. David Edwards says:

    Meanwhile, someone’s looking at an alternative, in the form of Robert Moir …

    Amyloid plaques as an immune response to infection

    There’s even a paper, published right here in Science Translational Medicine

  24. Me says:

    Well what can I say…..

    I applaud Merck and Lilly and everyone else for pushing these programs through – the science is only bunk when the studies fail to meet their endpoints.

    There are loads of other areas where AD patients have got aberrent function or deficiencies over non-AD, be it metabolic, inflammatory, immune, metal homeostasis and, yes Lane, oxidative stress among others. In my infinite wisdom as a med chemist working in AD, I’ve never really seen anything fundamentally ‘wrong’ with any of them – certainly I was trying to champion working on some of these in addition to amyloid/tau as a way of spreading our risk.

    Bottom line though:

    There are no drugs that turn grey hair brown/black/blonde again
    There are no drugs that make old skin soft, plump and elastic again
    There are no drugs that restore fertility in post-menopausal women
    There are no drugs that restore sight to patients with age-related macular degeneration

    But finding that there are no drugs to restore function to aged neurons is evidence of scientific incompetence, stupidity and corporate greed?

    1. Mol Biologist says:

      Hmm corporate greed…..Let’s take a better grip on the Li mode of action which shed more light on the fundamental processes that are guiding mood regulation and other neurological disease such as AD. There are meta analysis which found that patients with MILD cognitive impairment can be treated with Li.
      Thank you Derek for giving a food for thinking.
      IMO it may be next “magic bullet” for drug discovery in the future or even new Li6Si2 sensor for digital health diagnostics.

  25. loupgarous says:

    “SF scientists erase Alzheimer-causing gene in human brain”

    “Scientists in San Francisco may be close to finding a cure for Alzheimer’s disease. The key to their success was looking not at the brains of mice – a standard practice in scientific research – but of men.

    Researchers at Gladstone Institutes, an independent biomedical research institution in San Francisco, have discovered the cause of the primary genetic risk factor for Alzheimer’s disease, and they may have found a solution to erase its damaging effects.

    (This link is the actual paper)
    Their findings, published Tuesday in the journal Nature Medicine, are especially important because they conducted tests not on the brains of mice, but that of humans.

    The scientists found human brains that possess even one copy of a gene, called apoE4, are more than twice as likely to develop Alzheimer’s disease in their lifetimes. Having two copies increases the risk twelvefold.

    ApoE4 in the human brain increases production of the amyloid beta protein, the researchers discovered. This revelation was especially surprising because past studies found that the apoE4 gene in mouse brains did not lead to an increase in amyloid beta. Excessive amyloid beta in the brain can clump together and create plaques, which can disrupt neuron firing and lead to symptoms associated with Alzheimer’s.

    “One concern within the field has been how poorly these mouse models really mimic human disease,” said lead study author Yadong Huang, a senior investigator and director of the Center For Translational Advancement at Gladstone, in a statement. Huang noted that “many drugs work beautifully in mouse models,” but come up short in tests on human brain tissues.

    To correct the accumulation of harmful proteins, the scientists looked to alter the gene that produces such proteins, apoE4. By treating the human apoE4 neurons with a structure corrector – a compound that changes the shape of the apoE4 gene to resemble a similar, but innocuous gene – the scientists restored normal function to the brain cells.

    The next step is working with the pharmaceutical industry to test the structure correctors on human patients.

    “Drug development for Alzheimer’s disease has been largely a disappointment over the past 10 years,” said Huang. His team hopes to change that.”

    I know, “amyloid hypothesis redux”, and after verubecestat, we’ve been immunized against hope.

    But their “structure corrector” seems to work in humans, not mice. That in itself is a welcome change from where we were a while back.

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