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Underwhelming Alzheimer’s Results From Biogen and Lilly

OK, we have some Alzheimer’s data to talk about this morning. Biogen’s antibody aducanumab, about which people have been wildly enthusiastic, showed very little effect on mental decline at a 6mg dose, the company reported today. Note that the Phase I data that got all the attention was at 3mg and 10mg (with better results at the higher dose), but that the 3mg dose was still positive.

That, though, was a smaller and less powered trial. And the first thing that has to be learned from watching clinical research (especially for a disease like Alzheimer’s) is that you cannot draw conclusions until you see a large, well-run data set. Ignore this advice at your peril. The list of promising-looking Alzheimer’s ideas that have evaporated on contact with a larger trial is long and terrible.

What’s interesting is that aducanumab did seem to show the expected reduction in amyloid, which makes a person wonder (yet again) what it takes to draw that connection, assuming that it can be drawn. Biogen’s getting ready to go into a big Phase III (2700 patients), and that, of course, is where we’ll see what’s actually going on. If anything.

Meanwhile, Eli Lilly has released more data from the extended trial of their own antibody, solanezumab. That one’s gotten a lot of attention over the last few years as well (especially recently), as the company continues to develop it in the face of not-all-that-compelling clinical results. And by gosh, today’s data are. . .not all that compelling. The company claims that they’re seeing more effect in the patients who started the therapy earlier, but (as that link from Adam Feuerstein shows), not everyone is buying that interpretation. The effect they’re seeing may well be clinically meaningless.

Lilly is already going on with another Phase III in mild, early Alzheimer’s patients, chasing what they see as a real result and trying to make the most of it. With one hand, I cheer them on – Alzheimer’s is an awful disease, we can’t do a damn thing for it, and a new therapy is desperately needed. It’s actually sort of inspiring to see a company put so much money on the line in an attempt to do something about it. But with the other had, I’m wiping my brow as I shake my head. I’ve never been able to convince myself that solanezumab is much good. I think that marginal Alzheimer’s drugs are far, far more likely to flop than they are to hang on and become the first-in-class that companies dream of. And I wish that weren’t so.

82 comments on “Underwhelming Alzheimer’s Results From Biogen and Lilly”

  1. Kelvin Stott says:

    Why do I get the feeling that these data are a false signal in the noise – a mirage in the desert that people see only because they are thirsty?

  2. SteveM says:

    Re: “It’s actually sort of inspiring to [Eli-Lilly] put so much money on the line in an attempt to do something about it.”
    Well not quite. Lilly is playing the “desperation therapy” game. I.e., provide little therapeutic benefit for a very expensive treatment and hope desperate patients and/or their families mobilize for insurance coverage.
    So tactically, heavily politicize any payer resistance to subsidizing a marginal drug that costs tens of thousands per year and have crony politicians do the dirty work of strong-arming the payers.
    BTW, Lilly has a fine history of oily behavior regarding marginal and even dangerous drugs. If corporate perversity can be inspiring then I guess Lilly is inspiring.

  3. BiotechStartup says:

    I am not an expert in this field… what is the evidence that beta amyloid CAUSES disease in humans or even animals?

  4. Anonymous says:

    @3: The fact that 1% of AD cases are hereditary and all of those are genetically linked directly to the over-production and aggregation of beta amyloid.

  5. Anonymous says:

    Insanity is doing the same thing over and over and expecting a different result…

  6. bank says:

    The amyloid plaque aspect of Alzheimer’s can be reproduced in mice by expressing mutated forms of the APP protein, whence the amyloid peptide is derived. However the mice don’t get neurodegeneration; why is unclear, since humans with these mutant forms of APP do.
    However, almost all the mutations in APP that cause early onset inherited Alzheimer’s disease are found in the ~40-50 amino acid amyloid peptide region of APP, and not in the rest of this 695 amino acid protein. So *something* about that region of the protein (i.e. the amyloid peptide) is key to causing early onset Alzheimer’s disease, which has the same pathology as late onset Alzheimer’s disease.
    However… amyloid production actually goes *down* in the CSF of late onset Alzheimer’s patients…..
    Tricky, tricky….

  7. anchor says:

    @ 3 – This is the debate that is raging in this field. What the science has shown during the last several decades is the load of beta-amyloid whether small or large, a subset of people go on to develop AD. Lilly also has a diagnostic agent that can determine the plaque load and that’s about it. The question is whether this plaque is innocent bystander or causative for AD, no one can be definitive. I am not an expert but there are others who are like Dr. Simonian!

  8. luysii says:

    There is some data mining to be done (by any of you out there). A drug in clinical use (Gemfibrozil aka Lopid) for over 40 years, has been shown to increase the amount of PPARalpha, which chops up the amyloid precursor protein (APP) in such fashion that the Abeta peptide, which forms most (not all) of the senile plaque isn’t formed.
    I wrote the author of the paper suggesting that he mine HMO data to see if people on Gemfibrozil got less Alzheimer’s, but his response indicates that he can’t get a grant to do so. So have at it all of you out there. I’m a retired neurologist with no academic affiliation, so the field is wide open, and the data is out there. Have at it.
    If would great if something were to come of this. For details please see —

  9. Anonymous says:

    ^ FYI, Lane Simonian is NOT an expert in AD, nor even a scientist, but a historian who reads a lot of papers on AD and selectively picks out those which support his own pet hypothesis, which is a minority view and far from any scientific consensus.
    To be more accurate, only a small percentage of AD cases are hereditary and all of those are genetically linked to the over-production and aggregation of beta amyloid (some within APP, others via presinilin and ApoE). Furthermore, soluble oligomers of amyloid have been shown to be much more toxic than insoluble plaques and fibers, which seem to be inert. Other than that there is really no other evidence, only ideas.

  10. Nately says:

    Where are the Lane Simonians of yesteryear?

  11. Anonymous says:

    ^ Maybe doing his first ever experiment to test his hypothesis? Or maybe not.

  12. Mark Thorson says:

    To be fair, the reason that CSF amyloid beta goes down in AD is attributed to increased retention in the brain. The current version of the amyloid cascade hypothesis is that production is not increased in AD, but clearance is impaired.
    Amyloid beta has been shown in vitro to bind to a wide variety of receptors and enzymes, such as CD36 and various kinases implicated in tau hyperphosphorylation, which has allowed the construction of reasonable speculative mechanisms by which it could cause disease. However, I suspect that amyloid beta is a sticky molecule which can be demonstrated to bind to darn near anything, so I’m skeptical of these mechanisms. After all, it even has high affinity for itself, forming a wide variety of oligomers.

  13. Anonymous says:

    Soluble oligomers of amyloid have also been shown to form calcium-permeable channels (i.e., pores or holes) in cell membranes like in many other amyloid-related diseases (HD, CJD, etc.), which would effectively kill the cells as they struggle to maintain homeostasis. Personally I think this is a very plausible mechanism, but there is no way any antibody will be able to get into the brain and then into the cell membranes to disrupt that kind of stable structure.

  14. Curious about Lilly says:

    What is the current morale like at Eli Lilly? A few years back their CEO touted that they would have 2-4 (something like that) drug launches a year. How has that turned out while Lilly has fallen off the patent cliff? Indy is not exactly a hotbed of drug discovery.
    Is it possible to work at Eli Lilly now and not feel like you’re totally screwed? Just curious.

  15. Anonymous says:

    Typo errors, missing spaces between doses and units, three times.

  16. Anonymous says:

    Trulicity is expected to be a blockbuster and will be launching soon if not already

  17. Bernard Munos says:

    One key problem to me is the statistical design and the lack of adequate control. To put it differently, if the initial difference in patient scores between early- and late-starters is a fluke, and patients are given an ineffective treatment, what happens to the difference in patient scores? Does it persist? Does it vanish? I don’t think anyone knows. Unfortunately, at this stage, any claim of disease-modifying activity is premature, and most likely reflects hope, not facts.
    To highlight the risk of premature judgment, let’s remind ourselves that back in 2001, Lilly’s sepsis drug Xigris was approved after a phase III trial was stopped early because the results seemed amazing. Yet, 10 years later, the drug was pulled from the market for lack of efficacy. Additional analyses uncovered statistical flaws and an apparent attempt to strong-arm physicians into prescribing a drug that was in fact ineffective (
    We all hope that someone, somewhere is working on a useful treatment for Alzheimer’s, but claiming benefits based on limited data and their contrived interpretation is not the way to help patients.

  18. Kelvin Stott says:

    Hi Bernard, I couldn’t agree more.
    And I agree with #13 – quite possibly amyloid IS the ultimate cause, forming toxic pores, but there is no way any antibody will be able to block this.

  19. Chris H says:

    The BBC (and possibly lots more of British media) have been salivating over this development all day. Thanks for giving me some perspective on this. I do hope that the drug does help people with Alzheimers. However, I do wish that the scientists would not announce this stuff until they have better data.

  20. Mark Thorson says:

    Who you gonna believe, Derek or the Daily Mail?

  21. Kelvin Stott says:

    @19: BBC news is absolutely choc-full of news articles over the past 20 years claiming a breakthrough with a cure for AD just round the corner. They even ran a TV news slot on my own research when I worked in the field 15 years ago, and all I had were some compounds that blocked amyloid aggregation in vitro, of which there were countless others.

  22. Esteban says:

    @19,21: I regularly read the British press because I’m interested in what’s going on over there (I’m not from there, I’m just an anglophile I guess) and one thing I’ve noticed over the years is that scientific reporting in the mainstream press really stinks, noticeably more so than the US press. It’s just the tabloid-ian culture I guess to blow things out of proportion.

  23. Esteban says:

    PS: To be clear, scientific reporting in the US press often stinks, so I’m merely talking about degrees of stench.

  24. Kelvin Stott says:

    @22: Partly it is the culture of UK media to be sensationalist, but the problem is worse with reporting research on AD as it pleases the older demographic that vote to keep the BBC paid by mandatory license fees from younger folks.

  25. Christophe Verlinde says:

    Beta-amyloid gets cleared from the brain by the glymphatic system, BUT only when you sleep well. This was demonstrated by Maiken Nedergaard, the discoverer of the glymphatic system. See: Science 18 October 2013: Vol. 342 no. 6156 pp. 373-377 DOI: 10.1126/science.1241224

  26. bank says:

    @12, Mark,
    If decreased clearance of amyloid was the cause of lower CSF Abeta, and disease, one would expect an increased amount to be retained in the brain. However this does not appear to be the case: plaque levels are static through the period when CSF levels drop.

  27. SedatedFMS says:

    It’s nothing to do with sensationalism it’s all do to with an appalling lack of understanding of even basic science, let alone something as complicated as AD. I’ve lost track of the times some idiot from Sky/Beeb/ITV/C4 has asked a scientist a question, gotten an answer and come to a conclusion completely disconnected from what the scientist/medic has just said.

  28. steve says:

    So this is not my field, but my understanding is that non-human primates accumulate lots of amyloid but don’t get the taopathy and neurodegeneration seen in humans. Doesn’t this observation alone mean that amyloid is not the causative agent?

  29. biotechtoreador says:

    But that AXON had some good (cherry picked post-hoc from a few years ago) data….

  30. Brainless in Seattle says:

    What does it take to demonstrate causality between two parameters?
    Is it a time-course study showing what comes first?
    Something else, anyone?
    Thank you.

  31. Anonymous says:

    @30: Causality can never be fully proven as nothing can be proven in science. But you can do experiments to measure the effects of changing only the hypothetical cause, and the hypothesis of cause-effect becomes statistically stronger the more often you get the predicted effect.

  32. J. Peterson says:

    “Aducanumab”? One of these days, please indulge those of us outside your industry with some insight into how you come up with these crazy drug names.

  33. J. Peterson says:

    “Aducanumab”? “Solanezumab”? One of these days, please indulge those of us outside your industry with some insight into how you come up with these crazy drug names.

  34. Anonymous says:

    ^ “mab” is short for monoclonal antibody, which is what this is. But the prefix? Who knows, maybe from “aduct” or “aduvant”, but there is probably some logic to it.

  35. sgcox says:

    Aduca-NUMAB Nervous system hUman MAB
    Sola-NEZUMAB NErvous system hUmaniZed MAB

  36. bank says:

    @ 30,
    Causality requires an experimental model where introducing one or more Alzheimer’s associated mutations causes exactly the disease as seen in humans.
    Unfortunately, this does not currently exist. You can cause neurodegeneration by mutating the presenilin gene (the second cause of early onset Alzheimer’s) in mice, but these mutations don’t produce the pathology seen in humans.
    You can cause *some* of the pathology seen in humans by introducing mutated APP genes in mice, but these don’t cause neurodegeneration.
    You can introduce both, in which case the mice are quite messed-up.
    However, late onset Alzheimer’s disease, while pathologically similar to the early onset disease, isn’t associated with changes in the levels or expression either presenilin or APP…

  37. yetab says:

    @28 – So this is not my field, but my understanding is that non-human primates accumulate lots of amyloid but don’t get the taopathy and neurodegeneration seen in humans. Doesn’t this observation alone mean that amyloid is not the causative agent?
    Actually, I don’t think that amyloid is necessarily the only causative agent (there is the emerging category of SNAP – suspected non-amyloid pathology, for example, suggesting that amyloidosis is a representative core but not unique phenotype). That being said, in the vast majority of cases, and not least the early onset familial ones, the accumulation of amyloid would seem to be a necessary precondition for subsequent events, however mediated. So it is entirely rational to intervene early, and to intervene hard, and to intervene well, in amyloid production, or rather in the *consequences* of amyloid production *in humans*. No-one has really done this yet!
    @26 – plaque levels are static through the period when CSF levels drop
    Not true. Plaque accumulates during that period. CSF and PET (ie plaque) load are pretty much inversely correlated however you look at it. Which is indeed a bit weird, but also a reminder that biochemistry in reality is more complex that a single compartment model in an eppendorf tube.

  38. bank says:

    You might wish to review the data with respect to plaque levels, the following figure is from “Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease”, Batreman 2012.

  39. Mark Thorson says:

    bank, retained amyloid beta is not always in the form of plaques. It forms all kinds of other aggregates — oligomers, globs, fibrils — and it’s not known which contribute toward plaques (though the fibrils are widely believed to be the precursor to plaques).
    The correlation between plaques seen at autopsy and dementia prior to death is poor, so amyloid cascade hypothesis 1.0 seems to be reliably dead. Plaques don’t cause AD symptomology.
    Amyloid cascade hypothesis 2.0 is that it’s the toxic effects of amyloid beta oligomers which cause AD symptomology. The monomers don’t actually seem to have these effects. The oligomers up-regulate the activity of GSK-3beta and AMPK, the currently fashionable suspects in tau hyperphosphorylation, and accumulation of neurofibrillary tangles composed of p-tau does correlate well with dementia.
    I’m waiting for amyloid cascade hypothesis 3.0 — something else is upstream of amyloid beta accumulation and is responsible for both the symptoms of mild AD and initiating amyloid beta accumulation, and it is the latter which is responsible for the transition from mild AD to moderate/severe AD via up-regulation of tau phosphorylation.

  40. bank says:

    Actually the figure I posted shows an inverse correlation between CSF Abeta and plaque load, albeit *prior* to symptom onset :-/
    Amyloid 1.0 is definitely dead, as you say. I am not convinced about the the oligomer hypothesis either, since if these oligomers are toxic to cultured mouse neurons (which they are), why do they not cause neurodegeneration in living mice?
    I’m waiting for an alternative explanation for the AD-causing mutations in APP that doesn’t involve Abeta, at least not directly…

  41. Mark Thorson says:

    bank, inverse correlation between CSF Abeta and plaques is to be expected. Abeta readily binds with itself, so those plaques are presumably acting as sponges soaking up whatever soluble Abeta passes their way. This is the likely cause of the low Abeta in CSF and the apparent impaired clearance of Abeta.
    Why do Abeta-related mutations (like those in APP and presenilin) cause AD if that’s not the ultimate cause of AD? I think that’s because they skip the stage of mild AD and go directly to moderate/severe AD. That would also explain why they show up early (before age 65) and progress quickly.
    Mild AD and moderate/severe AD are like two separate diseases. Memantine is ineffective against mild AD, but it works for moderate/severe AD. If mild AD and moderate/severe AD were the same disease, memantine should work for mild AD. I think mild AD is a disease that greatly increases the risk for another disease that we call moderate/severe AD, but there are other things that increase that risk too (like these rare genetic mutations).

  42. Mark Thorson says:

    JB, that’s one hypothesis. My hypothesis is that the pharma companies want to make the generic name as difficult as possible. If you ever hear about a drug with the brand name Goodulin and the generic name xzqurictib, just try to forget I ever mentioned this.

  43. Mark Thorson says:

    I was going to mention that if xzqurictib was to become a generic name, it’s a shame that it wouldn’t be good in Scrabble because it’s ten letters. But if somebody else plays “URIC” and you’ve got XZQTIB, then available space applies.

  44. Anonymous BMS Researcher says:

    Had somebody told me 10 years ago, “in 2015 we STILL will not know for sure either way about the amyloid hypothesis,” I would have said “surely we’ll know that by then!”
    But we still do not know.

  45. Anonymous says:

    Is the poster they presented published anywhere? Or just the underlying data? I’m trying to find it but can only locate the abstract for the poster.

  46. anon says:

    By the way, how do these antibodies remove Abeta42? Opsonization?
    Why can these antibodies be active with such poor BBB penetration (0.1-0.2%)?

  47. AyatollahOfTheOutcomes says:

    AD, like ALS or CF, is likely hundreds if not thousands of diseases with the same symptom. Has any company tried developing a therapy to just target specific strains (e.g. a specific genetic one) just like Vertex has done for Delta-508 CF. That approach could have a greater chance of success than a random shotgun approach to all variants.

  48. Matthew K says:

    #47 – it’s often posited that it’s a source / sink kind of equilibrium – clearing Abeta from the blood lowers its concentration and hence increases the rate at which it leaches out of the CSF via clearance mechanisms. Kind of like drying a piece of fruit, you can’t take the water out of each cell but if you dry the air it’s sitting in, the water will come out. Anyone who knows better, feel free to correct me of course!

  49. bank says:

    That these antibodies decrease plaque in the brain is shown, in humans and mice. How so? It’s likely due to a incomplete understanding of the BBB.
    The antibodies reverse symptoms in mice (as do hundreds of other treatments), but as we are finding out, don’t do much for Alzheimer’s disease.

  50. DrSnowboard says:

    I found it curious that the fact that data was going to be released on solanezumab was trailed heavily on the BBC flagship news programmes that morning – admittedly ‘data will be released later today that MAY show a benefit in AD’ but still heavily promoted for data that was allegedly unknown. OK, it may well have been the AD Research charities PR machines rather than Lilly but it was a jumping the gun. I blame the BLair government for starting the “The govt is expected to outline later today how it expects to combat crime with a new initiative” type story format. How far ahead of the actual news can you be before you are just generating your own news and passing it off….

  51. bank says:

    Dr. Snow,
    I suspect someone is benefiting for the spike in stock prices that occurs with these kinds of announcements.

  52. steve says:

    Again, not my area of expertise, but in my experience when you have to keep adding ad hoc explanations to support your hypothesis (it’s not the plaques, it’s the oligomers! no, it’s the globs!) then it’s usually a sign that there’s something wrong with the basic idea. Since primates accumulate lots of amyloid as they age but don’t have accompanying neurodegenerative disease then either there is something fundamentally different about their amyloid vs humans (an unlikely hypothesis to me) or there is a different cause of the neurodegeneration and amyloid accumulation is just a passive sign of aging.

  53. Anonymous says:

    Lovely discussion guys 🙂

  54. Dr. Manhattan says:

    @51, 52. And yep, here are headlines about solanezumab on the Internet news feed:
    “Breakthrough in Alzheimer’s fight with trial results on drug” Irish News
    Then from BBC: “Early signs that drug ‘may delay Alzheimer’s decline'”
    and another (Helio) :”Delayed-start methodology shows benefits of early treatment for Alzheimer’s disease”
    I think Bernard Munos (#17) has it correct. The evaluation criteria (patient scores) are “soft” indicators, and only time will tell if the results hold up statistically.

  55. Anonymous says:

    Amyloid > Oligomers > Calcium-permeable pores in cell membranes > Cells struggle overtime to maintain homeostasis > Oxidative Stress > Free radicals (including peroxynitrites) and hyperphosphorylation > Inflammation > Apoptosis > Dementia
    There, done. Not so complicated, is it?

  56. David says:

    I just saw “yet another breakthrough in Alzheimer research” here:
    I would love to know if this is real.
    One quote from the article:
    “It’s the first insight to us changing the course of the disease, that’s what’s new here,” says Dr. Dean Hartley, of the Alzheimer’s Association.

  57. David says:

    Sorry… seems like more spin on the same drug.

  58. steve says:

    @56 – Hi Lane. My point is that the first step in your cascade isn’t all that likely since primates accumulate lots of amyloid but don’t get cell damage.

  59. Anonymous says:

    56 was just sarcastic.

  60. Harrison says:

    @48 (Ayatollah): I think your comment is quite on point. The disease endpoint we are talking about is dementia. One of the presentations at AAIC said 54% of Dementia is AD, 16% is Vascular Dementia, and 30% is other (DLB, FTD, or a mix). To make things even more muddled, 5% of AD cases are early onset, but only about 2.5% of those are accounted for by APP/PS1. ApoE4 may account for up to 60% of the Late-onset cases (but even two copies of ApoE4 still requires something else). That means at least 37.5% of the cases are related to a wide array of yet to be discovered factors. I think whole genome sequencing will eventually be needed and we will have to treat dementia the way we are starting to treat cancer: you match up the treatment to the genotype. It would be quite ludicrous to give an Amyloid antibody to somebody with vascular dementia, which is why amyloid imaging is being used to screen patients now. It still might not be enough of diagnostic as it only modestly correlates with symptoms.

  61. Anonymous says:

    @59 Steve: #56 here, and I’m not Lane. But I did mention where peroxynitrites fit in, in case Lane was reading. Also, tau fits in with hyperphosphorylation. But still, everything is downstream and completely explained by aggregation of amyloid into toxic pores that breach the cell membrane. And primates may well accumulate amyloid as insoluble plaques which are inert, but there is no evidence that amyloid can form such pores in primates, so that may explain why they don’t develop the same pathology. Or maybe they just don’t live long enough to develop it. But in any case, this mechanism is entirely credible and consistent with everything that we have observed to date, including the fact that antibodies are unable to block or reverse the formation of these pores.

  62. Eric says:

    Excellent discussion – a rarity with most blogs! It’s one of the reasons I keep coming back here.
    The more I think about these results the less encouraging they appear to me. An interesting question to ask is: if Lilly had switched everyone to placebo when they extended the study rather than switching everyone to sola – what would you hypothesize would happen? Presumably the placebo group would continue on their steady course of disease progression (which is essentially what happened). The sola group (which had now been switched to placebo) would also presumably continue with the exact same disease progression now that the excess amyloid is not being removed. The two groups would progress in parallel, which is remarkably like what was observed.
    So I wonder, did we really learn anything at all with this study design?

  63. Anonymous says:

    @63. “So I wonder, did we really learn anything at all with this study design?”
    I’d like to say we learned that we can be tricked by statistical noise, but I guess we haven’t yet. The wild goose chase continues…

  64. steve says:

    @62 – My understanding is that the protein sequence is 100% conserved between human and non-primate so it’s hard for me to believe that amyloid forms cell damaging pores in humans but only benign plaques in NHP. Again, not my field but from the outside looking in it doesn’t make much sense.

  65. Anonymous says:

    @65 Steve: You might be right, but then again the life expectancy of a chimp is about 50 years, long before most people develop AD.

  66. Anonymous says:

    …and in any case, if primates don’t develop AD then they are not good models to compare with humans anyway, regardless of the mechanism, and for whatever reason.

  67. Anonymous says:

    What is known about amyloid glycosylation? Time and again you’ll see mABs fail in in vivo studies because people have been trained too much in classical biology, where they think of proteins only as proteins. They almost always ignore or completely forget that virtually all extracellular proteins are glycosylated, and once they develop an antibody that is capable of binding to both a portion of the carbohydrate antigen and part of the protein backbone do they really see efficacy with a mAB.

  68. Anonymous says:

    I think part of the problem that needs to be mentioned more explicitly is that we are trying to interrogate a clinical phenotype (e.g., dementia) with chemical tools developed with an incomplete mechanistic understanding of the disease at the molecular level, and in preclinical species where the system under interrogation is not identical at the cellular and physiological levels to that in human.
    Kind of building a bridge between two countries using different metric units in their blueprints… and when we get to the center, the two half-bridges don’t meet…
    Complex diseases may need more complex ways of thinking and knowledge that the soft biological hypotheses we have these days…

  69. steve says:

    @67 – I think this is where we differ in philosophy. If I see an observation that clearly is in conflict with my hypothesis then I would want to know why. Primates accumulate lots of amyloid towards the end of their life like humans do but don’t have the cell damage you hypothesize is the trigger for the disease. The protein is the same and presumably the mechanism of accumulation is the same. Rather than just dismiss the observation, which directly contradicts the theory that amyloid is causative, I would investigate why primates accumulate the levels of protein but don’t get any damage. Maybe (just maybe) there’s something wrong with the hypothesis.

  70. steve says:

    @70 – I don’t know if you’re the same “Anon” but interesting article. If true it disproves the idea that other non-human primates that accumulate amyloid but don’t get neurodegeneration don’t do so just because they don’t live to be 70 or 80. It’s therefore still a puzzle that other monkeys (e.g., macaques) get lots of plaque but no neurodegeneration. Maybe comparing macaques vs vervets would give some insight into why and what the underlying cause really is.

  71. anon says:

    Please consider the link in post 70. Green African Monkeys appear to develop some of the cognitive clinical features of AD.

  72. anon says:

    Please consider the link in post 70. Green African Monkeys appear to develop some of the cognitive clinical features of AD.

  73. steve says:

    I already answered the link in post 70; vervet get neurodegeneration but macaques (which accumulate substantial amyloid) do not. See for review.

  74. Bernard Munos says:

    @62, Eric
    Agree. In fact, if sola is ineffective, LLY’s trial design amounts to switching everyone to placebo, with gradual parallel decline in both groups — which is what was observed. And if sola is effective, why did we not see more of a treatment response?
    LLY’s reasoning to explain why the late-starters would not be able to catch up with the early-starters looks awfully contorted, and based on bizarre logic. It could be true or not depending upon how sola’s interference with the amyloid cascade impacts disease progression. We really don’t know.
    It would have been a lot clearer if LLY had kept a placebo arm in its trial, allowing treated arms to be compared to placebo. Perhaps that was not possible, and we will have to wait for the results of EXPEDITION 3.
    More alarming for LLY, is the failure of Biogen’s trial. The interim Feb results rekindled the excitement about beta-amlyloid, raising hopes that LLY’s compound would bolster the hypothesis that early treatment would be disease-modifying. It turned out that the hype about Biogen’s compound was unjustified, and unfortunately the evidence from LLY’s EXPEDITION program is far less than clear-cut.

  75. Robert Miles says:

    The protein that forms amyloids has a second function – absorbing certain types of free metal ions, especially copper. Have they tested whether their method of blocking amyloid formation also blocks this second function, and therefore blocks control of damage from metal ions that the brain can only bind in the amyloids, and cannot remove from the brain?

  76. Anonymous says:

    @71/72 Steve: That’s because you’re looking at accumulation of amyloid plaques instead of soluble oligomers. The plaques are known to be non-toxic, and don’t correlate well with AD and neurodegeneration in humans let alone primates. So yes, if one supposes that amyloid plaques cause the disease then the hypothesis is simply wrong. But that doesn’t mean amyloid oligomers don’t cause the disease. See my posts above again about calcium-permeable amyloid pores. These have not been observed in primates for whatever reason.

  77. steve says:

    @79 – This may be an interesting read
    I like the quote from Popper at the beginning:
    “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.”

  78. Anonymous says:

    @80: I didn’t say this theory is the only possible one, but I am saying that you don’t have any evidence to eliminate it yet.

  79. steve says:

    Read the review; I’m not trying to eliminate it just saying there are a lot of things that don’t make sense, at least from an outsider looking in (though sometimes that helps from getting trapped in the prevailing Weltanschauung).

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