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Alzheimer's Disease

Lilly’s Alzheimer’s Data

That’s a post title that I could have used eight or ten times over the lifetime of this blog – Eli Lilly has been hammering away at Alzheimer’s for a long time now. They have yet another anti-amyloid antibody study out this week, and (as has happened over and over in this area) it as preceded by talk of interesting, tantalizing possible efficacy. Maybe possibly we might finally perhaps see something that sort of works?

Well, I’m not exactly overwhelmed. The study had 131 patients in the treatment group and 126 patients in the placebo controls. The treatment group got the antibody, donanemab, every four weeks for up to 72 weeks of treatment. That’s one of the the things about any Alzheimer’s trial – it’s a long, slow disease, and that means that any meaningful trial is going to be similarly long, slow, and very expensive. The primary outcome was a rating on the Integrated Alzheimer’s Disease Rating Scale, with secondary outcomes being ratings on a whole list of other assessment scales. In the end, the treatment group showed a (barely) significant change in the iADRS scores, but did not reach the the change in that scale that it was designed to be able to measure. No significant change was seen in the main secondary outcome, the CDR-SB assessment (there was an improvement, but it just missed statistical significance). The ADAS-Cog13 score looks like it might have been a bit different, but the paper notes that it partly depends on the CDR-SB assessment, and since that one failed no conclusion can be drawn. The other two scores (ADCS-iADL and MMSE) showed no change.

There are also biomarker outcomes looking at amyloid and tau levels, but you know what? I honestly don’t care about those, because they have never, in my view, shown any strong correlation with the real-world effects of Alzheimer’s disease. They didn’t here, either: the patients who showed the biggest decrease in brain amyloid were not correlated at all with any particular clinical improvement. Frankly, what does it mean if a patient has less amyloid protein if they’re just as impaired with or without it? The real-world effects that we do care about (memory, orientation, function) are measured by the ratings just mentioned, and to me this looks like yet another therapy that simply does not work. 131 patients is not a huge number of patients (this is just a Phase II trial), and seeing one barely significant result in one cognitive rating scale – while the others all showed no difference – does not inspire much confidence. The paper tries to make something out of a Bayesian disease progression model, but I can’t make myself care much about that, either, because the treatment differences that anyone could possibly notice are just not there. Everyone in this trial deteriorated (it’s Alzheimer’s), but the treatment group deteriorated at a slightly slower rate that could only be seen by very close attention to the statistics, and even then only by some measures (barely) and not by others. And as Matthew Herper and Adam Feuerstein noted at STAT (in a very good article) it looks like the treatment group and placebo group are coming together as the trial goes on, anyway.

And if you look at the paper’s Figure 1, you’ll see that these patients were out of 1955 patients who were assessed for eligibility, most of whom (1563) were turned down for “screening failure”. In the supplementary material, you see that 592 of them failed a tau-imaging PET scan with flortaucipir, 347 of them either failed an MMSE evaluation or had no historical tau PET data (an odd pair of factors to put together), 334 of them failed the CogState Brief Battery evaluation, etc. In other words, these patients were very carefully selected (early stages of the disease, clear evidence of classic Alzheimer’s pathology by brain imaging) – these are people for whom you would expect the best chances of donanemab working. With the results shown. I don’t believe I’ve mentioned yet that the treatment group, showed (on imaging) a greater decrease in whole-brain volume and an increase in ventricular volume as compared to the placebo group. If someone wanted to run with a headline of “Experimental Alzheimer’s Drug Shows Efficacy” I would object, but if they wanted to go with “Experimental Alzheimer’s Drug Shows Brain Shrinkage”, I would say that the data support that view much more strongly. The paper calls these changes “paradoxical”.

One more complication, also highlighted by Herper and Feuerstein: one of the problems that’s been noted in past amyloid-antibody trials is “amyloid-related imaging abnormalities with edema”, or ARIA-E, which (as the name implies) is swelling in the brain. (Maybe that would cancel out the shrinkage?) Anyway, there were patients who had to drop out of the trial because of this effect, which mostly seem to happen with people who have the APOE4 gene variant (which also causes worse Alzheimer’s outcomes). The STAT authors spoke with an investor looking over the trial data who says (correctly, from what I can see) that what efficacy the trial showed could have been driven by the survivorship bias introduced when these patients dropped out (which happened around the midpoint of the trial). Lilly argues against that, naturally, but remember, we’re talking about the ragged edge of statistical significance in either case.

I still don’t see how any of the effects seen in this trial translate into any real-world benefits. Even if they’re real, and there’s definitely reason to doubt that. I’m sticking with what I said nearly ten years ago about another failed Lilly antibody: there’s a nasty moral hazard in this business of marginal, hazy, Alzheimer’s statistical benefits, because the first company that manages to get anything approved by the FDA will reap billions of dollars from the huge backlog of desperate patients and families who want something, anything, that they can use against the disease. I feel the same way about Biogen’s aducanumab.

Of course, there is a Phase III underway already for donanemab – as the paper says, “longer and larger trials are required to study the efficacy and safety”. Well, what’s for sure is that longer and larger trials will be required to make Lilly give up on it. That much seems certain.

37 comments on “Lilly’s Alzheimer’s Data”

  1. David says:

    There’s something definitely strange going on with brain volume measures in AD trials. The resveratrol trial showed marginal benefits on biomarkers for treatment, but also showed greater brain volume loss in the treated group. (Turner Neurology. 2015 v85(16): 1383–1391). BACE inhibitors seem to reduce Abeta, but the class seems to be associated with worsening of function, as compared to placebo (Hrabinova et al Curr Neuropharmacol 2021 v19(1):61-77). Specifically verubecestat was associated with hippocampal volume loss (Sur et al Brain 2020 v143(12):3816-3826).

    It’s one thing to keep running trials blocking Abeta when prior trials have been equivocal, but there is accumulating evidence suggestive of harm.

    1. Ian Malone says:

      There’s a suspicion that inflammation may partially be to blame for this.

    2. M.Striker says:

      I’ve seen recent (past 6 months) research concerning brain adaption (how brains strengthen pursued interest linkages by auto-pruning) and why “sitting=bad”. Could the same process of neural adjustments be causing brain shrinkage?

  2. Mister B. says:

    Based on your experience and knowledge, what would be the “best” hypothesis on AD now ?

    The amyloid hypothesis gave, so far, no result.
    What would one should try to explore now ?

    I don’t want to give up on this too easily.

    Thanks !

    1. John M says:

      The 2018 Nature article linked in my URL does a decent job of listing the alternative hypotheses. Skip down to the “Neglected opportunities” section. Here they are in bullet form:
      – Amyloid-β and tau need to be simultaneously targeted
      – Inflammation-driven microglial overactivity
      – Microbial or viral infection with e.g. HSV

    2. Crocodile Chuck says:

      Brain infection via an increasingly leaky blood: brain barrier.

    3. Rtah100 says:

      The cell cycle hypothesis. CNS neurons re-enter the cell cycle in normal behaviour because neuronal plasticity reuses the machinery of G1. They are constantly shuttling between G0 and G1 but do not progress further because the G1/S checkpoint is tightly patrolled in neutrons (cell division is ruinous if you are supposed to encode memories by your shape and connectivity!).

      In AD patients, the G1/S checkpoint is incompetent. Neurons can pass beyond but this commits them irreversibly to a cell division they cannot achieve. They get stuck in G2. The biochemistry of the G2 phase is responsible for hallmark tau and amyloid pathology: phosphotau produce within the cell by upregulated kinases and disassembled cytoskeleton tau and Abeta by phosphorylated APP having altered processing on cell membrane. Numerous neuropath studies have shown neurons with doubled chromosomes, e.g. Braak, Smith, Nagy.

      1. LdaQuirm says:

        If this were the mechanism, it would be untreatable without gene therapy right?

        1. HFM says:

          I’m far into the hand-waving edges of my knowledge here, but I suspect that whatever the underlying biology, we could find somewhere to wedge a small molecule into the works such that the G1/S blockade gets stronger. The trick would be doing this in a way that does not interfere with cells that really should be dividing. Nobody wants to spend their golden years on something that’s basically chemo, even if it does slow down their Alzheimer’s.

    4. M.Striker says:

      Based on the data of Mexico city children brains showing AD-like changes, I’ll propose micro-particulate mitigation (maybe via a chelation therapy) as a route.

      ( ; abstract read on

      As micro-particles of titanium dioxide have been found in diabetic pancreases ( (included to point out an unexpected long-term mineral inclusion issue), chelation may be viable for the elderly and the overexposed.

    5. M.Striker says:

      Mister B:
      Micro-particulate chelation (based on “Hallmarks of Alzheimer disease are evolving relentlessly in Metropolitan Mexico City infants, children and young adults. APOE4 carriers have higher suicide risk and higher odds of reaching NFT stage V at ≤ 40 years of age” (on Elsevier or Science Direct) and brain plasticity research and “Possible link found between diabetes and common white pigment” (Science Daily)).
      Or, determining how to mitigate the damage triggered by said micro-particles – like (blue-sky guesswork) higher doses the hindered cellular signal precursors. (Kind of like how NMN from broccoli promotes NAD production in cells.)

      Apologies if my earlier response has already posted. I’m posting this one in case the 2 included page links hindered the earlier response from posting, and I think this is worth pursuing.

  3. metaphysician says:

    So, time to ask a stupid question: how many more trials have to turn out like this before we declare the Amyloid Hypothesis disproven.

    Note: don’t tell me “but genetics”. The Amyloid Hypothesis is not just “Alzheimers is caused by a mishandling of amyloid proteins,” its also “and so we can do something about it by targeting said proteins medically”.

    1. Ian Malone says:

      Tau PET is increasingly showing us that disease progression tracks closely to tau accumulation. (So, I’m not sure about Derek’s “I honestly don’t care about [amyloid and tau levels], because they have never, in my view, shown any strong correlation with the real-world effects of Alzheimer’s disease.” On the tau front anyway.)

      One common working hypothesis is now that amyloid build-up increases the brain’s vulnerability to tau spread, which is what does the damage. While amyloid seems to be deposited fairly broadly across the brain, tau seems more closely associated with the regions that are being affected. That wouldn’t mean the amyloid hypothesis (in the ‘disease modifiable’ form) was utterly wrong, but would require removing amyloid before tau started up, well before any symptoms. Which is not terribly useful and a difficult trial to run. Targetting tau is the next move, there are some therapies being tried already.

  4. JeffC says:

    I’m with Derek. The amyloid hypothesis is dead. It’s done. All we’re doing is trying to change something once the horse has bolted so to speak.

    Let’s use the pandemic as an example. Let’s say we had no idea that COVID was caused by a virus? So all of these people are dying on ventilators and we’re seeing all of these weird cardiovascular effects. So we treat the heart disease. We try to tamp down the inflammation. People still die. What’s going on we ask? Let’s keep hammering away at the cardiovascular effects…..

    We do need to really look at Alzheimers differently. It’s pretty clear that in a lot of patients we find viruses floating around and less in those without Alzheimers. Personally, I am immediately suspicious when I see a virus in a patient. Viruses are never fully silent; they should not be there. So my first hypothesis to test would be to see if we eliminate the virus (and I vote for HSV), do we see some disease arrest or improvement? If we treat early do we get a better effect? It seems to be worth testing in my view. When every single current approach has failed you have to admit that the biology is telling us something.

    1. confused says:

      >> Let’s say we had no idea that COVID was caused by a virus? So all of these people are dying on ventilators

      Isn’t this (minus the ventilators, that didn’t exist yet) basically what happened in the 1918 flu pandemic, when flu was thought to be caused by the bacterium Haemophilus influenzae (which turned out instead to be a secondary infection)? IIRC there were various desperate attempts to treat it on that basis…

    2. Harvey says:

      So if an HSV is associated, would we expect populations with less HSV to have less Alzheimer’s and can we identify such populations? Do nuns (who presumably have had, in general, less opportunities for HSV transmission) show reduced rates of Alzheimer’s? What about couples who were completely monogamous without any prior partners? (And I realize that would be very hard to verify, but presumably anonymous self-reporting might show a trend). I also realize that oral contact might be the cause, which would be even harder to tease out.

      1. cynical1 says:

        Neither HSV-1 nor HSV-2 is ubiquitous in the adult population which would make it rather easy to rule in or out with simple epidemiology. That is unless Alzheimer’s is multiple diseases and HSV-1 and/or HSV-2 causes only a portion of them. In theory, you could also rule in or out whether they were protective as well. It’s a really simple study. HHV-6B is another story. Everyone has that virus so then you have to figure out if it is causing disease in only a portion of the population by a mechanism unique to those with the disease.

    3. Weifeng Zhang says:

      The hypothesis of beta amyloid would not be truely dead except we separated autosomal dominant Alzheimer`s disease with sporadic AD with a certain approach, maybe including dementia emerged at the late stage of Down syndrome. We are still being stuck to the pathologic observation related amyloid plaques and tau tangles while there are really a handful nuances between them.

      Frankly, I really doubt the exact figures of AD`s incidence and prevalance if the high screening failure rates due to beta amyloid and tau PETs reflects something. Above all, PETs are far away from pervasive in the diagnosis of AD. Would it be better to redefine Alzheimer`s disease?

  5. Cassandra says:

    As someone who has been active in the AD area for a while, I find the continued emphasis on amyloid-directed therapies to be dismaying. It has been clear for some time that amyloid is just not a good drug target if you want to see meaningful benefits for AD patients. Continuing to pour money into this approach draws resources away from other ideas and contributes to the exodus of large players out of the area.

    Personally, I think the concept of “genetically validated” targets has been detrimental in the CNS space. It is true that genetic risk factors like APOE/AD or GBA/PD can inform understanding of disease biology, but it is a fallacy to assume that genetic association equates to a good target for therapeutic intervention. The reality is that we do not understand the underlying biology well enough to pick good targets for CNS disease. And efficacy in iPSC-derived neurons or transgenic mice is just a hoop to jump through; in and of themselves, these models have very little predictive value.

    I tend to think that some of the old-school empirical approach would be useful for CNS drug development – namely, trying different conceptual approaches with molecules that have a well-defined MOA. But that’s a tough sell in today’s concentrated, sclerotic, and risk-averse pharma CNS landscape. The old-timers can tell you about when immuno-oncology was some loopy idea that no one thought was going to work. Time to try a few of those for neurodegeneration.

    1. Adam Fogel says:

      As someone who worked in PD research for much of my postdoc and first stint in industry (thankfully I have since moved into a new field), I think this comment pretty much gets it all correct.

      The existing mindset/dogma may unravel the some of the mechanisms (although very slowly because the models recapitulate very little of the actual disease) but for real treatment benefit it seems like a totally new approach is needed.

  6. gippgig says:

    A treatment was recently shown to work in mice: Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease
    Science Signaling 14 eabc5429 doi: 10.1126/scisignal.abc5429
    Of course, there are lots of things that work in mice but don’t work in humans.

  7. Todd says:

    At this point, I’m way more interested in antivirals and antibiotics for Alzheimers. It at least passes the laugh test more than Amyloid at this point.

    1. Marko says:

      Amyloid as part of the innate immune response to brain infection makes a lot of sense to me:

      1. Mammalian scale-up person says:


        Source: worked on anti-abeta @ Wyeth. It seemed like a good idea at the time, but no matter what we tried, all clinical trials had the same pattern – doesn’t seem very toxic, initial Phase 2a looks promising, Phase 2b was “oh look at this interesting subgroup” and Phase 3 got nothing.

        Everyone has tried. We have thrown more money than Elon Musk at this thing. It’s not a lack of trying, or not smart enough people, or not enough motivation (and a hearty fk you to the non-pharma people who think we all don’t have parents dying of this to sufficiently motivate us). What seems to work anecdotally is intrathecal dosing of anti-inflammatories, but it’s very temporary – however, that does seem to support the infectious disease cause. DOI: 10.2147/ndt.s3685, doi: 10.1111/j.1532-5415.2011.03445.x. And many other infectious diseases have been found similar to Marko’s paper on herpesvirus – chlamydia, Porphyromonas, Hep C, CMV, Helicobacter, Toxoplasma. doi: 10.2174/1570159X15666170313122937

  8. Keith says:

    Gee…why doesn’t anybody seem to think it’s a metabolic disease or at least an immunometabolic disease?

  9. Surfactrant says:

    Tau levels have a much higher correlation to cognition than AB.
    So maybe not ready to throw Tau under the AB bus just yet.

  10. Picky Picky Picky says:

    Should “make something about of” read “make something out of”?

  11. MTK says:

    Not my area of expertise by any means, but a few years ago I spoke to someone who is, and his belief was that Alzheimer’s, and many other CNS conditions, isn’t even a disease per se. It’s a conglomeration of different diseases that all manifest themselves in a similar fashion and that we group together based on symptomology. If true, that would make any general hypothesis regarding cause or treatment limited at best. It would be like finding a “cure for cancer”, which can’t exist because there’s no such singular disease, but rather many different conditions that we group together based on unchecked cell replication.

    1. Peter Lansbury says:

      MTK, you are exactly right. This is the central problem in the field. There is a huge amount of data to support the idea that AD is not a single disease, but a collection of related diseases with different underlying causes. In fact, the one thing that argues for a single disease is amyloid (talk about circular logic), which is also present in many cognitively normal elderly.

  12. albegadeep says:

    What’s the probability that amyloid and tau are side effects/symptoms of the real cause? Thus treating those symptoms doesn’t have any effect on the other effects of the disease.

  13. TallDave says:

    “but the biomarkers!” is becoming a clarion call of futility across so many diseases

    suggests there is much more we do not yet understand

  14. ScientistSailor says:

    There are so many people who are going to have AD in the very near future, we really need to figure out how to care for them all humanely without bankrupting ourselves. It’s already too late for disease-modifying therapies for tens of millions of people, time to get real…

    1. metaphysician says:

      And what if the answer is “Sadly, there is no way to treat symptomatic Alzheimers with any technological means available within the next century”?

      That there is a large problem does not mandate that there must exist a usefully large solution.

      1. ScientistSailor says:

        I didn’t say ‘treat’, I said ‘care for’, specifically because there is no disease-modifying therapy on the horizon for the tens of millions of people who are already 65+ YO. We need to learn how to care for these people during their now inevitable decline.

  15. Antidote says:

    Alzheimer’s is a metabolic disease. It is the insulin resistance of the brain, which causes insufficient glucose influx and energy deficit. Brains starve. When dietary recommendations prefer eating 5-6 times a day, insulin never gets down to enable ketone bodies to surface. Brains do not get that fuel either. Metabolic errors can not be corrected by a single medicine.

  16. Barry says:

    Measuring levels of amyloid, and of tau may be irrelevant to curing AD, but they’re critical to falsifying the amyloid hypothesis. A drug candidate that knocks down amyloid w/o stopping AD kills that hypothesis. And that’s how science moves forward.

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