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The article says: Yet despite decades of research, no treatment has been created that arrests Alzheimer’s cognitive deterioration, let alone reverses it. Nowh

• caycep 2y ago
  yeeeess...but when you look at the slope of the decline on the NEJM papers describing the clinical trials of lecanumab and donemumab...are you really slowing the decline?
  • DavidSJ 2y ago
    To be clear, I think you're asking whether maybe the drugs just provide a temporary "lift" but then the disease continues on the same basic trajectory, just offset a bit? The studies aren't statistically powered to know for sure, but on lecanemab figure 2, the between-group difference on CDS-SB, ADAS-Cog14, ADCOMS, and ADCS-MCI-ADL (the four cognitive endpoints) widens on each successive visit. Furthermore, while not a true RCT, the lecanemab-control gap also widens up to 3 years in an observational study: https://www.alzforum.org/news/conference-coverage/leqembi-case-long-term-dosing https://www.alzforum.org/news/conference-coverage/leqembi-ca... On donanemab figure 2, there is generally the same pattern although also some tightening towards the end on some endpoints. This could be due to the development of antidrug antibodies, which occurs in 90% of those treated with donanemab; or it could be statistical noise; or it could be due to your hypothesis.
    • caycep 2y ago
      What kind of soured me on whether to recommend lecanumab in the clinic or not - the effect size and the slope, vs. the risk of hemorrhages/"ARIAS". I mean, if you're looking at an steady 0.8 pt difference in CRS-SB, but the entire scale is 18 points, yes, it's "statistically significant" w/ good p-values and all, but how much improvement is there really in real life given that effect size? Plus, if one is really going to hawk something as disease modifying, I'd want to see a clearer plateauing of the downward slow of progression, but it's pretty much parallel to the control group after a while. There is some chatter in the Parkinson's world - the issue and maybe the main effort isn't so much clearing out the bad stuff (abnormal amyloid clumps/synuclein clumps) in the cells, it's trying to figure out what biological process converts the normal, functioning form of the protein into the abnormal/insoluble/nonfunctional protein.....at least assuming amyloid or synuclein is the root problem to begin with...
      • DavidSJ 2y ago
        What kind of soured me on whether to recommend lecanumab in the clinic or not - the effect size and the slope, vs. the risk of hemorrhages/"ARIAS". I don't claim that it's obviously the right move for every Alzheimer patient at the moment. It would be great to increase the effect size and reduce ARIA rates. My central claim, again, is that the amyloid hypothesis is correct, not that we have a cure. the issue and maybe the main effort isn't so much clearing out the bad stuff (abnormal amyloid clumps/synuclein clumps) in the cells, it's trying to figure out what biological process converts the normal, functioning form of the protein into the abnormal/insoluble/nonfunctional protein Yes, but it appears that these are one and the same thing. That is, amyloid and tau (mis)conformation seems to be self-replicating via a prion-like mechanism in locally-connected regions. This has been established by cryo-electron microscopy of human proteins, as well as controlled introduction of misfolded proteins into mouse brains.
• getnormality 2y ago
  Downvoters, are you sure you have a rational basis for downvoting this informative post? Do us HNers really know enough to discredit the amyloid hypothesis when 99.9% of us know nothing other than it's gotten some bad press in recent years? I googled lecanemab and it does have the clinical support claimed. I don't see anyone questioning the data. I'm as surprised as anyone else, even a little suspicious, but I have to accept this as true, at least provisionally. For anyone who wants to start grappling with the true complexity of this issue, I found a scholarly review [1] from October 2024. [1] The controversy around anti-amyloid antibodies for treating Alzheimer’s disease. https://pmc.ncbi.nlm.nih.gov/articles/PMC11624191 https://pmc.ncbi.nlm.nih.gov/articles/PMC11624191
  • mhb 2y ago
    How do you know what the downvote status is?
  • BobaFloutist 2y ago
    https://www.reddit.com/r/medicine/comments/1057sjo https://www.reddit.com/r/medicine/comments/1057sjo fda_oks_lecanemab_for_alzheimers_disease/ "Lecanemab resulted in infusion-related reactions in 26.4% of the participants and amyloid-related imaging abnormalities *with edema or effusions in 12.6%*." https://en.wikipedia.org/wiki/Cerebral_edema https://en.wikipedia.org/wiki/Cerebral_edema "After 18 months of treatment, lecanemab slowed cognitive decline by 27% compared with placebo, as measured by the Clinical Dementia Rating–Sum of Boxes (CDR-SB). This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemab vs 1.66 with placebo; P < .001)" https://www.understandingalzheimersdisease.com/-/media/Files/uAD/Clinical-Assessment/CDR-Brochure.pdf https://www.understandingalzheimersdisease.com/-/media/Files... Sum of boxes is a 19 point scale. So, for those keeping track at home, this is an incredibly expensive treatment that requires premedication with other drugs to control side affects as well as continuous MRIs for an ~%2.3 absolute reduction in the progression of dementia symptoms compared to placebo, with a 12% risk of cerebral edema. Now, I'm no neurologist, but I'd call that pretty uninspiring for an FDA-approved treatment.
    • DavidSJ 2y ago
• msandford 2y ago
  There is anecdotal evidence and perhaps even some small studies showing that a keto diet can halt and even reverse Alzheimer's symptoms. Compared to that, reducing the speed of decline isn't terribly impressive. It's better than nothing to be sure! But what people want is BIG progress, and understandably so. Billions have been spent.
  • DavidSJ 2y ago
    Billions have been spent because it's a challenging disease to understand and treat. I want big progress too. But we shouldn't let our desire for big progress cause us to lose our ability to objectively evaluate evidence. I have no opposition to a properly controlled randomized controlled trial of the keto diet, or other proposed therapies (many of which have been conducted, and are for targets other than amyloid which are completely compatible with the amyloid hypothesis). Until a proper RCT of keto is conducted, anecdotal claims are worth very little compared to the evidence I referred to.
    • stefantalpalaru 2y ago
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    • msandford 2y ago
      I'm far, far more interested in anecdotes about completely halting or reversing decline than I am in rock solid data about a 30% reduction in decline speed. Antibiotics started out as an anecdote about something whose effect was so stark it couldn't be missed. Chasing promising anecdotes is far more valuable (in my opinion) than attempting to take a 30% effect to a 100% effect. Others are free to feel differently of course. I'm open to hearing about 100 different times that finding a tiny effect that got grown and magnified into a huge effect that totally changed medicine. I'm just not aware of many at this point.
      • DavidSJ 2y ago
        You can be interested in what you want. But the interest in anti-amyloid therapy came from the basic science indicating amyloid pathology as the critical but-for cause of the disease. It wasn't just a blind shot in the dark. To my knowledge, there's no such basic science behind a keto diet for Alzheimer's.
• kraussvonespy 2y ago
  Those quoting the 30% figure may want to research where that figure comes from and what it actually means: “Derek Lowe has worked on drug discovery for over three decades, including on candidate treatments for Alzheimer’s. He writes Science’s In The Pipeline blog covering the pharmaceutical industry. “Amyloid is going to be — has to be — a part of the Alzheimer’s story, but it is not, cannot be a simple ‘Amyloid causes Alzheimer’s, stop the amyloid and stop the disease,'” he told Big Think. “Although the effect of the drug will be described as being about a third, it consists, on average, of a difference of about 3 points on a 144-point combined scale of thinking and daily activities,” Professor Paresh Malhotra, Head of the Division of Neurology at Imperial College London, said of donanemab. What’s more, lecanemab only improved scores by 0.45 points on an 18-point scale assessing patients’ abilities to think, remember, and perform daily tasks. “That’s a minimal difference, and people are unlikely to perceive any real alteration in cognitive functioning,” Alberto Espay, a professor of neurology at the University of Cincinnati College of Medicine, told KFF Health News. At the same time, these potentially invisible benefits come with the risk of visible side effects. Both drugs caused users’ brains to shrink slightly. Moreover, as many as a quarter of participants suffered inflammation and brain bleeds, some severe. Three people in the donanemab trial actually died due to treatment-related side effects.” https://bigthink.com/health/alzheimers-treatments-lecanemab-donanemab/ https://bigthink.com/health/alzheimers-treatments-lecanemab-... And here’s a Lowe follow-up on hard data released later: https://www.science.org/content/blog-post/lilly-s-alzheimer-s-data-donanemab https://www.science.org/content/blog-post/lilly-s-alzheimer-...
  • DavidSJ 2y ago
    “Amyloid is going to be — has to be — a part of the Alzheimer’s story, but it is not, cannot be a simple ‘Amyloid causes Alzheimer’s, stop the amyloid and stop the disease,'” It's not quite that simple, and the amyloid hypothesis doesn't claim it to be. It does, however, claim that it's the upstream cause of the disease, and if you stop it early enough, you stop the disease. But once you're already experiencing symptoms, there are other problem which clearing out the amyloid alone won't stop. What’s more, lecanemab only improved scores by 0.45 points on an 18-point scale assessing patients’ abilities to think, remember, and perform daily tasks. As I point out in another comment, the decline (from a baseline of ~3 points worse than a perfect score) during those 18 months is only 1.66 points in the placebo group, It's therefore very misleading to say this is an 18-point scale, so a 0.45 point benefit isn't clinically meaningful. A miracle drug with 100% efficacy would only achieve a 1.66 point slowdown.
• oaktrout 2y ago
  From what I've read, those drugs are very good at removing amyloid, but despite that, they don't seem to make much of a noticeable (clinically meaningful) difference in the people treated with them. I personally would not call that a "huge success". If they are so good at cleaning up the amyloid, why don't people have more of an improvement? I think everyone agrees amyloid is associated with Alzheimer's, the question is how much of a causative role does it play.
  • DavidSJ 2y ago
    From what I've read, those drugs are very good at removing amyloid, but despite that, they don't seem to make much of a noticeable (clinically meaningful) difference in the people treated with them. I personally would not call that a "huge success". After many decades of research, we've gone in the last few years from no ability whatsoever to affect the underlying disease, to 30% slowdown. To be clear, that's a 30% slowdown in clinical, cognitive endpoints. Whether you call that "meaningful" is a bit subjective (I think most patients would consider another couple years of coherent thinking to be meaningful), and it has to be weighed against the costs and risks, and there's certainly much work to be done. But it's a huge start. If they are so good at cleaning up the amyloid, why don't people have more of an improvement? No one is expected to improve after neurodegeneration has occurred. The best we hope for is to prevent further damage. Amyloid is an initiating causal agent in the disease process, but the disease process includes other pathologies besides amyloid. So far, the amyloid therapies which very successfully engage their target have not yet been tested in the preclinical phase before the amyloid pathology initiates further, downstream disease processes. This is the most likely reason we've seen only ~30% clinical efficacy so far. I expect much more efficacy in the years to come as amyloid therapies are refined and tested at earlier phases. (I also think other targets are promising therapeutic targets; this isn't an argument against testing them.) I think everyone agrees amyloid is associated with Alzheimer's, the question is how much of a causative role does it play. To be clear, the evidence for the amyloid hypothesis is causal. The association between amyloid and Alzheimer's has been known since Alois Alzheimer discovered the disease in 1906. The causal evidence came in the 1990's, which is why the scientific community waited so long to adopt that hypothesis.
• jmward01 2y ago
  And that is the core problem with what happened. There may actually be a grain of truth but now there is a backlash. I'd argue though that the mounds of alternative explanations that weren't followed up on should likely get some priority right now since we know so little about them there is a lot to learn and and we are likely to have a lot of surprises there. I see this as the same problem with UCT (upper confidence for trees) based algorithms. If you get a few initial random rolls that look positive you end up dumping a lot of wasted resources into that path because the act of looking optimizes the tree of possibilities you are exploring (it was definitely easier to study amyloid lines of research than other ideas because of the efforts put into it). Meanwhile the other possibilities you have been barely exploring slowly become more interesting as you add a few resources to them. Eventually you realize that one of them is actually a lot more promising and ditch the bad rut you were stuck on, but only after a lot of wasted resources. To switch fields, I think something similar happened to alpha-go when it had a game that ended in a draw because it was very confident in a bad move. Basically, UCT type algorithms prioritize the idea that every roll should optimize the infinite return so it only balances exploration with exploitation. When it comes to research though the value signal is wrong, you need to search the solution space because your goal is not to make every trial find the most effective treatment, it is to eventually find the actual answer and then use that going forward. The trial values did not matter. This means you should balance exploration, exploitation AND surprise. If you do a trial that gives you very different results than you expected then you have shown that you don't know much there and maybe it is worth digging into so even the fact that it may have returned less optimal value than some other path its potential value could be much higher. (Yes I did build this algorithm. Yes it does crush UCT based algorithms. Just use variance as your surprise metric then beat alpha-go.) People intrinsically understand these two algorithms. In our day to day lives we pretty exclusively optimize exploration and exploitation because we have to put food on the table while still improving, but when we get to school we often take classes that 'surprise' us because we know that the goal at the end is to have gained -some- skill that will help us. Research priorities need to take into account surprise to avoid the UCT rut pitfalls. If they had for the amyloid hypothesis maybe we would have hopped over to other avenues of research faster. 'The last 8 studies showed roughly the same effect, but this other path has varied wildly. Let's look over there a bit more.'