4 ms·

>"The patients demonstrated improved brain function and showed a reduction in the protein plaque gumming up their neurons, the company’s report says." Still ch

by nonbel 8y ago

>"The patients demonstrated improved brain function and showed a reduction in the protein plaque gumming up their neurons, the company’s report says." Still chasing the amyloid hypothesis I see. This is a symptom, not a cause, so they are wasting their time (in terms of actually helping the patients, eventually someone will randomly get "positive" results and a bunch of money if enough trials are run). 1) Up to 30% of cognitively normal elderly have detectable amyloid deposits: https://news.ycombinator.com/item?id=17444214#17453147 https://news.ycombinator.com/item?id=17444214#17453147 2) Only 70% of dementia patients have detectable amyloid deposits: https://news.ycombinator.com/item?id=17444214#17445337 https://news.ycombinator.com/item?id=17444214#17445337 3) Amyloid-related genetics can only account for < 10% of Alzheimer's cases: https://news.ycombinator.com/item?id=17444214#17457198 https://news.ycombinator.com/item?id=17444214#17457198 4) Amyloids are the most thermodynamically favorable structure that polypeptides can form (ie require constant vigilance by the cell to prevent): https://news.ycombinator.com/item?id=14914528#14917057 https://news.ycombinator.com/item?id=14914528#14917057 5) Can anyone find a disease state where they looked for amyloids and didn't find a positive correlation? I doubt it.

fhood 8y ago
Assuming what you say is true, HN continues its trend of having great content for software and related topic, and being next to useless for meaningful physics or medical news. I didn't notice this till my buddy who is a physicist pointed out that almost all of the physics articles on here are either wrong, or wildly misleading. It would be nice if we could be better about vetting this stuff as a community.
- nonbel 8y ago
  >"Assuming what you say is true" Don't take my word for it. Follow the links to what the primary literature says. >"being next to useless for meaningful physics or medical news" Well, to be fair the "amyloid hypothesis" is still the mainstream hypothesis. It's just that this is for reasons that are baffling to me. Afaict, it has nothing going for it at all vs the prior "cholinergic" hypothesis (which has resulted in treatments that actually appear to do something for the patient).
  - vibrio 8y ago
    > the "amyloid hypothesis" is still the mainstream hypothesis. I agree with you. Amyloid may be the most popular but it isn't what it used to be 10-15 years ago (dogma). it has much weaker support. What is particular true and sad about what you've said is that it probably is the most popular but only due to lack of consensus on anything else. After running into the amyloid wall running at full-speed about a dozen times, significant chunks of pharma have nearly abandoned working on the disease, and put some funds into external research.
    - nonbel 8y ago
      Yea, but I don't even understand how it became dogma to begin with. The evidence was never that good for it.
      - vibrio 8y ago
        I'm in your camp and a previous career suffered for being there. I can't bear to count how many massive Phase 3 studies had to fail to raise doubts.
- pvaldes 8y ago
  You have a point, but a wrong statement can still lead to a interesting conversation. Just debunking it will help to the HN community.
SamBam 8y ago
> The patients demonstrated improved brain function If this part of the quote is actually true, then what you are saying is either wrong or irrelevant. They appear to have evidence it is true, and are continuing to verify it. There are various ways this could be helping (if it is): 1. The amyloids are a cause of Alzheimer's 2. The amyloids are a symptom of Alzheimer's, but are a cause of the memory impairments 3. The drug has a side-effect which helps the memory impairments. In any case, what is your expertise? I love random comments that say that scientists who have spent decades in a field are simply "wasting their time" because they haven't read some article that was posed on the web. (NB, this may not be the case with you, if you are indeed an expert in the field.)
- jcranmer 8y ago
  It's a Phase II trial, which means it is focused on identifying dosage ranges and side effects in human rather than a large-scale efficacy trial. (It's also the first time you actually give a drug candidate to humans). You also forgot that there is a fourth point: there is no actual effect, and the apparent effect is statistical fluke. It's hard to understand what could be going on from this article alone, because it spends a whopping 1.5 paragraphs on explaining any details about the putative vaccine. The rest of the piece reads as a generic PR fluff piece, which makes me think that this was largely based on company-provided PR and so anything approaching details is based on the most positive light that they can be spun into.
  - gumby 8y ago
    > ... a Phase II trial, which means it is focused on identifying dosage ranges and side effects in human rather than a large-scale efficacy trial. (It's also the first time you actually give a drug candidate to humans). FWIW your drug candidate is administered in all phases. Phase I you look for side effects ("safety and tolerability"). Phase II is, as you say, a dose ranging study, but you can't exceed dosages you've already tested for safety. You usually have multiple arms (a placebo and a couple of dosages); when you find an seemingly efficacious dose you then proceed to a Phase III where you test that dosage (or several) on a statistically representative enough sample to hopefully predict results in the population at large. (former drug designer who has designed some Phase I and II studies). == Fun fact: when you file your IND with the FDA to test a new drug you aren't actually asking for permission. You're asking them to tell you that if you follow the protocol you have sent them, based on the evidence you've sent them from what you know already, they won't prosecute you for violating the law on administering unapproved drugs. Section 505 for the food and drug law has a bunch of exceptions -- you ask then to tell you you fit in one of the exceptions. And if they don't tell you "no" in a 30 days...you can go ahead! I wonder if the shutdown extends that 30 days.
jcranmer 8y ago
Derek Lowe (of In the Pipeline, probably the most widely-read blog by a drug development scientist) had a funny take on the state of the amyloid hypothesis for Alzheimer's: http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-alzheimers-statement http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-... Considering that every single anti-amyloid Alzheimer's candidate has failed--even those that made it into Phase III trials--anyone suggesting something that attacks amyloids has to overcome a lot of skepticism.
- nonbel 8y ago
  Yep, exactly. It seems like something needs to be wrong/corrupted within Alzheimer's research to explain the continued obsession with this approach. As I said elsewhere in this thread, their behavior is baffling to me. In my experience, that usually means there is an ulterior motive somewhere.
tallanvor 8y ago
Honestly, by pointing to your comments from previous discussions, you look like you have an ax to grind rather than being helpful. The truth is that we don't know what causes Alzheimer's. Amyloids may or may not play as much of a role as some people think. But without a better hypothesis to test and get funding for, this is what they can do.
- nonbel 8y ago
  >"Honestly, by pointing to your comments from previous discussions, you look like you have an ax to grind rather than being helpful." I have no axe to grind. Just presenting the facts. Why would I requote everything? Nothing has changed since then. >"But without a better hypothesis to test and get funding for, this is what they can do." I mentioned the "better hypothesis" here. It is the only hypothesis that lead to treatments that seem to help at all: https://news.ycombinator.com/item?id=18922340 https://news.ycombinator.com/item?id=18922340
pstuart 8y ago
Do you have an ELI5 for your suspicions of cause and cure? (not snarky, genuinely curious).
- nonbel 8y ago
  No, just that it isn't going to be removing amyloid plaques. For the plaques to build up the neurons are clearly malfunctioning for some reason. Beyond that, who knows?
  - pstuart 8y ago
    No Nobel Prize for you!

by nonbel 8y ago

fhood 8y ago

Assuming what you say is true, HN continues its trend of having great content for software and related topic, and being next to useless for meaningful physics or medical news. I didn't notice this till my buddy who is a physicist pointed out that almost all of the physics articles on here are either wrong, or wildly misleading. It would be nice if we could be better about vetting this stuff as a community.

nonbel 8y ago
>"Assuming what you say is true" Don't take my word for it. Follow the links to what the primary literature says. >"being next to useless for meaningful physics or medical news" Well, to be fair the "amyloid hypothesis" is still the mainstream hypothesis. It's just that this is for reasons that are baffling to me. Afaict, it has nothing going for it at all vs the prior "cholinergic" hypothesis (which has resulted in treatments that actually appear to do something for the patient).
- vibrio 8y ago
  > the "amyloid hypothesis" is still the mainstream hypothesis. I agree with you. Amyloid may be the most popular but it isn't what it used to be 10-15 years ago (dogma). it has much weaker support. What is particular true and sad about what you've said is that it probably is the most popular but only due to lack of consensus on anything else. After running into the amyloid wall running at full-speed about a dozen times, significant chunks of pharma have nearly abandoned working on the disease, and put some funds into external research.
  - nonbel 8y ago
    Yea, but I don't even understand how it became dogma to begin with. The evidence was never that good for it.
    - vibrio 8y ago
      I'm in your camp and a previous career suffered for being there. I can't bear to count how many massive Phase 3 studies had to fail to raise doubts.
pvaldes 8y ago
You have a point, but a wrong statement can still lead to a interesting conversation. Just debunking it will help to the HN community.

SamBam 8y ago

> The patients demonstrated improved brain function If this part of the quote is actually true, then what you are saying is either wrong or irrelevant. They appear to have evidence it is true, and are continuing to verify it. There are various ways this could be helping (if it is): 1. The amyloids are a cause of Alzheimer's 2. The amyloids are a symptom of Alzheimer's, but are a cause of the memory impairments 3. The drug has a side-effect which helps the memory impairments. In any case, what is your expertise? I love random comments that say that scientists who have spent decades in a field are simply "wasting their time" because they haven't read some article that was posed on the web. (NB, this may not be the case with you, if you are indeed an expert in the field.)

jcranmer 8y ago
It's a Phase II trial, which means it is focused on identifying dosage ranges and side effects in human rather than a large-scale efficacy trial. (It's also the first time you actually give a drug candidate to humans). You also forgot that there is a fourth point: there is no actual effect, and the apparent effect is statistical fluke. It's hard to understand what could be going on from this article alone, because it spends a whopping 1.5 paragraphs on explaining any details about the putative vaccine. The rest of the piece reads as a generic PR fluff piece, which makes me think that this was largely based on company-provided PR and so anything approaching details is based on the most positive light that they can be spun into.
- gumby 8y ago
  > ... a Phase II trial, which means it is focused on identifying dosage ranges and side effects in human rather than a large-scale efficacy trial. (It's also the first time you actually give a drug candidate to humans). FWIW your drug candidate is administered in all phases. Phase I you look for side effects ("safety and tolerability"). Phase II is, as you say, a dose ranging study, but you can't exceed dosages you've already tested for safety. You usually have multiple arms (a placebo and a couple of dosages); when you find an seemingly efficacious dose you then proceed to a Phase III where you test that dosage (or several) on a statistically representative enough sample to hopefully predict results in the population at large. (former drug designer who has designed some Phase I and II studies). == Fun fact: when you file your IND with the FDA to test a new drug you aren't actually asking for permission. You're asking them to tell you that if you follow the protocol you have sent them, based on the evidence you've sent them from what you know already, they won't prosecute you for violating the law on administering unapproved drugs. Section 505 for the food and drug law has a bunch of exceptions -- you ask then to tell you you fit in one of the exceptions. And if they don't tell you "no" in a 30 days...you can go ahead! I wonder if the shutdown extends that 30 days.

jcranmer 8y ago

Derek Lowe (of In the Pipeline, probably the most widely-read blog by a drug development scientist) had a funny take on the state of the amyloid hypothesis for Alzheimer's: http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-alzheimers-statement http://blogs.sciencemag.org/pipeline/archives/2018/06/12/an-... Considering that every single anti-amyloid Alzheimer's candidate has failed--even those that made it into Phase III trials--anyone suggesting something that attacks amyloids has to overcome a lot of skepticism.

nonbel 8y ago
Yep, exactly. It seems like something needs to be wrong/corrupted within Alzheimer's research to explain the continued obsession with this approach. As I said elsewhere in this thread, their behavior is baffling to me. In my experience, that usually means there is an ulterior motive somewhere.

tallanvor 8y ago

Honestly, by pointing to your comments from previous discussions, you look like you have an ax to grind rather than being helpful. The truth is that we don't know what causes Alzheimer's. Amyloids may or may not play as much of a role as some people think. But without a better hypothesis to test and get funding for, this is what they can do.

nonbel 8y ago
>"Honestly, by pointing to your comments from previous discussions, you look like you have an ax to grind rather than being helpful." I have no axe to grind. Just presenting the facts. Why would I requote everything? Nothing has changed since then. >"But without a better hypothesis to test and get funding for, this is what they can do." I mentioned the "better hypothesis" here. It is the only hypothesis that lead to treatments that seem to help at all: https://news.ycombinator.com/item?id=18922340 https://news.ycombinator.com/item?id=18922340

pstuart 8y ago

Do you have an ELI5 for your suspicions of cause and cure? (not snarky, genuinely curious).

nonbel 8y ago
No, just that it isn't going to be removing amyloid plaques. For the plaques to build up the neurons are clearly malfunctioning for some reason. Beyond that, who knows?
- pstuart 8y ago
  No Nobel Prize for you!