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Comment by wiremine | Hacker News Reader

Anyone have any breakdown of what this means for the laymen out here on HN? I get the gist this was a major (but not unpredicted) failure, but am I reading it wrong? Was this for one category of drugs, or a hypothesis about the cause of Alzheimer's in general, or both?

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There was a good HN discussion a few weeks back about this: https://news.ycombinator.com/item?id=21911225 It's becoming increasingly clear that the entire Amyloid-beta plaque hypothesis has been wrong and last 20+ years of Alzheimer's research and drug development has been wasted.

Yup, and the infectious theory is the one that's gradually getting more and more mainstream traction (the premise being that beta amyloid has a tactical immune function in the brain but trades short-term success against pathogens at the expense of long term longevity in people who can't clear the plaques out effectively with restful sleep).

Good Google scholar queries include 'hsv apoe4' as well as 'gingivitis alzheimers', without quotes, and among others. I can dig up my past comments that went into depth on all the different studies here, but a lot of doctors have yet to be swayed on the new theory.

Edit: found a good reference page with all the different trials going on around different theories for Alzheimer's, including the infectious theory.

http://www.cumc.columbia.edu/adrc/patients-and-families/clin... has all the current trials

https://clinicaltrials.gov/ct2/show/NCT03282916 is the valacyclovir trial trying to replicate the 2018 results out of Taiwan.

A different angle is the recently discussed correlation between lithium intake and Alzheimer's, and that's also being explored: https://clinicaltrials.gov/ct2/show/NCT02129348

That clinical trials list doesn't mention the GAIN phase 2/3 trial [1] [2] currently underway to test COR388 from Cortexyme [3].

It's a small molecule that targets gingipains, cysteine proteases of the P. gingivalis, a periodontal pathogen responsible for gingivitis that has been found in Alzheimer's patients.

Here [4] is a paper on the gingivalis hypothesis funded by Cortexyme.

[1] https://clinicaltrials.gov/ct2/show/NCT03823404?term=NCT0382...

[2] https://gaintrial.com/en/about

[3] https://www.cortexyme.com/?page_id=6022

[4] https://advances.sciencemag.org/content/5/1/eaau3333

It's not necessarily pathogens only but it can also be commensal dysbiosis. See the discussion linked by the parent comment or my other comment here.

We should start thinking about all diseases that involve the HLA gene and dysfunctional immune responses as autoimmunity. Not just the obvious ones. Hence the question is simply why is the immune system misclassifying our own tissues? It's a CS / information theory problem.

Yes. My comment triggered most of that discussion.

I have really good solid evidence for another common disease being caused by infection or microbiome dysbiosis. But I am encountering a lot of resistance in the field despite my theory, models and data being much more solid than the status quo to explain said disease and my research coming from a famous lab.

I guess it's really hard for lots of people to accept most of their careers were spent chasing the wrong hypothesis.

I've reached a tipping point where I think I can only push it further and develop a drug in a startup. Alzheimer's and Parkinson's are also something I want to tackle because the mechanism is analogous. If someone wants to help or some VC is interested, just let me know. Contact email is in my profile. These diseases have a big CS / information theory component.

What’s the disease?

My personal experience and the research I’ve read makes me believe you are absolutely right.

Probably something like MS or another auto-immune disorder that could be microbiome and/or dopamine related. Could also be type 1 diabetes, RA, Crohn's, etc. Those would be my guess.

No idea if this is nextos's thing, but there's evidence for inflammation as a root cause of depression. cf Bullmore, the Inflamed Mind.

What's the disease and what's the resistance from the field? Microbiome stuff isn't as hot an area of investment as it was a few years back, but there's tons of biotech funding to go around (assuming you're in the US) and if you have solid data and an actionable drug, it shouln't be extraordinarily difficult to form a company around it in this economy.

If the past 20 years of research & drug development have been wasted, how does the average person help steer the ship away from clearing the plaque, and more towards identifying and treating the cause of the plaque in the first place?

Kinda both. Increased presence of amyloid (a type of protein) plaques are common in patients with Alzheimer's disease, so it was hypothesized that these plaques contribute to alzheimers. The drugs mentioned specifically targeted these plaques (via monoclonal antibodies). These drugs didn't slow the progression of alzheimers in the patient population that was certain to get it. The drugs could have failed for two reasons I think: 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue) or 2) the amyloid plaques themselves are actually being broken up by the drug...but the plaques may not really be a cause of alzheimers (in which case the hypothesis is the issue).

> 2) the amyloid plaques themselves are actually being broken up by the drug

This is actually what several studies have shown--the amyloid plaques were being removed by the drugs, but the progression of Alzheimer's was not slowed or halted.

Different disease, but if you really want to be depressed: https://blogs.sciencemag.org/pipeline/archives/2017/05/18/no...

> 1) the antibodies from the drugs were unable to break up the plaques (in which case the drug is the issue)

Shouldn't it be possible to have a look at the patients brains to see if there's any difference in plaque formation in those that underwent treatment vs those who had the placebo.

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