[xenadu02]

Let's put all of that aside for a moment.

When the first drugs targeting HIV arrived the results were undeniable. Yes the drugs sucked for various reasons and yes HIV would evolve resistance. But the data demonstrated a very clear link that these drugs suppressed HIV and suppressing HIV made people live longer. Or consider mRNA and COVID, a great success story where the technology was put to good use and the results are obvious.

On the flip side we have certain cancers like certain breast cancers, melanoma, etc that never had a "wow" moment where some miracle turned them from highly fatal into treatable but we have seen decade after decade treatments improve and survival rates march ever upward such that what were once almost guaranteed death sentences are now often very treatable.

These are two disease treatment models worth keeping in mind. Sometimes major leaps are made. Sometimes progress is slow.

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree.

That concerns me and I think justifies some skepticism of the amyloid hypothesis. The data is messy but if amyloid beta were a symptom not a cause that could certainly fit the results we are seeing. That doesn't mean the amyloid beta hypothesis is wrong but I think skepticism of the "state of the art" in the field is warranted given the pathetically ineffective progress made to date.

[DavidSJ]

Now if we consider amyloid beta therapies: we have treatments that target amyloid beta with varying degrees of success but at least some show definite reductions in amyloid beta plaques. To the best of my knowledge that has not shown to improve outcomes in Alzheimer's patients to any meaningful degree.

This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.

[pama]

I work in drug discovery. For the past twenty years or so, my personal analogy for this hypothesis has been a fantasy story around the days after the bombing of Dresden, when a new civilization suddenly visits Dresden and has no priors about what may have happened there. The aliens see bricks all over the place and assume that the bricks were the cause of the catastrophe. They take great efforts to pick up the bricks and save a couple of lives from the people who were covered in the ruble. The aliens build better systems to pick up bricks in the future and get ready to act next time. When a nearby city gets bombed, they quickly visit and help recover bricks saving a couple more lives. A different civilization could have instead focused on reducing the bombs or detecting and defending against the attacking airplanes.

Our immune systems are complicated, much more so than airplanes and bombs. The amyloid deposits are very likely part of an immune response, and although in principle immune responses going wild are horrible and can be fixed, it is very important to work on identifying and addressing the causal factors of this disease. There have been more therapies tested on the amyloid hypothesis that mere statistical fluctuations could explain away. I don't always agree with Derek, but I'm with him on this one. New ideas are urgently needed here, or this horrible disease will be an increasingly common end state for our aging populations.

[DavidSJ]

The hypothesis that amyloid is simply a downstream effect, not a cause, is of course worth considering, and where my mind was at when I first approached the literature skeptically. The widespread presence of amyloid-beta plaques in Alzheimer's disease has been known since 1906, but the field didn't adopt the amyloid hypothesis for decades precisely because of this possibility. But then in the early 1990's, strong genetic causal evidence emerged, which is why the amyloid hypothesis emerged at that time. Other important causal evidence has emerged since, especially that tau pathology (the proximate cause of neurodegeneration) is causally downstream of amyloid pathology, which we know from many lines of evidence now. (See the article for a lot more detail on all this, if you are curious.)

As for the possibility that the successes of amyloid therapies might be explicable by chance, this is highly implausible. Only three (aducanumab, lecanemab, and donanemab) of a dozen or more amyloid therapies successfully cleared plaque, and it is precisely those three that achieved a slowdown of cognitive decline in phase 3 trials (with aducanumab succeeding in only one of its two, but with the others succeeding in their only phase 3), several of which with p-values below 0.001. This is not p-hacking or reporting bias.

[pama]

Regarding lack of p-hacking. The placebo arm of blinded trials breaks when your brain can detect a medication. The effect is tiny in these studies; approval was rushed to give hope to patients. The drug was discontinued later.

[DavidSJ]

The drug was discontinued later.

You're thinking of aducanumab. Lecanemab and donanemab have been in widespread use for several years now, and open-label extensions vs. external controls showing increasing benefits over longer treatment durations.

[stinkbeetle]

Would you expect progression to cease if not reverse if the cause was cleared?

[DavidSJ]

Not reverse; the neurons have died.

Cease, yes, if the cause is removed early enough. But if you intervene too late (once symptoms are detectable), then the downstream tau pathology, which is what directly kills neurons, likely spreads on its own via a prion-like mechanism.

So far, no clinical trial has completed prior to clinical onset for an antibody which actually removes plaque. This is probably the main reason only 30% slowdown has been achieved so far. The donanemab prevention trial is due to complete next year. That will be an important one to watch.

[DaveZale]

Yes, and the fact that something like oral hygiene can influence AD would support your thesis. Often an infection in the gums/teeth can result in boils or worse in distant parts of the body. Add a dysfunctional blood brain barrier and you are screwed.

Brush and floss bruddahs.

[laughing_man]

Amyloid plaques could be part of a disease cascade. Not the root cause, in other words, but an additional downstream problem than probably still needs to be addressed.

[xenadu02]

> This is false. They slow down disease progression by about 30%, as measured by cognitive outcomes. This is discussed in the article.

Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer.

Maybe it is simply too early to tell but I would naively expect something much more significant. Perhaps this is the sort of thing that requires much earlier treatment to demonstrate better results.

I'm not saying amyloid beta research should be terminated. Merely that everyone in the field should be willing to entertain other ideas.

[DavidSJ]

Perhaps I am just not well-informed but 30% slowdown in progression translates to sufferers have some mild improvement in cognitive tests and live a few months longer.

A few years longer. It's obviously frustratingly far from where we'd like to be. It was only a direct response to the claim that Alzheimer treatment isn't even in the "sometimes progress is slow" category, but rather in the "no meaningful benefit at all" category.

I'm not saying amyloid beta research should be terminated. Merely that everyone in the field should be willing to entertain other ideas.

We agree that people should be willing to entertain other ideas! I don't think anyone is saying otherwise.