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Comment by getnormality | Hacker News Reader

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

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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

"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...

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.

"This was an absolute difference of 0.45 points (change from baseline, 1.21 for lecanemab vs 1.66 with placebo; P < .001)"

…

Sum of boxes is a 19 point scale.

It's an 18 point scale, but more to the point: the decline in the placebo group was only 1.66 points over those 18 months, and the mean score at baseline was just over 3 points. So even 100% efficacy could only possibly have slowed decline by 1.66 out of 18 points (what you would call a 9.2% absolute reduction) in the 18 months of that experiment. And full reversal (probably unattainable) would have only slowed decline by about 3 points.

I agree that the side effects of anti-amyloid therapies are a serious concern. The reasons for this are being understood and corrected in the next generation of such therapies. For example, I expect trontinemab to achieve better efficacy with much greater safety, and there is already preliminary evidence of that. Furthermore, there are improved dosing regimens of donanemab which improve side effects significantly.

Note that my claim is not that the existing drugs are stellar, and certainly not that they're panaceas. Simply that the amyloid hypothesis is true and there has been tremendous progress based on that hypothesis as of late.

As much as you're chiding people for being a part of a "misguided popular uprising", you're not really making a good case for anti-amyloid therapies. It started at "wow, 30%!" in this comment chain, and now it's at "barely having an effect over a placebo" being tremendous progress?

It seems like you didn’t understand my comment if you think I’ve changed my position from 30% efficacy.

I don't think you've changed your position. Reading the thread, your mention of 30% is super misleading and you should've lead with how little progress has been made instead of chastising people correctly upset with the lack of progress.

To emphasize your point, I don't think anyone will notice if someone's alzheimers is 2.3% better.

These rating scales like CDR-SB (invented by drug companies or researchers who are funded by drug companies) are very good at making the tiniest improvement sound significant.

You have to understand that CDR-SB is a very sensitive measurement. Yes, it's an 18-point scale, but from 4.5 to 18 it's just measuring how bad the dementia has gotten. The vast, vast majority of healthy people will score 0. Going from 0 to 0.5 is a massive difference in cognitive ability.

> Downvoters, are you sure you have a rational basis for downvoting this informative post?

Citing relative improvement (30%) instead of absolute improvement (2%) and not explicitly designating it as such.

“Slowed decline by 30%” is explicitly designating it as such.

I disagree. "Slowed decline by 30%" to me means an absolute reduction of 30% in some rate expressed as unit X over unit time, and that's what I thought you meant until another commenter pointed out that it was a relative reduction. IMHO it's not an explicit callout unless you are using the words 'relative' and or 'absolute'

I did not downvote, but OP failed to provide a link to back up his claim, or to make explicit what "slowing decline by about 30%" even means.

In light of the fraudulent and scandalous approval of aducanumab [0] (which also targeted amyloid), such claims must be thoroughly referenced.

[0] https://en.wikipedia.org/wiki/Aducanumab#Efficacy

If it helps, here’s info from Dr. Derek Lowe, a 30+ year pharma chemist and author of In The Pipeline. For further research on the topic, he has many other posts on the topic, some of which are linked in the links below.

https://www.science.org/content/blog-post/aduhelm-again

https://www.science.org/content/blog-post/goodbye-aduhelm

https://www.science.org/content/blog-post/alzheimer-s-and-in...

How do you know what the downvote status is?

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