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-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.
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...
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.
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-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.