γ-secretase modulators is a recurring concept in the Astral Codex Ten archive, appearing 1 times across 1 issues between August 14, 2025 and August 14, 2025. The archive places it in contexts such as "as well as γ-secretase modulators". It most often appears alongside A. Bejanin, A. de Calignon, A. Elobeid.
- Reference entry
- γ-secretase modulators
- Mention count
- 1
- Issue count
- 1
- First seen
- August 14, 2025
- Last seen
- August 14, 2025
Outbound links
- http://web.archive.org/web/20221104130431/https://stevekirsch.substack.com/p/1m-bet-rules
- http://web.archive.org/web/20221129133112/https://blog.rootclaim.com/rootclaim-accepts-500000-challenge-on-covid-vaccine-safety-efficacy/
- http://web.archive.org/web/20221224061743/https://www.skirsch.com/covid/SaarWilf.pdf
- https://archive.ph/pY4gF#selection-663.103-683.190
- https://en.wikipedia.org/wiki/Stargate_Project_(U.S._Army_unit)
- https://web.archive.org/web/20230104080248/https://www.rootclaim.com/
- https://www.amazon.com/Closing-American-Mind-Education-Impoverished/dp/1451683200/ref=sr_1_1?crid=SAPRLAFUD8ML&keywords=Closing+of+the+American+Mind&qid=1680632698&s=books&sprefix=closing+of+the+american+mind%2Cstripbooks%2C221&sr=1-1
- https://www.astralcodexten.com/p/selection-bias-is-a-fact-of-life
- https://www.nytimes.com/2020/12/27/business/media/heather-cox-richardson-substack-boston-college.html
- https://x.com/RichardHanania/status/1867335298491068769
Issue trail
Related pages
Source context
I am not claiming that the disease is “as simple as” amyloid deposits directly inducing neurodegeneration. As described above, they act indirectly, via the eventual downstream tau pathology, and possibly an associated microglial/astrocytic inflammatory response. Therefore, there are many people in the preclinical, amyloid-only disease phase who will eventually progress to dementia but have not yet. These two clarifications imply that even though amyloid pathology is a necessary and (in enough severity) sufficient cause of the disease under normal circumstances, therapies with other targets might still be effective, either intervening upstream such that amyloid deposits never occur, or downstream so as to prevent the neurodegenerative process. The testable prediction I would bet on the following: A therapy whose sole intended mechanism involves amyloid production or clearance, in a randomized, double-blind, placebo-controlled trial, will, in the next 12 years, achieve a slowdown of cognitive decline of at least 75%, with a p-value below 0.001, in its preregistered primary cognitive endpoint (or an average of all such endpoints if more than one exists). I’d eventually expect better than 75% efficacy, but getting stuff to work takes time, and I wanted to make a prediction which can be tested in a reasonable timeframe. On the other hand, if a clinical trial completes earlier than 12 years from now (perhaps [73], reading out in 2027), sustains extremely good amyloid clearance at the preclinical stage, and has a good safety profile, but doesn’t make substantial progress towards this 75% goal, then I would consider this prediction refuted in advance. For targeting amyloid, I’m most optimistic about a blood brain barrier (BBB)-penetrating antibody such as trontinemab [74–76], but with an epitope more like lecanemab’s, and given in the preclinical disease stage. Other options for targeting amyloid include antisense oligonucleotides for APP as well as γ-secretase modulators. The successes and failures of amyloid antibodies There have now been three amyloid antibodies with positive phase 3 (and earlier) clinical trials on cognitive endpoints (but with much less than 75% efficacy): Aducanumab in phase 1b [77] (19% on my average across cognitive endpoints for the highest two doses) and one of two phase 3 trials [78] (22%, but negative 2% in the other trial, which also gave a lower dose on average).