What if Alzheimer's isn't just about the buildup of toxic proteins — but about the immune cells that were supposed to clean them up, and why they eventually stop doing their job?
Thank you for this article, Hussein! I keep thinking about how anti-amyloid antibodies might actually be exhausting already-compromised microglia in APOE4 carriers rather than rescuing them. The timing question feels underappreciated in the clinical conversation.
It is a good question. These treatments trigger microglia to phagocytose and clear abeta. Whether they induce a state of exhaustion is not known. However, tiggering this pathway in blood vessels with abeta provides an explanation for the side effect ARIA, where the blood vessel becomes inflamed with immune cells trying to clear amyloid.
Great piece, Dr. Yassine. It is intriguing to see that the shift in microglial activation from M1 to M2 is getting more and more support coming from different trials.
I am very curious about the protective mechanism behind the shingles vaccine - I have just written about a similar effect with the BCG vaccine, and it looks like the mechanism behind it involves improved trafficking of ab42 from brain to plasma, which could in turn be attributable to microglial function.
Thank you for this article, Hussein! I keep thinking about how anti-amyloid antibodies might actually be exhausting already-compromised microglia in APOE4 carriers rather than rescuing them. The timing question feels underappreciated in the clinical conversation.
It is a good question. These treatments trigger microglia to phagocytose and clear abeta. Whether they induce a state of exhaustion is not known. However, tiggering this pathway in blood vessels with abeta provides an explanation for the side effect ARIA, where the blood vessel becomes inflamed with immune cells trying to clear amyloid.
Say more!!!
Great piece, Dr. Yassine. It is intriguing to see that the shift in microglial activation from M1 to M2 is getting more and more support coming from different trials.
I am very curious about the protective mechanism behind the shingles vaccine - I have just written about a similar effect with the BCG vaccine, and it looks like the mechanism behind it involves improved trafficking of ab42 from brain to plasma, which could in turn be attributable to microglial function.
Would be curious to hear your thoughts on this!
Dear Petr, my views in shingles are here: https://hyassine.substack.com/p/could-a-shingles-vaccine-protect?r=5ha6ys&utm_medium=ios