Cagrilintide; a science-based perspective

[nurseratchit]

Rather than add to the already contentious and argumentative thread concerning Cagri and fibrils, I thought I would repost @TessaM ‘s well reasearched piece that is buried within that thread for those who are just trying to make an informed decision for themselves and not get caught up in the back-and-forth.

I apologize for any of my previous comments that may have muddied the waters. I have read many thoughtful posts on various subjects by Tessa M, and she has a gift for explaining complex and nuanced topics in an accessible manner.

Some final thoughts shared by TessaM in response to another user on Roundtable that she gave me permission to share here:

• Member comment:
  I think it’s a lot of information to try to decipher and align the points of argument for a novice. It’s a he said she said game and impossible to really determine who’s right and wrong for some of us.
• TessaM’s response:
  That's totally fair. For things that aren't in my area of expertise, yeah: I trust the experts. But here? We're a bunch of anonymous nerds pontificating about grey-market drugs based on incomplete trialsand without access to any of the preclinical data. There's no way to assess credentials here, no peer review process, nor any of the typical vouching mechanisms people should use as a gauge for the trustworthiness of information outside their fields.
• So if you're not sure: play it safe. Don't use it. I'm a big fan of the precautionary principle here. These drugs might be life-changing in their effects, but these are NOT chemo meds or blood thinners or something that's actually life and death. We don't need them to survive. So when in doubt? Err on the side of doing nothing for now.
• And I believe this about ANY of these peptides, especially ones in the earlier stages of clinical trials. This community tends to push the envelope a lot, and even encourage it, but it's totally valid to set your risk bar around 'post-P3,' 'pharma dispensed', or etc.

 

[hexagonal]

Effect of β-amyloid on blood-brain barrier properties and function - PMC

The deposition of beta-amyloid (Aβ) aggregates in the brain, accompanied by impaired cognitive function, is a characteristic feature of Alzheimer’s disease (AD). An important role in this process is played by vascular disorders, in particular, a ...

pmc.ncbi.nlm.nih.gov

I've seen this shared as proof that the underlying thesis that fibrils and oligomers can't pass through the blood brain barrier is false:

Aβ peptides which are in different states of aggregation (monomers, oligomers, and fibrils) can pass through the BBB at different rates and affect the state of endothelial cells in different ways. Oligomers have the greatest damaging effect. The clearance rate for the release of oligomers from the brain into the bloodstream is higher than for fibrils and monomers. With regards to the entry and passage of Aβ in different aggregative states through the BBB, data are not yet available. Disturbance of the redox status and mitochondrial respiration of BBB endothelial cells is an important component of the damaging effect of Aβ peptides. Despite the similar binding constants of the Aβ40 and Aβ42 isoforms with RAGE, the rate of their entry through the BBB from the blood into the brain differs. A potentially promising line of investigation would be to consider the passage through the BBB and the effect on endothelial cells of pathogenic Aβ isoforms with post-translational modifications, such as isomerization, since this may be an important factor in the development of AD pathogenesis.

Much of the study seems to be about them going the opposite direction, though some of it seems to discuss entering the brain, but mentions that different types pass through at different rates, so I also have no idea how cagrilintide compares to what was studied.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11257072/ seems to be a mechanistic study that indicates that amyloid oligomers can accumulate at the BBB and disrupt it's ability to block passage as well.

(Edit: Trying to do some research of my own here and I can find references to other types of amyloid related fibrils traveling through the bloodstream without being broken down as well: https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr )

I don't understand these well enough to have any idea if they're relevant to what's being said here, so would love if TessaM could weigh in.

 

[Dee X]

Effect of β-amyloid on blood-brain barrier properties and function - PMC

The deposition of beta-amyloid (Aβ) aggregates in the brain, accompanied by impaired cognitive function, is a characteristic feature of Alzheimer’s disease (AD). An important role in this process is played by vascular disorders, in particular, a ...

pmc.ncbi.nlm.nih.gov

I've seen this shared as proof that the underlying thesis that fibrils and oligomers can't pass through the blood brain barrier is false:



Much of the study seems to be about them going the opposite direction, though some of it seems to discuss entering the brain, but mentions that different types pass through at different rates, so I also have no idea how cagrilintide compares to what was studied.

https://pmc.ncbi.nlm.nih.gov/articles/PMC11257072/ seems to be a mechanistic study that indicates that amyloid oligomers can accumulate at the BBB and disrupt it's ability to block passage as well.

(Edit: Trying to do some research of my own here and I can find references to other types of amyloid related fibrils traveling through the bloodstream without being broken down as well: https://my.clevelandclinic.org/health/diseases/17855-amyloidosis-attr )

I don't understand these well enough to have any idea if they're relevant to what's being said here, so would love if TessaM could weigh in.

Paging @TessaM