Sarcastinator t1_iyc16pu wrote
Reply to comment by Relevant_synapse in Alzheimer’s Drug In Development, Lecanemab, May Benefit Some Patients But Carries Risks of Brain Swelling and Bleeding by Relevant_synapse
Before the fraud was discovered several studies were stopped because Amyloid therapies had disappointing results in human trials.
Relevant_synapse OP t1_iycd88b wrote
The amyloid hypothesis is by no means the whole story and the -mabs may be barking up the wrong tree altogether. Does not mean that the whole amyloid link is bunk, as the comment I responded to suggests. Mutations in the amyloid precursor protein often lead to dominantly-inherited, early-onset AD, for example, so the link should not be casually dismissed.
Darkhorseman81 t1_iycgvkq wrote
Amyloid and tau build up in everyone with age. It's just a side effect of loss of nutrient sensing and epigenetic quality control, leading to a build-up of cholesterol and fatty acids between cells, instead of feeding those cells.
A single gene is responsible MOF.
The Max Planck institute have already worked out what causes Alzheimers and all vasculature dementia.
Relevant_synapse OP t1_iych9ko wrote
If there is no amyloid link, then please explain the changes in CSF amyloid/tau/p-tau composition in AD patients that predate clinical symptoms by years and are now being used as part of AD diagnostic criteria:
https://www.nature.com/articles/s12276-019-0250-2
Note: CSF beta amyloid decreases as AD disease severity progresses, not increases as your hypothesis seems to suggest.
Darkhorseman81 t1_iychxsz wrote
That happens to everyone, and is a part of ageing and loss of epigenetic quality control/epigenetic drift.
The reason it happens faster in APOE4 variants is because that gene is linked to superior cholestrol efflux across the blood brain barrier, which is also linked to higher IQ, and cognitive resilience in children in 3rd world countries who suffer starvation, chronic dirahhea, or toxic metal exposures.
They don't lose IQ like most do during hardship, due to superior brain cholesterol metabolism. They are cognitive powerhouses.
They want to treat the amyloid build-up as a prescription model to make money, and have you on drugs the rest of your life, while it is little more than a side effect of the core dysfunction of ageing.
Fixing MOF repairs the blood vessels and nutrient sensing, so fatty acids and cholestrol don't build up between cells. It also repairs cellular waste management and repair, which prevents the build-up of TAU and Amyloid in the first place.
Study the effect of MOF(Myst1/Kat8) on blood vessels, cellular waste management and repair, chromatin structuring, the integrated stress response, and neural metabolic imbalance.
I'm telling you, fix the acetylation patterns of MOF, a single treatment would do it, and the condition is fixed.
Maybe have to do it again once every 30-40 years, if we don't find a way to correct epigenetic drift, but it's a quick fix.
Dementia and Parkinsons are even easier. Dementia is the integrated stress response alone, parkinsons is the ISR + PGC1A gene, which regulates mitochondrial quality control, becoming dysfunctional.
MOF is slightly upstream from all of them. A spectrum of the same condition.
Sarcastinator t1_iycszoc wrote
Could I get a link to this?
Darkhorseman81 t1_iydbteu wrote
Type brothers in arms, the brain and its blood vessels, or janus faced MOF, into a search engine. Good starting point.
On a phone atm, so it's annoying to post links, until I get back to the PC.
[deleted] t1_iydf0ky wrote
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Sarcastinator t1_iycu4jl wrote
It's not casual dismissal when human trials fail and the ground laying research included forgery.
Relevant_synapse OP t1_iycuijf wrote
It’s important to understand what the extent of the forgery was before making sweeping pronouncements. It’s a common misconception that the forgery invalidates the field. Holding such a frequently-parroted opinion has unfortunately become a litmus test for being uninformed in this space. You can read about the scandal yourself here: https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease
Sarcastinator t1_iycwwgt wrote
It's not just about the forgery but don't take it from me:
https://www.science.org/content/blog-post/positive-amyloid-trial-finally
> At the same time, though, news like this needs to be examined carefully. As the world knows, the anti-amyloid clinical landscape for Alzheimer's is absolutely littered with failures in every direction: anti-amyloid antibodies of various types, attempts to inhibit beta-secretase and gamma-secretase enzymes, attempts to prevent aggregation, you name it. Nothing has worked. The presumption at this point is that such therapies will not succeed, so if lecanemab has indeed worked, the question is what makes it different. There's a ready answer (up to a point) because antibodies can indeed be quite different (that's their point!) and if you do manage to hit exactly what needs to be hit, you could expect efficacy when apparently similar attempts have led to nothing.
So being skeptical towards amyloid therapies isn't unwarranted, or casual dismissal.
Relevant_synapse OP t1_iycyb3d wrote
Being skeptical is not the same as dismissing the entire connection as “bunk”. Derek is a much respected voice in the field. I actually agree with his take, and he is spot on with the quote you provided.
What makes lecanemab different? Compared to other drugs in its class that we’ve seen thus far, it has much higher affinity for amyloid fibrils and soluble oligomers than plaques.
https://www.frontiersin.org/articles/10.3389/fnins.2022.848215/full
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