Rapamycin and Alzheimer disease: a double-edged sword?

This is a commentary from 2019, but given the recent discussions and interest I thought I’d post this series.

The Takeaway Point: Rapamycin looks much better / more likely to be good at preventing dementia / Alzheimers than as a treatment after its progressed.

Commentary by Matt Kaeberlein and other researchers/MDs below the article in this thread:

Rapamycin and Alzheimer disease a double edged sword.pdf (988.8 KB)

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Agree with MK here, there are rapamycin pathways we don’t even know about that are implicated in AD, so early administration may have profound impact.

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The drug’s developer, Roche, along with Banner Alzheimer’s Institute, the Phoenix-based organization helping lead the study, announced the negative results Thursday. After years following a family believed to be genetically predisposed to the disease, researchers found no significant difference in cognition or the ability to store and retrieve new memories between participants who received the drug and those who got placebo.

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Amyloid is bust. Pharma have moved on upstream to soluble oligomers vs targeting plaques, and even these are just “barely” slowing down progression, with some serious side effects (ARIA: Amyloid Related Imaging Abnormalities). We still do NOT know root cause. It’s very likely polygenetic, so finding a pharma narrow “single” pathway magic bullet is going to be prove extremely difficult.

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I’m moving upstream too, like up my nose!

Here’s a great paper on Rapamycin and ADDITIONAL therapeutic pathways! Amazing.

And they didn’t even measure pmTOR directly!

Rapamycin confers neuroprotection against aging-induced oxidative stress, mitochondrial dysfunction and neurodegeneration in old rats via activation of autophagy

Animals were randomly allocated to the following four treatment groups having 12 rats in
each group.

  1. Young control: Young rats were given single oral administration of vehicle solution (0.9%
    NaCl solution containing 0.5% DMSO) for 4 weeks daily.
  2. Young rapamycin: Young rats were given single oral administration of rapamycin (0.5
    mg/kg b.w.) for 4 weeks daily.
  3. Old control: Old aged rats were given single oral administration of vehicle solution (0.9%
    NaCl solution containing 0.5% DMSO) for 4 weeks daily.
  4. Old rapamycin: Old aged rats were given single oral administration of rapamycin (0.5
    mg/kg b.w.) for 4 weeks daily.
    The dose of rapamycin (0.5 mg/kg b.w.) was selected on the basis of our earlier published reports.

0.5mg/kg/bw in rats to humans is about 5.6mg @ 70kg human. A hefty daily dose.

Clearly though, getting enough Rapamycin into the brain is key…but how much and what dosing? This isn’t a walk in the park, few mg/week?? We just don’t know!

“Our data demonstrated the significant age-related oxidative stress, apoptotic cell death, elevated inflammatory response, and reduced level of markers associated with rejuvenation and neural integrity including the activities of ion channel transporters and acetyl cholinesterase (AChE) in the brain of old aged rats. Furthermore, rapamycin (0.5 mg/kg b.w. for 28 days) induced activation of autophagy provided significant protection to aging rat brain by reducing the aging-induced oxidative stress, apoptotic cell death, and markers of neurodegeneration.”

I don’t think I’ve seen a rapamycin paper showing so many impacted pathways. Inflammation reduction in old cohort was HUGE.

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Excellent post - this is important stuff! Glad you found that paper and summarized it… very helpful.

I reached out to this author, see if I can extract some more “human extrapolation” insight.

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If they can give rats 0.5% DSMO orally, daily and not impact their findings, I figure it’s gotta be ok for me. LOL

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Very nice article. Many of those protective mechanisms would help in virtually all age related diseases, including cardiovascular.
Some studies are showing a link between brain inflammation involving the microglia and CAD . The body is very intertwined. Not an island as the gut microbiome is proving.

A big blow to the amyloid theory. Again.
Doesn’t mean that amyloid is totally irrelevant but it doesn’t appear to be the central actor.
It’s very complex. People treated with anti viral meds for herpes have much less risk.
Exercise and viagra help showing a vascular connection.
Mitochondria, autophagy, senescence, on and on it goes.
But is the rapamycin- amyloid connection now less relevant. Maybe.

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Very impressive the effects on IL 6 and TNF alpha. Also rapamycin unregulated the longevity FOXO 3. Something that astaxanthin does as well.

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We still don’t know what APP (amyloid precursor protein) does…and we think we can pharmacologically prevent AD?!

Remember this paper is JUST ABOUT THE BRAIN, which is phenomenal. 99.9% of the time, all these biomarkers are just measured in the periphery.

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