#6

We don’t even know if the β-amyloid plaques cause AD. They might be irrelevant (that’s my guess). See also: Increases in amyloid-β42 slow cognitive and clinical decline in Alzheimer’s disease trials 2024

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Omega-3 Needs B Vitamins for Benefits (Dementia Prevention)
#7

By the way, sirolimus 2–6 mg daily failed in Multiple System Atrophy (MSA): mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis 2022

The authors pursued the analysis and concluded that: “sirolimus at dosages 2–6 mg/day was unable to inhibit the brain mTOR pathway in patients with MSA” (Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy 2023).

There was also this n=10 early Phase 1 trial: Cognition, Age, and RaPamycin Effectiveness - DownregulatIon of thE mTor Pathway (CARPE_DIEM) in “older adults with Mild Cognitive Impairment (MCI) or early Alzheimer’s disease (AD)”. They published the results but not a paper: what does it mean? :man_shrugging: They’re now running a Phase 2 trial, n=40, results in 2026: Rapamycin - Effects on Alzheimer’s and Cognitive Health (REACH), so I assume at least the Phase 1 trial showed that rapa was safe in this population?

This trial will end in a few months and might tell us more: Evaluating Rapamycin Treatment in Alzheimer’s Disease Using Positron Emission Tomography (ERAP)

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#8

This discussion might be an indication for some of us, to use lower doses, This to avoid that too much rapamycin penetrates the blood brain barrier. and letting the system clear the rapa for a few days before next dose.

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#9

Do we have evidence that rapa crosses the BBB? The above paper found no brain mTOR engagement even at 6 mg per day.

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#10

I can not say we have evidence, but in one part of the lecture given by Prof David Dodick (starting at 28 minutes and ends at he 40 min mark) he speaks of GLPs, metformin and rapamycin in relation to brain health and Alzheimers. This is a reasoning from his point of view and that rapamycin might have a negative effect on Alzheimer’s. But it depends on the timing of the intervention. And one has to consider that he, as a doctor, most likely plays a risk-aversive role. (above all, do no harm)

As I see it, there is a risk, and we don’t have evidence. So what I consider is more of a risk management strategy.

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#11

Low-dose rapamycin might have its own issues unfortunately (although I don’t understand why at all…): Top 5 - Which Currently Available Longevity Interventions Do You Think Are the Best - #201 by Jonas

#12

yes, we face conflicting ideas, and we have to decide on which strategy to use.

#13

Thanks for sharing the info about these clinical trials, adssx. Do you have a link to the pre-print publication of the CARPE-DIEM results? I see the clinical trial data online but not the study results.

#14

That’s the thing: they didn’t publish anything (besides the raw data). You can try to email the lead researcher?

#15

Although β-amyloid plaques probably do not cause AD, it seems unlikely that they’re “irrelevant.”

Trem2 activity in the microglia may hold one possible answer to Alberto Espay’s question, Why do most old people with β-amyloid plaques not get AD?

“Mutations in TREM2 were found to disrupt microglial energy state and function, thus sabotaging microglia’s ability to protect the brain against toxic amyloid plaques (Hong and Stevens, 2017; Ulland et al., 2017). Ulland et al. (2017) also found that microglia in AD patients carrying TREM2 risk variants and in TREM2-deficient mice with AD-like pathology were defective in rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways.” (my emphasis)

As I stated in my initial post, a 2022 study by Shi et al. found that, in knockout mice, “Inhibition of mTOR pathway with rapamycin, a well-established immunosuppressant, downregulated Trem2 in microglia and reduced Aβ plaque clearance indicating that mTOR inactivation may be detrimental in Aβ-associated AD patients.”

It seems that the AD pathology has something to do with the brain’s clearance of toxic β-amyloid plaques–that is, it has something to do with autophagy.

I’m specifically interested in the “TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative disease” (The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases - PMC)

The research on TREM2 is new to me, and the Shi et al. 2022 study seems to suggest that rapamycin may downregulate TREM2 and block its potential benefits. That’s what I’m curious about.

I hope someone who read the Shi et al. (2022) and/or knows something about TREM2 and microglial function will respond to this thread.

#16

Where did you find the raw data?

#17

The “Results Posted” tab: ClinicalTrials.gov

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#18

Thanks, that’s very interesting…and a little unexpected.

I think the thing to remember for both of these is that we are cycling or pulsing rapamycin and mTor inhibition. So I would allow a good interval after taking rapamycin before I would experiment with psychedelics, but the “Psychoplastogens” concept I find fascinating and am reading up on. The mouse study used rapamycin continuously and it took a month before they saw changes. That’s quite different than taking very moderate doses once a week, or less. I think it’s clear that you need mTOR activation, the problem is when it’s over active. Low dose pulsed rapamycin is meant to modulate it, not eliminate it.

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#19

That’s my understanding, too. Thanks for affirming my attempt at understanding of the factors at play: high vs. low dosage and chronic vs. pulsed administration.

The other factor seems to be AD stage. It seems that early administration of rapamycin (before cognitive symptoms appear) promotes beneficial autophagy, but late administration (when AD is already established) exacerbates existing dysfunction of the lysosomal system.

This 2023 summary of recent research cites Shi et al (2022) to come to that same conclusion:

"Rapamycin was found to increase the number of autophagosomes and autophagic lysosomes … Rapamycin has an autophagy-promoting effect on Aβ-depositing cells and attenuates further cellular damage by Aβ, which may be one of the mechanisms by which rapamycin can be used to treat patients who have already developed pathologic features. However, the lysosomal system in the brain is less expressed and slower in the later stages of AD and with aging. Rapamycin inhibits mTOR and activates autophagy to clear Aβ. Decreased lysosomal clearance leads to autophagosomes accumulation, causing autophagic stress and promoting the amyloid plaques formation. Thus rapamycin has a complex, even harmful effect on late AD.

[. . .] Furthermore, rapamycin inhibits microglia activation in the brain and reduces microglia proliferation, yet microglia activation may play a dual role in the AD pathogenesis. "
Si-Jia Hou, Sheng-Xiao Zhang, Yang Li & Sui-Yi Xu, “Rapamycin Responds to Alzheimer’s Disease: A
Potential Translational Therapy” (2023) Clinical Interventions in Aging
(https://www.tandfonline.com/doi/pdf/10.2147/cia.s429440)

On that last point, Hou et al cite the following article that elaborates on the “dual role” of microglia in AD: “Microglia are perpetually engaged in a mutual interaction with the surrounding environment in CNS; thus, diverse microglial reactions at different disease stages may open new avenues for therapeutic intervention and modification of inflammatory activities.” Sarlus H, Heneka MT. Microglia in Alzheimer’s disease. J Clin Invest. 2017;127(9):3240–3249. doi:10.1172/JCI90606

This point backs up Carosi and Sargeant’s metaphor of rapamycin as “double-edged sword,” mentioned earlier in this thread by adssx: “Treatment with rapamycin at a later point would carry a higher chance of exacerbating existing lysosomal problems.” (https://www.tandfonline.com/doi/pdf/10.1080/15548627.2019.1615823)

#20

PS, I came to the same conclusion on this point also: To avoid inhibiting neurogenesis, “I would allow a good interval after taking rapamycin before I would experiment with psychedelics.”

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#21

Hi Bridget
I have had similar concerns about using rapalogues in dementias considering that not only is it logical that the mTOR down-regulation would slow down cell renewal, but that mouse studies support this.
On the other hand it seems that older people (including myself) are probably mostly in an mTOR hyperactive state and that if we look at the mouse muscle studies, they show that altho there can be a short term catabolic effect on the muscle, the long term rapamycin effects mean that we should expect an improved performance of those muscles - better mitochondrial functioning, better endoplasmic reticular functioning and reduced oxidative stress (no evidence that I have yet seen for improved mTOR signalling). Therefore it is not unfair to assume that the same benefit could be expected of other cells in the body and that rapalogues may have a neuroprotective effect but that if used continuously could be expected to inhibit new neurone development.
With this in mind we took 2 moderately advanced dementia patients (1 Alzheimer’s age 74 years, and 1 vascular dementia aged 80years ) who volunteered to go on a course of rapamycin 5mg daily for three months followed by 3 months of micro dosed ketamine nasal spray (5mg/day). Ketamine was used as a potent BDNF stimulator.
It is important to note that both are star pupils who have done our the lifestyle suggestions (high intensity exercise + weight lifting, saunas + cold plunges) and the AD patient has cut out all alcohol, sugar and gluten (the vascular patient takes these in moderate amounts).

There was no noticeable dip in brain functioning in the rapamycin period for either person and subjectively there was a feeling of improved brain functioning in the ketamine period for the AD patient over the 6 months.
Objectively, both have deteriorated with neuropsychiatric testing over the past year but less severely than expected.
I hope this is useful. All suggestions welcome.

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#22

Everolimus is easier to cross BBB(brain blood barrier) than Rapamycin

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#23

This is interesting because in the papers here ( mTOR activation and AD - #2 by adssx ), the brain-penetrant tacrolimus and everolimus seemed to perform better than sirolimus (for instance: “tacrolimus (RR 0.50, CI 0.40–0.61), everolimus (RR 0.35 CI 0.23–0.53), sirolimus (RR 0.59, CI 0.37–0.95)”).

Is there a case to prefer everolimus to sirolimus? (in general, not just for neuroprotection) [EDIT: apparently there might be: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying? ]

[EDIT 2: does everolimus really do better than sirolimus at BBB crossing? Everolimus instead of Sirolimus / Rapamycin? Anyone else trying? - #117 by 59vw ]

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#24

Interesting ongoing trial but it’s supposed to be finished and yet no results published: Adjunctive Everolimus Treatment of Refractory Epilepsy NCT05613166

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#25

Ever over siro - uhm, the ITP trial showed rapa as lifespan extending, not ever. You are speculating that ever is superior to rapa. Maybe. Now you are asking to abandon rapa in favor of ever, so, the classic “give up the sure bird in the hand for the speculative two birds in the bush”. Maybe.

Miller (ITP) makes a good argument that results in mice vs aging interventions are relevant to humans. I think he is right. At the same time, it is also true that there are limitations in translating all effects from mice to humans.

Does rapa cross the BBB in mice? If not, but they live longer, then one might be tempted to say “it’s good enough for mice, it’s good enough for me”. Except mice don’t tend to get AD, so that may be a limitation in translating from mice to humans.

Which is a generalized problem. Maybe rapa is particularly well suited to take care of mice-specific pathologies, but less well to human-specific pathologies of aging, and therefore we cannot expect the same size effect in humans as in mice wrt. health/life extension. What we really need is rapamycin for humans. Maybe everolimus is the rapamycin for humans?

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