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.
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)”).
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?
Here’s the result: “EEG was monitored through the predrug period (baseline) to the postdrug period for each patient. Interictal epileptiform discharges (IEDs) recorded in EEG are generally considered to reflect the hyperexcitability of neuronal cells causing the seizure onset, and the reduction of IEDs may represent a beneficial effect of a drug on seizure recurrence (57, 58). Therefore, we compared the frequency of IEDs before and after drug administration. We found that 1-hour everolimus administration significantly decreased IED frequency in all three subjects in the treatment group (Fig. 5, A and D). However, the frequency of IEDs did not change in the 8-hour delayed everolimus treatment group (Fig. 5, B and E) or the placebo control group (Fig. 5, C and F). The data elucidate the effect of everolimus on decreasing IEDs in patients with refractory epilepsy when administered within the reconsolidation time window after epileptic seizure events.” (Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams 2024)
I didn’t mean literally asking us, just that you’re asking us to consider - theoretically - that ever might be the way to go, rather than rapa. Sorry if it wasn’t clear.
As Matt Kaeberlein said, it is certain that there are rapalogues that are vastly superior for humans, it is just a matter of discovering or inventing them. So, regardless of whether everolimus is superior overall, what we really need is that human superstar rapalogue, but until then all we have are these two.
Thanks so much for your very helpful and encouraging post, Duncancar.
I feel so grateful for the work you and others like Dr. Green are doing to help people with AD. It’s very encouraging to hear the positive outcomes in these cases. I’m going to try the sauna and cold plunge at the gym today!
According to Blagosklonny’s hyperfunction theory of aging, it seems correct that mTOR hyperfunctions with age and perhaps even gets stuck “on.” I think that may be particularly true for APOE4 types. I wonder if it’s related to APOE4’s hyperimmune response (cytokine storm, inflammation).
Anyway, thanks for your thoughtful post. I’m a “worrier” (homozygous) COMT genotype who ruminates way too much on this topic, particularly in autumn, when my father died from AD.
(And, just like that, the thought occurred: Perhaps homozygous COMT interacts with APOE4’s increased risk of AD? The answer appears to be yes:
Since you mention saunas and cold plunges, I assume you are familiar with the extensive AD prevention protocol developed by Richard Isaacson and the fantastic work he and his collegues do at his clinic, and his thoughts around ApoE4/4.
However there may be others reading this now or in the future who could use some resources, so here are some podcasts by Peter Attia centered around AD prevention and patient experience:
There are other AD ones on his site in the episode archive, but theses are a good start.
Quote: Such beneficial effects of rapamycin include reducing amyloid-β(Aβ) deposition, reducing pathogenic tau phosphorylation and abundance of misfolded tau species including neurofibrillary tangles, restoring cerebral blood flow and cerebromicrovascular density, preserving blood-brain barrier integrity, preventing human tau-induced neuronal loss, and improving cognitive function
Few diseases are more insidious than Alzheimer’s. Because I am dazzled by brilliance, I am reading a biography of Judge Richard Posner, the retired professor and legal scholar who wrote dozens of books and thousands of opinions, as broad as they are deep. Yet he too is now nearly helpless in a nursing home.
