Commentary by Blagosklonny:
5 Likes
Thanks for that RapAdmin.
Rapamycin is , as Blagosklonny states, primarily a preventative drug. Disease states like AD run along a spectrum where rapamycin may be very beneficial before, or even in earlier stages, by protecting mitochondrial function via enhanced mitophagy.
Later in the disease rapamycin may actually be exacerbating and I believe that’s where we are:
1 Like
Or it may slow down progression. Rapamycin is anti proliferative.
The San Antonio Phase 2 study of 1mg/day Rapamycin in MCI patients with confirmed amyloid “may” give us a signal. I sure hope they also measure mTOR inhibition (CNS levels of Rapamycin would be nice too)
3 Likes
And another of Dr. Green’s responses on this study, to a question from one of his patients:
Dr. Green’s response to my question about this:
"This study is like a magician’s trick; how does the impossible seem possible.
First amyloid doesn’t cause Alzheimer’s. It is the downstream byproduct of the upstream disease process.
Second, mice don’t get Alzheimers. So need a good model that show something happening in humans.They used a special mouse, 5X FAD. Probably a screwed up mouse that makes extra amyloid.
Microglia are like macrophages, they gobble up stuff like amyloid.
Rapamycin decreases the action of entire innate immune system including macrophages.
Therefore, rapamycin has decrease in action of microglia in removing amyloid plaques.
If the researcher knew what they were doing, I would consider it a malicious study to sow confusion.
However, in reality, the researchers were just totally clueless.
Concocting studies like this are fairly easy. The hard part is figuring out why the results are total bull shit.
However, it does show why in late Alzheimer’s disease with a brain full of amyloid plaques, rapamycin would not remove the plaques; but that would have no effect good or bad.
An example of this same action in real humans is in Gout.
Macrophages remove uric acid crystals.
Rapamycin decreases the action of macrophages to remove uric acid crystals.
So rapamycin can increase risk of gout.
In AD an action of rapamycin is to decrease inflammation caused by amyloid fibrils by decreasing inflammation due to microglia and this would lead to less senescent cells etc.
Action is not to remove amyloid; but amyloid is not the problem.
I hope this helps."
2 Likes
Agree that the focus on amyloid is misguided - how many billions of $ in research have they poured down this rabbit hole. There are probably many underlying causes of AD, from neuroinflammation, to faulty cholesterol trafficking and/or mitochondrial, ER lysosomal dysfunction - or even some process not yet elucidated. I’d wager that the Western diet, processed foods, environmental factors like microplastics, and an increased sedentary lifestyle (lack of exercise) work together to greatly influence one of more of these underlying dysfunctional processes, which result in (some) cases an accumulation of tau or whatever else.
1 Like
Unfortunately, reversing hippocampal grey matter loss, myelin sheath loss, p-tau build is not possible, so it’s all about prevention.
But other than that, Dr G, like the rest of us, has NO idea the upstream causation pathway. It’s quite possible it’s multiple genes and pathways (plethora of studies showing this smoking gun) at play.
No two ways about, we will need human RCT clinical trials.
2 Likes
The knives are out.
Someone ask Dr B which “correct animal models, rapamycin prevents AD”?
Which itself is a dysfunctional comment??
Since in which “CORRECT animal models” do we see “AMYLOID DEMENTIA” = definition of Alzheimer Dementia = HUMAN trait?
3 Likes
Wonder how they evaluate cognitive function in a mouse. Some kind of running through a maze I guess.
In humans we ask questions having to do with memory and cognition.
Alan G has hundreds of very elderly that he’s been treating. Some of them must have some degree of plaque formation. Have any of them experienced sudden symptoms of AD? Even some increase in recent memory loss?
Yes Dr Green likely has the largest and best uncontrolled Rapamycin random trial. You’d think he would be seeing some type of signal either way?
I am going to pursue the cancer/transplant angle to see if I can find something meaningful. Nothing yet.
This comes back to the issue of tracking brain / cognition / memory over time… still looking for a standard measure that is cheap, easily done, and verified by academic studies:
At this point, this study has raised my RHR to 54.5.
I have been around long enough to see the publication of medical findings from major research groups only to be discredited in later years.
Since I am 81 yrs. old, I can be the canary in the coal mine. People I have known personally were well aware of their increasing signs of dementia and onset of Alzheimer’s long before they became non-functional. My family history has had zero Alzheimers or dementia, at least in recent generations. So, if I see signs I am getting Alzheimer’s or dementia and haven’t died from other causes, I will let you know because it may be from taking high doses of rapamycin.
https://journals.plos.org/plosmedicine/article/file?type=printable&id=10.1371/journal.pmed.0020124
P.S,: I am a retired engineer and we are not noted for our great English skills, so please discount English errors as a sign I am losing it.
5 Likes
We used to use the mini mental exam as a screening tool in a very large independent living facility. You could administer it every year or so and check for lower scores.
The test isn’t perfect but it’s easy to do and follow.
There’s a max score of 30 . Most of it is easy but serial 7’s can be a challenge.
2 Likes
I reached out to one of the oncologists in the rapamycin/cancer/GFJ trial asking about Sirolimus/mTOR inhibitors and reports on cognition.
He sent me this paper:
Cognitive function after heart transplantation: Comparing everolimus-based and calcineurin inhibitor-based regimens
https://onlinelibrary.wiley.com/doi/epdf/10.1111/ctr.12927
https://sci-hub.se/https://doi.org/10.1111/ctr.12927
The study found NO difference between everolimus or CNI groups.
Within this paper, others were referenced.
Immunosuppression using the mammalian target of rapamycin (mTOR) inhibitor everolimus: pilot study shows significant cognitive and affective improvement
https://sci-hub.se/10.1016/j.transproceed.2009.08.050
“This report describes favorable psychiatric outcome variables using everolimus in maintenance heart transplant recipients”
Effects of immunosuppressive drugs on the cognitive functioning of renal transplant recipients: A pilot study
https://sci-hub.se/https://doi.org/10.1080/13803395.2011.595396
“Planned comparisons revealed that groups treated with sirolimus or tacrolimus resolved cognitive tasks worse than those treated with cyclosporine and controls. More specifically, performance of sirolimus and tacrolimus groups was significantly impaired in comparison with that of controls in the direct and time arithmetic tasks and numbers key test. In sum, we observed impairment in the resolution of various cognitive tasks in those patients treated with sirolimus or tacrolimus”
2 Likes
High incidence of cognitive impairment in renal transplant patients I believe. Rapamycin may well exacerbate it. And prevent it if early enough.
2 Likes
Not probably: definitely. It’s a model of early-onset Alzheimer’s. EOAD actually is driven by amyloid beta.
2 Likes
170 ng/ml would be a gargantuan dose in humans. Is that avg. levels? That would be like taking 100 mg every four or days for a 70 kg person.
2 Likes
Thanks. Seemed like it would take a very hefty dose.
1 Like
In the meantime fish consumption over 1 serving per week lowers AD risk by 60 % and viagra lowers it by 70%. Exercise also lowers it.
Certainly wouldn’t stop rapamycin over this study.
3 Likes