https://alzheimer-prevention.com/

[Brian4]

Hi everyone,

I just found out about Dr. Alan Green's new website:

https://alzheimer-prevention.com/.

I've dug into the research, and think that his low-dose, periodic rapamycin protocol is very promising (and likely very safe, compared to the every-day use in immune rejection-avoidance). People on fairly severe CR (or on some other comprehensive CR-mimetic drug regimen) likely don't need rapamycin, of course. But rapamycin could be useful for most people.

Brian

[Julie G]

Terrific find! I like his aggressive stance based upon our very real risk. I'm going to reach out to learn more for us all.

That said, rampamycin is an immune suppressant... and not to be taken lightly. We need a trial with our population.

[Brian4]

That said, rampamycin is an immune suppressant... and not to be taken lightly. We need a trial with our population.

Julie, agree strongly -- as does Green -- that we need a trial with our population. We should be able to make this happen. I just emailed you.

The idea of Green's once-a-week protocol is that the immune-suppressing effects will be minimal. But that needs to be studied, to be sure.

Brian

[Orangeblossom]

Just looked it up, on Wiki.

https://en.wikipedia.org/wiki/Sirolimus

and

https://en.wikipedia.org/wiki/Mechanist ... _rapamycin

After reading, I don't think it would be something I would risk taking preventatively, but would be interested to hear of any results.

It has only been shown in mice, right, not humans?

"In humans, conditions which increase mTOR also increase risk of development of AD, especially in APOE4 carriers. A high calorie diet increases mTOR and increases risk of AD. Obesity causes insulin resistance which cause high insulin levels and high mTOR levels and increases risk of AD."

Therefore wouldn't intermittent fasting and low carb diet do the same thing (lower mTOR) without having to try this drug? It mentions this on the Wiki link- "It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity"

I also didn't find it very clear if there is a direct link between mTOR and the process by which APOE4 causes AD.

[alangreenmd]

Hi Orangeblossum,
I have been on intermittent weekly rapamycin for 2 years. No side-effects. I would estimate intermittent rapamycin (6mg once a week) is probably like 30-40% caloric restriction as regards lowering mTOR.
I think your real question is what is connection between APOE4 and AD and how rapamycin blocks the link.
First need to understand Zlokovic 2 hit theory and first hit is to vascular system decades before the second hit (amyloid-tau).
E4 carriers begin to show deterioration of vascular system shown on PET scans in 20-39 y/o old group.
Here is the specific molecular defect: ApoE4 lipoprotein forms a very weak bond to LRP1 a brain transporter. (E3/E2 form strong bond) Result is accumulation of CypA a proinflamatory molecule which activates Nf-KB (the usual suspect) which activates MMP9 (dissolves proteins) which damages blood brain barrier and cerebral blood flow. Rapamycin lowers mTOR and lowering mTOR decreases the CypA-->NF-kB--->MMP9 pathway. High mTOR involved with decreasing autophagy which increases Amyloid and high mTOR huge role in hyperphosphorylated Tau; but for APOE4 carrier it is only ApoE4 doesn't form a strong bond with LRP1.
For best discussion see very short 1 1/2 page 2016 paper by Ai-Ling Lin, "mTOR: Alzheimer's disease prevention for APOE4 carriers."
In Lin 2015 study rapamycin prevents AD-like pathology with mouse model with human APOE4 genes. Big problem: Rapamycin is a generic drug and nobody to pay for human clinical trials. Note: Rapamycin is only for prevention in latent and prodromal stage.

[Brian4]

Dear Dr. Green,

Thanks for taking the time to share information with us.

I'm amazed that I missed the Ai-Ling Lin paper. By the way, here's a link to the full (very short and readable) text:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216689/

I appreciate Orangeblossum's (and others') concerns about side-effects, but I know many people who have started once-a-week rapamycin (usually between 3 and 7 mg. -- personally I think below 5 mg won't do much for an avg. size person) and have not seen any signs of problems. But of course we need to continue to test this (as you, Dr. Green, are doing).

For anyone under, say, 60 or so, who's reasonably healthy, I would recommend at least attempting severe calorie restriction instead, but CR can't be instituted very safely in the elderly, but, based on the rodent data, it appears that rapamycin can be.

So, my view would be, to lower mTOR signaling:

1) if you're not too old, biologically (which will correspond to a chronological age of 45-65, depending on one's state of health/aging), try fairly severe CR. (Mild CR won't be enough.)

2) if you can't institute CR safely, consider trying weekly rapamycin, perhaps ramping up from 2–3 mgs.

Dr. Green, are there affordable ways to measure mTOR signaling, or must we really on downstream effects?

A lot of people here are on ketogenic diets. This appears also to lower mTOR, but I'm not sure how much.

Brian

[Orangeblossom]

Thank you for explaining more.

I am still concerned about the immunosuppressant side effects. In the past (when my immune system was compromised due to surgery) I got Shingles. That was really horrible and still have post herpetic neuralgia from it. So I would be very wary of messing with the immune system.

I feel that if there are other ways of getting the same result I would prefer to use them really.

It is nice to see that some of the main things people are already doing (intermittent fasting combined with exercise and therefore calorie restriction) probably have the similar affect as the drug on mTOR, isn't it.

[circular]

I appreciate these explanations too. I really haven’t looked into mTOR. What about the idea this article highlights, that there are two mTOR pathways, one that increases longevity and another that leads to glucose dysregulation? Apparently mTOR stimulates both?

[circular]

I really haven’t looked into mTOR. What about the idea this article highlights, that there are two mTOR pathways, one that increases longevity and another that leads to glucose dysregulation? Apparently mTOR stimulates both?

Just bumping this in case anyone has thoughts, because the question keeps coming back to me.

[alangreenmd]

Hi Everybody,
For starters, Is rapamycin an immune suppressant. See two papers, Mannick study (ref 51 and Blagosklonny Ref 43) and also my discussion on rapamycintherapy.com. Rapamycin was approved in 1999 as a biologic poison. Specifically to be used for transplant medicine. This required daily dose to knock out mTOR1 and mTOR2. As used in this manner rapamycin is certainly an immune suppressant and certainly can't be used to prevent age-related disease or AD. In December 2014 study Mannick showed Everolimus (the rapalog from Novartis and used twice a day for transplant medicine) when given to elderly (60 y/o) people as WEEKLY dose improved immune system as shown from response to flu shot. I have been taking weekly rapamycin for 2 years and no colds etc. In low intermittent dose improves immune function in old people.

Rapamycin has one function lowers mTOR.
The people here are very familiar with idea of lowering mTOR to prevent AD. That is 100% of the Dr.Dale Bredesen Protocol. Caloric restriction, avoid carbs, physical activity and creating ketosis all have a single purpose, lower mTOR.
The Longo plan of intermittent fasting is primarily to lower mTOR. Rapamycin is merely a pharmacologic way to lower mTOR activity.

Lowering mTOR1 increases lifespan in all living things (25% in mice); but more importantly prevents most age related disease. Lowering mTOR 2 is bad for your health and does nothing good. The trick is to lower mTOR1; but not interfere with essential function of mTOR2.

People interested in how rapamycin works as an anti-aging agent should study the papers of Mikhail Blagosklonny, first paper 2006, a paper which revolutionized understanding of what we call aging in the 60-100 age group. The Blagosklonny references to study are 40-44.
People interested in how rapamycin prevents AD in APOE4 carriers should study work of Ai-Ling Lin. ( especially a 2015 study in mice with human APOE4 genes). All mouse studies and basic science studies in two sections [Mouse studies and Basic science.] The leading scientists are Ai-lIng Lin, Beric Zlokovic, Salvatore Oddo and Patricia Galvan in field of prevention AD with rapamycin.

In short, Rapamycin is a poison or an extraordinarily valuable medication depending on dose. Worth recalling that Paracelsus, the father of Toxicology, proclaimed 500 years ago that everything was a poison, just a matter of dose.

The difference between Bredesen method of reducing mTOR and pharmacologically reducing mTOR with rapamycin is that with diet, CR and ketosis can't "overdose" on reducing mTOR. Of course, when pharmacologically reduce mTOR, must know proper dose and regime and monitor,

Since 2010 rapamycin has prevented development of AD-like pathology and neurologic impairment in 8 mouse studies. What is needed now is proof that weekly (intermittent) rapamycin will prevents AD in APOE4 carriers and that proof will require extremely advanced neuroimaging.

Stick a pin in that.