Rapamycin and Neurocognitive Decline
Rapamycin (Sirolimus in the U.S.), named as such, due to being found on Easter Island (Rapa Nui), was discovered in 1964. This article gives a fascinating history.
A critical energy signaling aspect of mitochondria (the organelle in cells that produces energy) was discovered to be inhibited by Rapamycin. This is designated as mTOR or the mammalian target of Rapamycin. Interestingly, this same target is available in all organisms and animals tested, even back to yeast.
Administration of Rapamycin has consistently yielded life extension in every animal or organism tested. Many individuals choose to take this medication on a cyclical (not daily) basis to inhibit mTOR for 24-48 hours, then have a recovery period and repeat. The most common regimen is weekly dosing if taking for longevity or cognition. Rapamycin is an FDA approved drug which has been used extensively for a number of conditions with daily dosing, with the most common use being an immunomodulator in individuals with a kidney transplant.
The side effects with use of Rapamycin weekly is usually minimal. The benefits are speculative, due to insufficient human trials with outcomes focused on longevity or cognition. Trials are slowly starting to occur, but this is a generic medication, and there is no big pharmaceutical company funding behind it. If we wait for a clear result from human research, it is likely that many of us will be dead, and if life extension is proven, this will have been missed. Conversely, there could be risks to taking this medication. This study details observed side effects with taking Rapamycin with cyclic use: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187519/
A brief summary of adverse effects with Rapamycin taken weekly:
- During the first 6 months, about 15% of individuals have some blisters in their mouth (aphthous ulcers/canker sores) that heal by themselves
- There may be a slight increased risk in the 24-48 hours after taking Rapamycin, that you could be susceptible to bacterial infection (like soft tissue or lung infection)
- Most individuals will have a slight increase in their HbA1C and their ApoB, but those items should be managed anyway as part of a longevity strategy, and are easy to keep optimized for most individuals whether on Rapamycin or not
A brief summary of probable short/long term benefits with Rapamycin taken weekly:
- Enhanced T cell immunity (ability to respond properly to viral infections, vaccines, self surveillance for areas of malignancy that your immune system should identify which worsens with age)
- Less depression and anxiety
- More lean body weight and less sarcopenia
- Slowing of aging, diseases related to aging, including cognitive decline
Another excellent resource for individuals investigating use of Rapamycin is Rapamycin News, which is available here: https://www.rapamycin.news/news
This is a forum filled with individuals trying to increase health-span, lifespan and decrease risk of neurocognitive decline. Reading the introduction, and looking through topics can be a great source of information. It should be noted that there is a rapidly growing group of individuals worldwide who are taking Rapamycin, off-label for slowing aging.
One video worth watching is that of Dr. Alan Green. He treats approximately 1400 patients with Rapamycin. He has reported having over 300 patients with ApoE4’s, and indicates that to his knowledge, none have developed dementia while under his care. This is interesting information, and should be taken into consideration, however, it isn’t a properly conducted trial.
The video of Dr. Green discussing Rapamycin is a slower and less vigorous presentation than many; but the content is interesting. By Dr. Green’s own report, he is pretty certain he’d have died years ago had he not started himself on Rapamycin. https://youtu.be/zWJQecgNloU?feature=shared
I’m going to give a very brief summary of my reading of the literature on this topic in regard to Alzheimer’s Disease (AD) and Parkinson's Disease (PD). We have animal models that seem reliable for AD that reverse or stabilize with Rapamycin. We see cellular changes of Tau protein reverse in mice who have induced AD changes to their brains. With PD we have less literature, but what we do have is indicative of Rapamycin decreasing the changes that lead to PD, namely alpha synuclein.
It is critical to point out that lifestyle is a huge cofactor to mitigation of risk of AD - but Rapamycin is possibly the most significant pharmacotherapeutic available currently for those with risk of AD (essentially everyone with ApoE4’s and those with E3’s to a little less priority).
The other general benefit of taking Rapamycin, is the likely benefit of slowing one’s rate of aging. A good review is here in Nature Aging https://www.nature.com/articles/s43587-023-00416-y
For those interested in some of the relevant literature, Below are articles of interest, first on AD and then on PD.
With AD the data we have, and our ability to target high risk individuals (ApoE4’s) allows for a primary prevention approach with a drug that has low risk of adverse effects. With PD, it is more problematic, as we have less ability to identify individuals at high risk, and by the time they come for treatment, they already have established disease. In general, Rapamycin looks much better at preventing disease than fixing it once present; especially in the case of PD.
On that topic, a condition that is somewhat similar to PD, Multiple System Atrophy (MSA) which also is caused by misfolded alpha-synuclein, did not have benefit from Rapamycin. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.28923
Another useful article discusses the issue of Rapamycin being sensible and with reasonable evidence before disease is established (for AD and probably for PD also). However, once there is significant disease, it might not be useful, and could even be harmful - especially in advanced disease. https://pubmed.ncbi.nlm.nih.gov/31066320/
Currently there are two ongoing trials of sirolimus/Rapamycin for AD:
There are no current trials ongoing for PD.
Here is my general advice to my patients who are starting on Rapamycin
#2 Below are my detailed instructions that I give to patients, but each patient will have an individualized modification of this.
If on Rapamycin, unless told otherwise, avoid Grapefruit/Pomegranate and look at any prescription drugs for interactions especially during the day of, and 2 days after taking Rapamycin. It is best to take Rapamycin with a consistent dose of the same fatty food (such as 1 ounce of nuts) as this enhances absorption.
Trehalose 5 grams daily considered with Rapamycin for neurocognitive decline/Parkinson's. See reference https://pubmed.ncbi.nlm.nih.gov/30582934/
You will also be prescribed 14 capsules of doxycycline (unless allergic). In the event you have signs of a bacterial infection, primarily soft tissue infection (red swollen, painful area on the skin) or a lower respiratory tract infection (no runny nose, but having cough, fever, shortness of breath), we recommend taking a single capsule of doxycycline and immediately contacting Dr. Fraser to have him assess what is occurring and need for ongoing treatment. If you are significantly unwell, obviously seek emergency/urgent care review by a licensed healthcare professional.
Dosing for most individuals can start at 2 mg initially, then 4 mg a week later, then 6 mg a week later – and increase dosing weekly, until you are on your final recommended dose. Hold any dose escalation for side effects and contact Dr. Fraser.
Alternatively, for patients who want to dose conserve - with physician consultation and review we can choose to take the Rapamycin with Grapefruit Juice (GFJ). It should be noted that a single glass (8 oz) of high quality GFJ, taken 3 hours before taking the Rapamycin will generally triple the potency of the Rapamycin, as GFJ inhibits CYP3A4 in gut and liver. The effect lasts 24-48 hours. The following dosing is typically recommended if doing weekly (once every 7 days) dosing. Note that GFJ is used intermittently during weaning up, but will be used every time once you are on your final weekly dose. Another important point is one needs a review of their medications to make sure no other medications interact with GFJ (the most common will be statins, where Rosuvastatin should be used if taking GFJ). We recommend monitoring of blood levels in patients taking Rapamycin with GFJ. This generally done under specific guidance from Dr. Fraser, even though the blood test is self ordered (see below).
Week 1: 2 mg (no GFJ)
Week 2: 1 mg with GFJ
Week 3: 4 mg (no GFJ)
Week 4: 2 mg with GFJ [for many patients this will be the final dose and no further escalation, as going beyond this will be based upon indication and body weight]
If escalating to higher doses based upon discussion with Dr. Fraser, continue escalating to the final dose as discussed. Higher dosing usually requires spacing out to dosing every 10-14 days based upon blood levels.
When to take Rapamycin? Some individuals find it affects sleep. We’ve not consistently seen this, but if it does, take in the morning. Most individuals who are on a standard work week where they workout during the week, and take the weekend off of weight lifting, prefer to take their Rapamycin on Friday night. The rationale is that you are less likely to build muscle in the 48 hours after taking a therapeutic dose of Rapamycin. During these 2 days, zone 2 aerobic exercise is sensible, but heavy weights are best at least 2 days after Rapamycin.
Dosing interval: For some patients at high risk of neurocognitive decline – we will work to optimize some higher dosing, along with monitoring, which generally results in a dosing interval of 14 days, instead of 7 days.
Rapamycin/Sirolimus Levels: Email: help@hippevoshop.com This is self ordered and doesn’t require me to order this. Their price for LabCorp test 716712 Sirolimus – Whole Blood is $48.00 (ordered through normal means cash pay is usually a bit over $100 so this is the best source currently). Please include the following information to allow us to make a lab requisition: Patient name, Date of Birth, Phone, Address, Email, Payment Information. *Please let them know to Fax the result to Grant E Fraser M.D. at (931) 591-3353.
Alzheimer’s Disease Articles
Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease | PLOS ONE
Inhibition of mTOR by Rapamycin Abolishes Cognitive Deficits and Reduces Amyloid-β Levels in a Mouse Model of Alzheimer's Disease - PMC
Effect of rapamycin on aging and age-related diseases—past and future - PMC
Rapamycin Responds to Alzheimer’s Disease: A Potential Translational Therapy - PMC
mTOR signaling and Alzheimer's disease: What we know and where we are? - PMC
Rapamycin and Alzheimer’s disease: Time for a clinical trial? - PMC
APOE Genotype-Dependent Pharmacogenetic Responses to Rapamycin for Preventing Alzheimer’s Disease - PMC
mTOR signaling as a molecular target for the alleviation of Alzheimer's disease pathogenesis
Towards disease-oriented dosing of rapamycin for longevity: does aging exist or only age-related diseases? - PMC
Full article: It may be possible to delay the onset of neurodegenerative diseases with an immunosuppressive drug (rapamycin)
Effects of rapamycin and TOR on aging and memory: implications for Alzheimer’s disease - Santos - 2011 - Journal of Neurochemistry - Wiley Online Library
Effect and Mechanism of Rapamycin on Cognitive Deficits in Animal Models of Alzheimer’s Disease: A Systematic Review and Meta-analysis of Preclinical Studies - IOS Press
The Interaction of mTOR and Nrf2 in Neurogenesis and Its Implication in Neurodegenerative Diseases - PMC
https://www.jneurosci.org/content/41/19/4305.long
Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease | Acta Neuropathologica Communications
Rapamycin Ameliorates Cognitive Impairments and Alzheimer's Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice
Rapamycin Activates Mitophagy and Alleviates Cognitive and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer's Disease
Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer’s disease - PMC
Rapamycin rejuvenates oral health in aging mice - PMC
Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer's disease
The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy | PLOS ONE
As an aside - this video by Dr. Greger is an interesting presentation on why maintaining your teeth is critical to decrease risk of neurocognitive decline. Dental Implant Overdentures and Cognitive Function
Healthy Teeth and Gums
Parkinson’s Disease Articles
Reduced Prevalence of Parkinson’s Disease in Patients Prescribed Calcineurin Inhibitors - IOS Press
Neuroprotective Effects of Temsirolimus in Animal Models of Parkinson's Disease
Effects and potential mechanisms of rapamycin on MPTP-induced acute Parkinson's disease in mice
Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions - PMC
[Neuroprotective effect of rapamycin against Parkinson's disease in mice]
Rapamycin Protects against Neuron Death in In Vitro andIn Vivo Models of Parkinson's Disease - PMC
In vitro modulation of mTOR and mGlur5 influence α-synuclein accumulation - PMC
mTOR inhibition alleviates L-DOPA-induced dyskinesia in parkinsonian rats
Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture
What have we learned here?
There are indicative animal and cell based studies, along with a reasonable mechanistic reason for Rapamycin to delay onset of aging related diseases, such as AD and PD. We need human data with individuals taking cyclic dosing.
- The side effects of Rapamycin, taken cyclically, are generally minimal. This should be managed under the care of an experienced prescriber.
- Would I take it myself if I had early PD, was at high risk of developing AD, or early cognitive decline? I have an ApoE3/E4, and have chosen to take Rapamycin, not only for that reason, but for lifespan and healthspan extension.
- Are there some drugs available for PD and/or AD that have better data? We are in an area of speculative treatment, with consistently positive data, but no data directly answering the questions we have in humans. The data around GLP-1’s and both PD and AD are also looking good, and have pharmaceutical company money backing the research.
- There may be reason for caution in use of Rapamycin for well established or advanced AD or PD - it could make things worse. This medication seems better as a preventer than a treatment in those with substantial disease.
Additional Similar Resources:
Disclaimer:
- This blog provides general education only and should not be used to diagnose or replace the advice of a qualified medical professional.
- This content is not intended to be a substitute for consultation with a qualified and licensed physician or another medical provider.
- Readers should consult a medical professional for advice, diagnosis and treatment relating to their individual case.
- You should discuss any supplement/medication being considered with your medical professional before starting it.
- This post could contain affiliate links. I may receive a small commission if you click on the links of the products and make a purchase.
Credit:
Special thanks to Antoine Dusséaux of www.adssx.com for his assistance with research and authoring of this blog.
