This new paper is from Tim Sargeant’s group out of Australia. Tims one of the leaders in autophagy research. We’ve covered Tim’s work here in the past in these threads:
here: Measuring Autophagy in Body and Brain, Comparing Autophagy Activators
here: What’s autophagy? It’s the ultimate detox that doesn’t yet live up to the hype
In 2019 we summarized work relating to the potential use of rapamycin for treating Alzheimer disease (AD). We considered the commentary necessary because use of rapamycin in people with AD is a very real prospect and we wanted to present a balanced view of the likely consequences of MTOR (mechanistic target of rapamycin kinase) inhibition in the AD brain. We concluded that use of rapamycin, an MTOR inhibitor that increases macroautophagy/autophagy, could hold promise for prevention of AD if used early enough. However, MTOR inhibition appeared ineffectual in resolving existing amyloid pathology in AD mouse models. In this View article, we update these observations with new studies that have used rapamycin in AD models and provide evidence both for and against its use in AD. We also discuss rapamycin in the light of new research that describes rapamycin-induced autophagic stress in the ageing brain and autophagic stress as the origin of the amyloid plaque itself. We conclude that rapamycin will have complex effects on the brain in AD.
Paper (paywalled):
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After reading the studies/trials of Rapamycin on mice and the possibility of it causing Alzheimer’s, we are not sure whether we should continue taking Rapamycin and giving it to our dog. I would like to see a study of the people who have been taking Rapam for organ rejection purposes to find out if a number of those people have Alzheimer’s. What are your thoughts ?
I think most of the data suggests that rapamycin is much more likely to prevent alzheimers than cause it.
Have you seen these papers and threads?
Here: Intranasal Rapamycin Lessens Alzheimer-like Cognitive Decline in a Mouse Model of Down Syndrome
Did you listen to the podcast with Arlan Richardson: Introdução à Rapamicina, Uma Entrevista com Arlan Richardson, Gerocientista
Here is the thread about the one mouse study suggesting increase in plaques: Rapamycin increases Alzheimer's-associated plaques in mice, study finds
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Thank you for the submissions, I think it’s safe to say Rapa is not going to cause Alzheimer’s
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A new paper, small pilot trial, no significant results:
Rapamycin treatment for Alzheimer’s disease and related dementias: a pilot phase 1 clinical trial
The 1 mg/day dose of rapamycin is selected based on our prior data in older adults demonstrating acceptable tolerability using this dosing regimen20. The primary aim of the study is to evaluate the central nervous system (CNS) penetrance of the drug by performing mass spectrometry on cerebrospinal fluid (CSF) collected prior to treatment and within 20–60 min of the final study drug dose.
The drug rapamycin has been shown to increase longevity and reverse changes in the brain associated with Alzheimer’s disease and related dementias in animal models. However, rapamycin’s role in the clinical setting is unclear. Here we show data from a phase 1 clinical trial in ten participants with mild cognitive impairment or Alzheimer’s disease who were treated with rapamycin (1 mg/day) for eight weeks. Findings show that rapamycin levels were not detectable in cerebrospinal fluid before or after treatment. All participants knew they were receiving rapamycin and did not experience any serious negative health events due to the treatment. Additionally, several Alzheimer’s disease and inflammatory biomarkers were increased from baseline to post-treatment. These results highlight the need to better understand the impact of rapamycin on Alzheimer’s disease in humans.
Open access paper:
https://www.nature.com/articles/s43856-025-00904-9
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I would think it is significant that rapamycin was not detected in CSF. This is much easier to test for than in brain tissue. It also gives a mechanism for testing higher dose rapamycin and seeing if that gets into CSF although CSF flow is not that good and that needs considering.
An interesting question is whether Rapamycin in the interstitial fluid in the brain could get from there into the CSF. Whichever way this is a good route to solid testing in vivo in homo sapiens as to better understanding of Rapamycin’s links to the brain.
I asked a chatGPT question about the difference between BBB and BCSFB.
Here’s a comparison of the two CNS barriers across several key features:
1. Location & Overall Architecture
2. Cellular Components & Tight Junctions
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BBB
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Endothelial cells possess continuous tight junctions (claudins, occludin) and minimal pinocytotic vesicles.
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Pericytes regulate barrier integrity and blood flow.
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Astrocytes induce and maintain barrier properties.
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BCSFB
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Choroid plexus epithelial cells form the selective barrier via their tight‐junction complexes.
- Underlying capillaries are highly permeable (fenestrated), so it’s the epithelium, not endothelium, that restricts passage.
3. Permeability & Selectivity
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BBB
- Extremely low paracellular permeability—only very small (<400 Da), lipophilic molecules, or those with dedicated transporters can cross.
- Robust efflux pumps (e.g., P-glycoprotein) that eject many xenobiotics back into blood.
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BCSFB
- Controls composition of the CSF rather than brain interstitial fluid.
- More permissive to metabolic waste moving from CSF into blood, and provides active secretion of electrolytes and nutrients into CSF.
4. Transport Mechanisms
| Mechanism |
BBB |
BCSFB |
| Passive diffusion |
Lipid‐soluble gases and drugs |
Similar, but contributes to CSF levels |
| Carrier‐mediated |
Glucose (GLUT1), amino acids, etc. |
High activity of nutrient transporters for CSF production |
| Receptor‐mediated |
Insulin, transferrin |
Less prominent |
| Efflux pumps |
Very high (P-gp, BCRP, MRPs) |
Present but generally lower activity |
5. Functional Roles
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BBB
- Protects neuronal environment by strictly regulating ions, neurotransmitters, and plasma proteins in the interstitial fluid.
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BCSFB
- Produces and maintains the ionic and protein composition of CSF (~500 mL/day turnover), providing buoyancy and waste clearance.
6. Implications in Disease & Drug Delivery
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BBB
- Often the primary obstacle for CNS drug delivery; its disruption is implicated in stroke, multiple sclerosis, and Alzheimer’s.
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BCSFB
- Altered CSF secretion/composition can contribute to hydrocephalus, meningitis, and drug clearance issues in the ventricles.
Summary
- The BBB is a capillary‐based endothelial barrier reinforced by glia, optimized to protect the neuronal milieu.
- The BCSFB is an epithelial barrier in the choroid plexus specialized for CSF production and maintenance.
Though both serve to shield the CNS, their distinct locations, cellular structures, and transport systems tailor them to complementary but different roles in brain homeostasis.
This is an interesting sub response from chatGPT
Efflux and clearance mechanisms
Even if rapamycin diffuses into the interstitial fluid, it is a known substrate for P-glycoprotein and other efflux transporters at both the blood–brain and blood–CSF barriers. These pumps rapidly shuttle rapamycin back into the bloodstream, preventing accumulation in the CSF or deeper into the parenchyma.
Which if we can substantiate that would
a) Indicate why Rapamycin is generally thought not to pass the BBB
b) But explains why high dose Rapamycin is thought to pass the BBB
But also indicates that what is needed for the brain is an mTOR inhibitor that is not a known substrate for P-glycoprotein and other efflux transporters (whatever the other ones are)
More from chatGPT
Research on rapamycin’s interactions with ATP-binding cassette (ABC) efflux transporters has demonstrated that it is a transport substrate for both P-glycoprotein (ABCB1) and the breast cancer resistance protein (ABCG2/BCRP), and that these transporters substantially limit its accumulation in the CNS.
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Substrate affinity and impact on brain penetration at the BBB
In a concentration‐equilibrium transport assay (CETA) using LLC-PK1 cells transduced with murine Mdr1a (the rodent homolog of human ABCB1) and Bcrp1, rapamycin was actively translocated from the basolateral to the apical compartment, demonstrating significant P-gp– and BCRP-mediated efflux (DSpace). Moreover, in Abcb1a/b–/–;Abcg2–/– knockout mice lacking both transporters, brain penetration of rapamycin increased approximately 13-fold compared to wild-type animals, confirming that these pumps at the BBB “profoundly impair” rapamycin entry into the parenchyma (DSpace).
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Expression and function of P-gp at the blood–CSF barrier
P-glycoprotein is not only abundant in brain capillary endothelial cells but also highly expressed on the apical membrane of choroid plexus epithelial cells, where it contributes to the blood–CSF barrier. Immunohistochemical and in vivo SPECT imaging studies using the P-gp/MRP substrate ^99mTc-sestamibi have shown a strong blood-to-CSF concentration gradient across intact choroid plexus epithelium in humans, indicating active efflux into the blood compartment (PubMed ). General surveys of P-gp distribution further confirm its presence in the choroid plexus epithelium, functioning analogously to its role at the BBB to pump xenobiotics back into the vasculature (Wikipedia).
Taken together, these data establish that rapamycin is a bona fide substrate for P-gp (and BCRP) at both the BBB and the blood–CSF barrier, and that these transporters actively shuttle the drug from the CNS compartments back into the bloodstream, severely limiting its CNS exposure.
I think this is really important because both PD and ALS/MND appear to result from mitochondrial problems and to actually fix those means getting to CNS cells. What it does is identify what sort of mTOR inhibitor might actually do the job.
