I should have provided more info. Kurve is in the process of getting FDA approval for their device. They are focusing on delivery of insulin to the brain. But, there is a mechanism by which they can sell the device with a doctor prescription. I mentioned intranasal rapamycin to the CEO of the company and he indicated that he could configure the device for a specific dosing regimen if there were demand for it. So. . . we would need a bunch of people to be interested. Also, the device is not cheap. It’s likely to cost a few thousand $. But. . . it ensures consistent dosing and proper nubulization (not sure that’s the word) of the drug for best absorption.
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I think now I recall having seen it before — and it’s supposed to cost roughly $2.5 grand once and if available. I’m not interested. It looks like a fancy nasal spray. ChatGPT once gave me the proper info to dissolve Rapa into a solution that should have good intranasal uptake. I’d use it with a simple nasal spray or nebulizer. Thing is no one knows what the idea dosage should be anyway so I’m not sure that much is gained by having such a precise device. With insulin I can understand why the dosage needs to be very precisely controlled.
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Is the idea with intranasal rapamycin to make it easier to cross the blood brain barrier?
Yes, that is the idea.
That’s a useful chart. How hard is it to plot other dosages. I would be curious to see how to get close to the 1mg daily using 2mg pills. It would also be interesting to see what bi-weekly 10mg looks like.
There are various dosage scenarios in the original thread here: Rapamycin pharmacokinetics model
Plus a few more in the model adjusted with my own blood results: Blood concentration of rapamycin (N of 1 dosage, model and biomarkers)
I can add more of them if needed. That said there is an individual variability so people should get their levels tested. I can use the model with other people measurements if they have enough data points taken as I’ve indicated in the original threads.
Would this type of administration, nasal spray, be a good process to use high purity Rap powder with no excipients?
Thanks. I am feeling inspired by this study on hippocampus volume. I have not seen anything in this newsgroup about taking a daily dose for a short period of time like one month.
My own supply of Rapamycin is 2mg pills, so I was considering 2mg every other day for four weeks. I should mention that I’m an APOE-4 carrier and at 58 I have plenty of signs of a compromised hippocampus.
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Ai-Ling Lin’s full text preprint: Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers 2025
Rapamycin, known for its anti-aging properties, shows promise as a preventive strategy for Alzheimer’s disease (AD) in APOE4 carriers—the highest-risk group for late-onset AD. Here we show that a 4-week open-label trial of low-dose Rapamycin (Sirolimus; 1 mg/day) significantly improved cerebral blood flow (CBF) relative to baseline in cognitively normal APOE4 carriers (E4(+)) aged 45–65. It also reduced inflammatory cytokines, enhanced lipid metabolism, increased short-chain fatty acids (SCFA) and enriched gut microbiome composition linked to SCFA production. Conversely, non-carriers (E4(-)) displayed stable baseline-to-post-treatment CBF and SCFA and demonstrated different treatment-related patterns of metabolic and anti-inflammatory effects than E4(+). Serum amyloid A and tau remained unchanged for both groups. These findings suggest Rapamycin may counter early vascular and metabolic deficits in E4(+) individuals, with genotype-specific effects. By bridging anti-aging research and AD prevention, this study highlights a novel, safe, and precision-based approach to mitigating AD risk in APOE4 carriers.
Ultimately, 23 Caucasian participants completed the intervention between March 2, 2023, and July 19, 2024. Among them, 9 were APOE4 carriers—1 homozygous (e4/e4) and 8 heterozygous (e3/e4). The remaining 14 were non-carriers, including 12 with the e3/e3 genotype and 2 with e2/e3. Both groups had comparable age, BMI, MoCA scores, blood glucose, and HbA1c levels (Table 2).
An intriguing finding in this study is the reduction in RDW following Rapamycin treatment in both E4(+) and E4(-) groups. RDW reflects the variability in the size of circulating red blood cells (anisocytosis) and is traditionally used in clinical hematology to assess conditions like anemia. Emerging evidence suggests that RDW is increasingly recognized as a marker of biological aging, chronic inflammation, and oxidative stress. The observed reduction in RDW may support the idea that Rapamycin, as an mTOR inhibitor, can slow down aging-related processes. Interestingly, this finding aligns with previous research showing that, in midlife, RDW and CBF exhibit different patterns in APOE4 carriers and non-carriers27. This suggests that E4(+) may have a distinct hemodynamic response to changes in red blood cell health. Our data further support this connection, showing that Rapamycin not only restored CBF but also reduced RDW specifically in the E4(+) group, reinforcing its potential as a precision intervention for vascular and metabolic aging in this high-risk group.
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Any details on this? Anything more than “outside the normal range”?
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This is a super interesting paper, now that I’ve had time to properly read it.
If we take RDW as a strong predictor of aging rate (based on Levine calculator), this paper showed that, in non-carriers, you’re getting reduction in RDW (from RDW dropped from 13.1% → 12.5% in 4 weeks (p = 0.0002). That’s after only one month of Rapamycin. However, RBC turnover is usually around 120 days. So I’m not sure how to interpret that. Does it mean subjects were producing more uniform sized RBCs? Or they are clearing oddly sized ones at a more rapid pace? Since RDW is a distribution measurement, it is strongly affected by tails at both ends - i.e. very large or very small cells.
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RDW is a potential victim of Goodhart’s law. "When a measure becomes a target, it ceases to be a good measure."
In many ways so is WBC. (also in the formula)
The formula says lower WBC is better, but in fact you can over weaken the immune system thereby having WBC too low. I personally tend to always be officially “leukopenic” and when I take Rapamycin my WBC goes even lower and the lab start phoning me up every week.
I don’t myself think the lower WBC that I am getting from Rapamycin actually means I am healthier.
Similarly Rapamycin will vary MCV hence intermittent rapamcyin will mean a higher RDW.
It would be interesting if forum participants could indicate their RDW and their frequency of Rapamycin. Mine is every 2 months, the last RDW I had was 14.9. Before rapamycin it was in the 12% area.
However, I don’t think this is a sign of worse health it is merely a side effect of infrequent Rapamycin.
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This is a really interesting post, but I’m not sure I agree with you on this. I agree we don’t want to chase arbitrary metrics, but here it entirely depends on what RDW% is reflecting and I don’t think we know enough to discount it so easily. RDW% may be a sign of better clearance of junky RBCs, better function of macrophages in your spleen, or a sign of more consistent haematopoesis (which involves autophagy from what I remember, because RBC progenitors need to remove organelles to become mature RBCs). Any of those could be direct effects of Rapamycin and RDW% could be a legit, easy to measure, biomarker for its activity. (To be clear, I’m saying “could be”, I am not saying “it is”)
In the study, Rapamycin did not affect MCV in the non-carriers and in the carriers, it was a tiny change (though P = 0.026). RDW% is a distribution, so it’s more weighted towards being affected by outliers of very small or very large cells that won’t have that much effect on MCV.
The point you make about daily vs intermittent dosing is really interesting. Though with people taking the popular protocol of 5g once per week, the total dose isn’t that much different to the study (1mg/day). By my (bad) math, if you took 5mg once per week and assume a 60h half life, you still have ~0.7mg remaining when you take the next dose. As a crude estimate, that’s not terribly far off the 1mg/d dose in the study.
And for WBC, what you probably care about more is the function of the immune system, of which the total concentration of circulating WBCs is just a small portion. I agree that one probably doesn’t want to be actually leukopenic, but a better question is can you still respond as needed to infections. I think it’s reasonably well documented that “normal” people with higher WBC counts tend to be worse off because this likely reflects chronic inflammation.
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I agree it is worth measuring although my preferred lab that has a lot of biomarkers for a good price does not include it.
I also agree that the function of the immune system is key, but you do need some WBCs. My WBC is always under 3G (billions of cells per litre), at times it goes under 2G and then the lab has to phone me up.
You are right that people with higher WBC tend to be more inflamed. With me CRP is often too low to measure at 0.15mg/L.
My point about dosing is not daily vs weekly, but weekly vs fortnightly or even my high dose, but really infrequently.
In other words I don’t think we disagree much if at all.
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APOE4 impairs autophagy and Aβ clearance by microglial cells 2025
Tel-Aviv University
Alzheimer’s disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.
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I just completed a 4 week course of 2mg every other day. I was trying to approximate the 1mg / day dosing used in the study, but I only have 2mg pills. Symptoms were mild. I felt a little sluggish toward the end of the month, especially at the gym. I also found that it took me several days to recover from a particular intensive leg workout. No mouth sores.
On the day after my last dose, I measured my blood levels of Rapamycin at Labcorp. My levels were 4.6 mg/dl.
My current plan is to take a month off and then go back to semi-monthly dosing. (I originally wrote this wrong as “bi-monthly”. I went back and edited.)
Given how easy this 4 week course was, I’m thinking to do it again in 3 or 4 months, unless new info comes to light or one of you convince me that it’s a bad idea.
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N = 10?
They are all over 65
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I think the peak concentration matters, but also the trough matters. If you mean by “bi-monthly” taking it for a month every other month I think that has insufficient trough. Furthermore I think the peak is not that good either.
Thanks, John. I wrote that incorrectly and went back and edited. I meant semi-monthly - or more accurately ever other week. But, now I realized that I have caused more confusion in the way I wrote it.
I have actually been following your general protocol of a large dose every 2 weeks with nothing in between.
I’m now thinking to mix that up and maybe 2x or 3x per year, take a four week period of daily 1mg (or every other day with 2mg). Then I would take a few weeks off and go back to the bi-weekly (every other week) protocol.
BTW, I did some blood level testing at 6 hours after dosing. My numbers were:
2mg + GFJ = 9.6ng/dl
8mg w/o = 14.3ng/dl
I split the difference and have been doing 4mg w/ GFJ but have not gotten around to the blood work to see how that translates. I will try to do the blood work next time.
What do you think of this concept of doing a daily (or bi-daily dose) for four weeks, then taking a break, then going back to the usual pulsed protocol? I don’t know the reasoning behind Ai-line Ling’s decision to use daily 1mg dosing, but it seems that it has done some good and it does not seem like it did any harm.
Thanks.
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I take a large dose less frequently than every 4 weeks. It is now two months and I have not yet rescheduled rapa. I think mTOR inhibition should be normal most of the time.
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