Alzheimer’s disease (AD) is characterized by amyloid-beta (Aβ) accumulation and tau protein pathology. The Aβ42/40 ratio serves as a key biomarker of amyloid burden, with lower ratios associated with disease progression. Similarly, elevated levels of phosphorylated tau at threonine 181 (p-Tau181) reflect tau pathology and correlate with early neurodegenerative changes in AD. While monoclonal antibodies targeting Aβ have shown efficacy in modifying these biomarkers, alternative therapeutic approaches such as mTOR inhibition remain underexplored in humans. Three amyloid-positive patients received sirolimus (7 mg/week) as an off-label use of an FDA approved drug, with an average treatment duration of 22 weeks. Plasma levels of Aβ42/40 and p-Tau181 were measured at baseline, mid-treatment and post-treatment. No concurrent plaque-modifying therapies were administered. All patients demonstrated increases in the Aβ42/40 ratio (range: + 19.4% to + 37.0%), while p-Tau181 levels decreased in two patients (−11.1% and −28.9%). The first biomarker changes, observed within 12 weeks, may reflect an early and potentially rapid effect. Sirolimus was well-tolerated with no reported side effects or clinical decline. These exploratory findings suggest that sirolimus may affect key plasma biomarkers associated with AD. Given its FDA approval and lower cost relative to monoclonal antibodies, sirolimus may warrant further clinical investigation as a potential disease-modifying approach. Further studies with controlled designs are required to determine whether these biomarker changes translate into clinical outcomes.
Disclaimer: low quality journal (“Bratislava Medical Journal” wtf).
This is fascinating … obviously need a better study, Interestingly, I do get patient’s into my practice that have ApoE4’s and are not on sirolimus. It might take me a year or so to get some folks in their late 60’s through 70’s and get baseline Amyloid Beta 42:40, p-Tau 181, p-Tau 217 and replicate this. I’d be only doing this in individuals at significant risk - would be best if they were ApoE4/E4 …
I think I’ll do a youtube video upcoming on this paper …
I think this points out that Sirolimus/Rapamycin likely has real effects in the brain, despite lack of BBB penetrance.
Of note, I have a fair number of older individuals with ApoE4’s who have been on rapamycin for years … none have cognitive decline at this time. However, I’ll need to more formally document on this going forward.
It appears that rapamycin gets perhaps 5% of the serum concentration into the brain maybe 10%. What I think is happening it it gets through the barrier, but is pumped back quite quickly, but not perfectly.
Hence it seems to have a minor effect, but that can be good.
That looks a paper that it would take a bit of time to analyse as to what is actually happening and I need to leave home to take my son to climbing at the moment.
They seem to be measuring NEVs whilst they are in serum.
I am not an expert in this specific field, but a lot of substances (exosomes and Rapamycin) have indirect effects by immune modulation. So maybe the exosomes or Rapa don’t need to actually enter the brain, but they affect immune system components which subsequently act on the brain. Immune cells can cross the BBB. The cytokines that they secrete can bind to receptors on brain endothelial cells and pericytes.
I would also point out that, to my knowledge, one feature of Alzheimer’s disease is a dysfunctional BBB - hence the leakage of these proteins into the plasma. And it’s also worth pointing out that the BBB isn’t some sort of impenetrable wall. It’s a whole system of tight junctions, transporters, efflux pumps etc. It is dynamic and the function can vary depending on whatever stimulus is applied (drugs, injury, hypoxia etc)
Yes, rapamycin can be beneficial without crossing the BBB. Similarly, the non-BBB-crossing immunosuppressant azathioprine had a positive result in an RCT in PD: Parkinson's disease - #730 by adssx
I was just questioning the point about rapa crossing the BBB. This doesn’t make sense to me. I’m sure that rapa can have benefits (for instance, via the gut axis, see this paper: Parkinson's disease - #948 by adssx ). And the paper I mentioned was in MSA, another neurodegenerative condition with a leaky BBB similar to AD. Also, previous trials of rapamycin in AD didn’t find traces rapa in the CSF (I posted that in another thread, forgot where…).