Pre-print publication so preliminary. 7 mg weekly dose for 26 weeks. Several CSF biomarkers increased (including total tau) indicative of possible neuron injury. Some Increases in brain glucose metabolism seen which is positive. Overall, kind of a mixed bag IMHO.
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As Matt Kaeberlein said in the Radiolab Dirty Drug podcast: If you have Alzheimers - rapamycin will repair and pull you back some.
If you don’t have Alzheimers and take rapamycin, you won’t get it.
Maybe along the lines of this study.
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Analysis of CSF biomarkers showed significant increases in NfL, total tau, and Aβ40, and a numerical, but non-significant increase of similar effect size in Aβ42. These findings parallel those reported in the only other published AD-rapamycin trial by Gonzales et al. [16], who demonstrated broad increases in CSF markers (Aβ42, Aβ40, p-tau and NfL) after only 8 weeks of daily rapamycin treatment. The short duration of that trial suggests that the shifts in CSF markers are unlikely to reflect natural disease progression and instead represent a reproducible drug effect. A difference between our study and that of Gonzales et al. lies in the reduction in p-tau/total tau ratio shown here (total tau was not reported in the previous study [16]). There are multiple potential explanations for the shifts observed in CSF markers, such as: (i) enhanced autophagy-mediated protein clearance from neurons (i.e., secretory autophagy) [45, 46], (ii) reduction of CSF turn-over [47, 48], and/or (iii) detrimental effects on neural cells [49, 50]. There were no significant correlations between increases in total tau or NfL and loss of gray matter volume (assessed using MRI) in any of the regions included in our study, implying that the observed increases in CSF are not related to acute accelerated atrophy. However, several factors complicate the interpretation of CSF results in our trial: baseline LP was performed during diagnostic clinical workup (median 8 months prior to enrollment, see Supplementary Information 1), and all participants started cholinesterase inhibitors during the same time period. Still, the CSF results reported here and by Gonzales et al. warrant further investigation.
So we don’t know if the observed elevated CSF biomarkers indicate damage or a change in how the brain “clears” proteins. Any thoughts on that @John_Hemming?
The authors conclude:
This pilot study demonstrates the feasibility of conducting a clinical trial of rapamycin in earlystage AD. Neither our study nor a previous similar trial showed improvements in primary efficacy measures, though both documented consistent elevations in CSF biomarkers that warrant further investigation. In the pre-registered primary regions of interest, [18F]FDG PET and MRI CBF outcomes remained stable over six months. Notably, several exploratory regions showed increases in [18F]FDG SUVR, a pattern that could be compatible with a neuroprotective effect of the study drug. The absence of decreases in metabolic and perfusion measures, despite the expected decline in this patient population, may in itself suggest relative preservation of function, though such a conclusion requires confirmation in larger controlled trials.
What Gemini tells me:
The most likely “guess” (and the one the authors lean toward) is that the CSF spike isn’t a sign of damage, but a sign of cleansing.
- Mechanism: Rapamycin’s primary job is to inhibit mTOR, which “turns on” autophagy (the cell’s trash-disposal system).
- The Theory: If rapamycin is working, it should be breaking down protein aggregates (Tau and Amyloid) and “flushing” them out of the brain cells. Where do they go? Into the Interstitial Fluid and eventually the CSF.
- The Proof: While Total Tau went up, p-tau (phosphorylated tau)—the specific toxic form that creates tangles—did not. This led to a decreased p-tau/T-tau ratio, which is usually considered a positive health indicator in the brain.
If the drug were truly neurotoxic (killing cells), you would expect to see:
- A decrease in glucose metabolism (PET).
- A spike in p-tau along with the T-tau.
- Worsening cognitive symptoms (which were not reported).
Instead, we see a brain that is metabolically more active but “shedding” more waste products. This suggests the drug is successfully “tuning up” the cellular machinery and clearing out the molecular trash, even if that trash makes the spinal fluid look “messier” in the short term.
The Caveat: The MRI did show continued brain atrophy (shrinkage). This suggests that while rapamycin is boosting the function of the remaining neurons (PET), it may not be strong enough (or the trial was too short) to stop the physical loss of brain tissue entirely.
I asked the authors: https://x.com/ADssx/status/2003038315344237017
I think the first question is whether the cell stops functioning properly. If it stops functioning properly then any biomarkers will shift depending upon the nature of the cell. I take a simplistic engineering type approach to this which is to fix the cell and see what problems remain rather than try to do a complex theoretical calculation which is almost certainly going to be wrong.