Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: targeting brain metabolic and vascular restoration

[Beth]

Finding those 300 people would be easy. Heck, I just did one brain mri I could donate! I imagine the issue would be finding people interested who have a baseline mri before starting rapa?

[L_H]

@adssx

one could just do 4 weeks of 1 mg/day once a year to protect their brain.

I appreciate the study was tiny but the findings were encouraging, as you say. Listening to Matt Ks podcast, he quoted a 14% increase in hippocampal volume after 4 weeks of rapamycin.

To put that in context:
we lose about 1% volume per year from middle age (so this could turn the clock back 14 years?)
exercise increases volume by about 2%
the MEND (nutrition, supplements and exercise) program increases volume by about 10%

if the 14% figure proves to be accurate and persistent, it would be astonishingly promising.

It also raises the question of whether there might be aggregation from MEND + Exercise+Rapamycin.
And also whether the effect size is greater similar or smaller in older age

[adssx]

At the end we don’t care about hippocampal volume, we care about cognition, and in the CARPE_DIEM trial cognition got worse after 8 weeks of daily rapa by many metrics, especially the MoCA score.

Among all the things they measured I don’t know the typical variation even in normal people. We don’t have the baseline either so we don’t know the change in % (but I tried to get an idea by adding the % out of the max theoretical score). And we don’t have the p-value:

(table and potential mistakes are mine )

There’s some consistency: the 3 tests measuring delayed recall (Hopkins, Craft story and Benson) got worse!

That’s not great. And that’s just 8 weeks of rapa 1 mg/day…

[dicarlo2]

I know that hippocampus volume decline is associated with neurodegenerative disease, but do we know if it’s causal? Or is it like amyloid and tau proteins where just clearing them doesn’t seem to modify the disease. Your post seems to indicate that it’s not disease modifying.

I’m mostly curious because my hippocampus volume is in the 1 percentile, and probably always has been. I do seem to have worse long term memory than others, and I’ve been interested in interventions that might improve hippocampus volume, but this study dissuades me given the lack of change (or even worsening) in functional metrics.

[Jonas]

@L_H

The study used 1mg/d but only for 4 weeks!

Yet it had an effect, which was surprising.

[adssx]

These are two different studies so we cannot conclude at this stage. Also, the brain volume study looked at asymptomatic APOE4 carriers whereas the CARPE_DIEM trial included people with “Mild Cognitive Impairment (MCI) or Alzheimer’s disease”. It might be that rapamycin is beneficial in asymptomatic people at risk but detrimental in symptomatic people.

[John_Hemming]

It is a strong mTOR inhibitor that operates in the nanoMolar ranage. 1mg/d will perhaps give a concentration equivalent to the peak of a 4mg one off dose.

[adssx]

@dicarlo2

I know that hippocampus volume decline is associated with neurodegenerative disease, but do we know if it’s causal?

Same question for cerebral blood flow by the way. Long-term coffee consumption seems protective against many neurodegenerative diseases and yet caffeine lowers CBF by 20 to 30%.

[John_Hemming]

Caffeine enhances mitochondrial activity

[macneu2299]

It is interesting that Matt still denies that Rapamycin may negatively affect glucose and lipids metabolism.
Does anyone know why Matt cycles Rapamycin for 12 weeks on and then for 6 months off.

[cl-user]

BTW here is a comparison of rapamycin 1mg daily vs 6mg weekly.

[John_Hemming]

That’s a nice chart. People who are perhaps less mathematical than some on this forum should note that this is a logarithmic chart in that the Y axis is the log (10) of the concentration. It may not be immediately obvious to everyone. (It will be immediately obvious to many).

Log (10) means that the power to base 10 is reported and it means that equal multiplications of a value have equal distance on the graph.

There is a multiple compartment approach potentially to rapamycin which treats tissues differently to serum.

[adssx]

@adssx

The ERAP trial in AD (NCT06022068) is supposed to have just completed. “7 mg taken once per week during 26 weeks.” So we should expect results soon? I’ve just emailed the researcher. In their protocol, they wrote:

The team behind the ERAP trial just published this: In vivo medical imaging for assessing geroprotective interventions in humans

They’re measuring a lot of things in that trial:

• [18F]FDG brain uptake
• MoCA & other neuropsychological cognitive tests
• CSF levels of amyloid beta, p-tau, and t-tau
• Cerebral blood flow
• Physical performance
• Whole blood rapamycin concentration
• Periodontal oedema and bone remodeling
• Thickness and thickness ratios of retinal nerve fiber layers in the macula and optic disc
• Pulse wave velocity in the aorta
• [18F]FDG uptake in atherosclerotic plaques in large arteries
• Diastolic function, microvascular function, myocardial-volume and strain
• Bone mineral density in lumbar vertebrae

It might be the best rapa trial ever done. Can’t wait for the results

[John_Hemming]

As long as they dont compound the rapa. To be honest, however, i think weekly is too frequent. The peak needs to be higher and the trough lower.

[adssx]

They use Rapamune.

Protocol is here: Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol 2024

It’s a six-month trial, so weekly might be okay @John_Hemming?

[L_H]

@adssx

It might be the best rapa trial ever done. Can’t wait for the results

Ditto, it’s obviously only a pilot (n=15) but what a great study.

[John_Hemming]

Its the trough that is the issue

[Jonas]

Aubrey de Gray has some new data on his multiple intervention trials. Additive effect on females. Complicated for males. I have not listened to the whole thing myself.

Breaking the Pro-ageing Trance | Dr Aubrey de Grey

[adssx]

In 2020, Mannick did a trial for a brain-penetrant mTOR inhibitor (RTB101): resTORbio reports interim data from Parkinson’s trial 2020

The multi-centre, randomised, double-blind, placebo-controlled Phase Ib/IIa trial is being conducted to investigate the safety and tolerability of once-weekly RTB101 alone or along with sirolimus.
Participants have been enrolled in three cohorts to date and were treated with 300mg RTB101 alone, 2mg of sirolimus alone, or 300mg of RTB101 plus 2mg of sirolimus.
Meanwhile, 2mg sirolimus, alone or in combination with RTB101, was not detected in the CSF. Enrolment for the combination cohort is ongoing.
resTORbio co-founder and chief medical officer Dr Joan Mannick said: “We are pleased to have observed that RTB101 is well-tolerated and crosses the blood-brain barrier in Parkinson’s disease patients at concentrations that have the potential to induce autophagy, the process by which cells break down toxic misfolded protein aggregates.

Unfortunately, the trial was suspended during the COVID-19 pandemic, the results were never published, and the sponsor (resTORbio) merged with another company (Adicet Bio) in 2020. Mannick left Adicet and Adicet is not working on neurodegenerative diseases anymore: Pipeline | Adicet Bio

Mannick then co-founded Tornado Therapeutics but they’re not working on NDDs either: Team

In the MSA trial they found “no brain mTOR engagement by oral sirolimus up to 6 mg/day”: Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy 2023. The protocol was the following: https://cdn.clinicaltrials.gov/large-docs/76/NCT03589976/Prot_SAP_000.pdf

We will use sirolimus dosages of 2 mg, 4 mg or 6 mg, once a day based on therapeutic drug monitoring in order to maintain sirolimus drug levels within a FDA-recommended target-range: 5-20 ng/ml. This daily dosage is within the range that is used clinically, and we expect this dose to be well tolerated.

So based on the above, I conclude that rapa does not cross the BBB at doses of 2 to 6 mg daily and serum levels of 5–20 ng/mL. Do you agree @DrFraser @AnUser @John_Hemming @CronosTempi?

Then, the potential benefits seen in the above small study (increased brain volume and CBF) and the ketamine study + the lower risk of AD and PD seen with rapa use in longitudinal studies could be (assuming the studies are correct) outside the brain? Improved BBB integrity? Immunosuppression? Improved cardiovascular function (and indirectly cerebral perfusion?)?

But one of the most bullish rapa experts, Joan Mannick, seems to have abandoned this path: not a good sign?

[AnUser]

RTB101 wasn’t a mTORC1 inhibitor according to Kaeberlein (Rapalog companies? - #9 by AnUser), it failed its phase 3 to improve immune response to flu vaccine (Rapalog companies? - #8 by AnUser), which is most likely why it merged. IIRC mTORC1 is what people believe provides the longevity benefits in animal models.

I don’t have evidence to the contrary for sure that rapamycin crosses the BBB in significant amounts, and I think the null hypothesis is that rapamycin doesn’t cross the BBB. So I’d agree that it doesn’t. Feels like we’d know pretty easily.

They believe that TOR101 (the lead candidate and different from RTB101) can have effect on NDD, it’s just not the clinical focus for trials, based on historical mTOR trials and success?