I enjoyed this piece as it highlights one of the most important lessons in translational aging research: remarkable results in mice do not automatically translate into humans. Rapamycin remains one of the most intriguing longevity interventions, but the gap between extending lifespan in animal models and improving human healthspan is where the real challenge lies. As a physician-scientist, I believe it’s important for both doctors and patients to distinguish enthusiasm from evidence. The mechanistic rationale for mTOR inhibition is compelling, and preclinical data are impressive, but questions regarding dosing, timing, safety, and long-term outcomes in humans remain largely unanswered. Biology is rarely as straightforward as it appears in model organisms. Perhaps the “rapamycin problem” is really a reminder that longevity medicine requires both curiosity and humility. Translating promising science into meaningful human benefit is far more complex than reproducing results in mice. Thanks for sharing this thoughtful and nuanced perspective!
Appreciate the balanced review, Dr. Yassine. I agree that we don't yet have human evidence showing rapamycin prevents Alzheimer's disease.
That said, some of us with APOE4/4 don't have the luxury of waiting decades for perfect data. We make decisions based on the totality of evidence available today: mechanistic data, animal studies, observational experience, individual risk profiles, and personal risk tolerance.
The late Dr. Alan Green (I was his patient from 2021 until he passed in September 2024) believed one of rapamycin's most important potential benefits for APOE4 carriers was protection of the blood-brain barrier. The APOE4-associated CypA–NFκB–MMP9 pathway leading to pericyte injury and BBB dysfunction remains, in my view, a compelling biological rationale for intervention, even if it has not yet been proven in humans.
For me, the question isn't whether rapamycin is proven. It isn't. The question is whether the potential benefit outweighs the potential risk in someone already carrying a substantially elevated lifetime risk of Alzheimer's disease. My answer remains yes.
My personal experience with once-weekly 6 mg rapamycin over the past several years has been uneventful. I take periodic breaks to allow washout and skip doses around dental procedures or other situations where infection risk may be increased. Dr. Green also encouraged practical precautions and ensured his patients had a Z-Pak on hand for prompt treatment should an infection arise.
For now, based on the available science, I will definitely continue taking rapamycin.
I agree with Karin Dee. The interesting thing is why there does not appear to be follow up study on humans to this 2020 study showing e4 genotype specific benefits in mice https://doi.org/10.1016/j.nbd.2020.104834ice.
The fact sirolimus is out of patent might be a factor? Considering e4 including with e3 underlies about 65% of late onset ALZ ( recent published research) makes this non interest very problematic. To say it’s mice only - with results like that - is actually an indictment of scientists and the funding bodies public and private. Why the silence? I’m looking at you Eli Lilly and Roche etc. The problem with gene therapy etc when it arrives is that for millions of people the horse has bolted. It seems very lacking that individuals are now having to do the work here? Of course this doesn’t capture the scope of everything that is happening but neither does it capture none of it. Hopefully the apoe4 alliance will get a rocket going where it helps.
1. They used a model with 5 autosomal dominant mutations in addition to E4. This model does not develop neurodegeneration, tau pathology or neuronal cell loss with aging. It is useful, but we have to be careful when interpreting what it shows.
2. The study design was not randomized or blinded, and unfortunately, this introduces bias if you knew the groups as you analyze the data
3. Sample sizes for behavior are small even for mouse studies
4. Gold standard for BBB measures (Evan blue, IgG, Alb Q were not measured.
As to why funding agencies are not supporting rapamycin studies in APOE4 humans, I have no say in this. All I can say is that research funding as a whole is under stress now, and many scientists are contemplating other careers. We need to support science.
Just one other thought , why on earth would the researchers have used what sounds like as stated an obviously poor model animal? That certainly needs an explanation and hoping some of the authors might respond? It is galling when ‘ALZ’ studies are not genotype specific and adequately gender powered. Not to mention potentially a wrong research model?
One other thing having had more time the 5FAD mouse model is described as having “early amyloid deposition starting as early as 1.5 months of age, “also “tau hyperphosphorylation at ser396 from as early as 2 months” And this appears to be why the model is widespread in ALZ research. Am I missing something (?) as might appear at odds with your comment?
Thank you very much for this very useful and clarifying response Dr Yassine, much appreciated. If you ever had time to look with your tremendous detail at Urolithin A research esp re E4 that would be of great interest. Apologies if I sounded unfairly strident. The slowdown in iv capsid aav dna e4 silence/e2 transfection by voyager therapeutics and intracranial route by Lexeo is disappointing , although rna/ ribozyme based editing may be advancing eg rz Korean company / Roche might be hopeful and trontinemab also moving forward. Good luck with your work and understand how stressful doing science is at the moment. I do wonder if the process can be sped up with more direct and courageous interactions with the often well informed , non scientist, patient group. This has been manifest in Huntingtons Disease and eg HD buzz publication ( often by significant scientists in the field) and trial recruitments etc where a much rarer disorder is finally making progress .
I enjoyed this piece as it highlights one of the most important lessons in translational aging research: remarkable results in mice do not automatically translate into humans. Rapamycin remains one of the most intriguing longevity interventions, but the gap between extending lifespan in animal models and improving human healthspan is where the real challenge lies. As a physician-scientist, I believe it’s important for both doctors and patients to distinguish enthusiasm from evidence. The mechanistic rationale for mTOR inhibition is compelling, and preclinical data are impressive, but questions regarding dosing, timing, safety, and long-term outcomes in humans remain largely unanswered. Biology is rarely as straightforward as it appears in model organisms. Perhaps the “rapamycin problem” is really a reminder that longevity medicine requires both curiosity and humility. Translating promising science into meaningful human benefit is far more complex than reproducing results in mice. Thanks for sharing this thoughtful and nuanced perspective!
Appreciate the balanced review, Dr. Yassine. I agree that we don't yet have human evidence showing rapamycin prevents Alzheimer's disease.
That said, some of us with APOE4/4 don't have the luxury of waiting decades for perfect data. We make decisions based on the totality of evidence available today: mechanistic data, animal studies, observational experience, individual risk profiles, and personal risk tolerance.
The late Dr. Alan Green (I was his patient from 2021 until he passed in September 2024) believed one of rapamycin's most important potential benefits for APOE4 carriers was protection of the blood-brain barrier. The APOE4-associated CypA–NFκB–MMP9 pathway leading to pericyte injury and BBB dysfunction remains, in my view, a compelling biological rationale for intervention, even if it has not yet been proven in humans.
For me, the question isn't whether rapamycin is proven. It isn't. The question is whether the potential benefit outweighs the potential risk in someone already carrying a substantially elevated lifetime risk of Alzheimer's disease. My answer remains yes.
My personal experience with once-weekly 6 mg rapamycin over the past several years has been uneventful. I take periodic breaks to allow washout and skip doses around dental procedures or other situations where infection risk may be increased. Dr. Green also encouraged practical precautions and ensured his patients had a Z-Pak on hand for prompt treatment should an infection arise.
For now, based on the available science, I will definitely continue taking rapamycin.
I agree with Karin Dee. The interesting thing is why there does not appear to be follow up study on humans to this 2020 study showing e4 genotype specific benefits in mice https://doi.org/10.1016/j.nbd.2020.104834ice.
The fact sirolimus is out of patent might be a factor? Considering e4 including with e3 underlies about 65% of late onset ALZ ( recent published research) makes this non interest very problematic. To say it’s mice only - with results like that - is actually an indictment of scientists and the funding bodies public and private. Why the silence? I’m looking at you Eli Lilly and Roche etc. The problem with gene therapy etc when it arrives is that for millions of people the horse has bolted. It seems very lacking that individuals are now having to do the work here? Of course this doesn’t capture the scope of everything that is happening but neither does it capture none of it. Hopefully the apoe4 alliance will get a rocket going where it helps.
thank you for bringing this paper up
1. They used a model with 5 autosomal dominant mutations in addition to E4. This model does not develop neurodegeneration, tau pathology or neuronal cell loss with aging. It is useful, but we have to be careful when interpreting what it shows.
2. The study design was not randomized or blinded, and unfortunately, this introduces bias if you knew the groups as you analyze the data
3. Sample sizes for behavior are small even for mouse studies
4. Gold standard for BBB measures (Evan blue, IgG, Alb Q were not measured.
As to why funding agencies are not supporting rapamycin studies in APOE4 humans, I have no say in this. All I can say is that research funding as a whole is under stress now, and many scientists are contemplating other careers. We need to support science.
Just one other thought , why on earth would the researchers have used what sounds like as stated an obviously poor model animal? That certainly needs an explanation and hoping some of the authors might respond? It is galling when ‘ALZ’ studies are not genotype specific and adequately gender powered. Not to mention potentially a wrong research model?
One other thing having had more time the 5FAD mouse model is described as having “early amyloid deposition starting as early as 1.5 months of age, “also “tau hyperphosphorylation at ser396 from as early as 2 months” And this appears to be why the model is widespread in ALZ research. Am I missing something (?) as might appear at odds with your comment?
Thank you very much for this very useful and clarifying response Dr Yassine, much appreciated. If you ever had time to look with your tremendous detail at Urolithin A research esp re E4 that would be of great interest. Apologies if I sounded unfairly strident. The slowdown in iv capsid aav dna e4 silence/e2 transfection by voyager therapeutics and intracranial route by Lexeo is disappointing , although rna/ ribozyme based editing may be advancing eg rz Korean company / Roche might be hopeful and trontinemab also moving forward. Good luck with your work and understand how stressful doing science is at the moment. I do wonder if the process can be sped up with more direct and courageous interactions with the often well informed , non scientist, patient group. This has been manifest in Huntingtons Disease and eg HD buzz publication ( often by significant scientists in the field) and trial recruitments etc where a much rarer disorder is finally making progress .