Well, I will be the canary in the coal mine. If I start to lose it I will let you know before I’m too far gone. I am not too worried about it. Dr. Green is treating a plethora of old people like me. He should be able to see if there is a cognitive decline in patients that had no cognitive problems.
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Really we should be seeing a lot of early Alzheimer in transplant and cancer patients that get high doses of sirolimus/everolimus
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Do we have any data on these transplant patients? I am assuming that due to the seriousness of their underlying condition that their lifespan may be compromised already. Therefore, they may not develop AD and therefore it would not show up.
It’s like the statement that smokers have a much lower risk of developing Alzheimers…
because they die of cancer before they get it.
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Yes - the data on transplant patients is really dirty for many reasons… not the least of which is that they frequently don’t live as long as healthier people. Also - if you need a kidney transplant, for example, you’ve typically been sick for a very long time already.
The things that drive the need for a kidney transplant (end stage renal disease) are explained below - so most of these people have been unhealthy, and likely on many medications, for a long time:
Some conditions of the kidneys that may result in ESRD include:
- Repeated urinary infections
- Kidney failure caused by diabetes or high blood pressure
- Polycystic kidney disease or other inherited disorders
- Glomerulonephritis, which is inflammation of the kidney’s filtering units
- Hemolytic uremic syndrome, a rare disorder that causes kidney failure
- Lupus and other diseases of the immune system
- Obstructions
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Yes, that’s what I was afraid of. Alzheimer’s has the latest onset of the major aging diseases…
My problem with rapamycin is the same with metformin: under some circumstances, they seem to increase b-amyloid in the brain. https://ncbi.nlm.nih.gov/pmc/articles/PMC6613906/… Although the problem in the animal model appears to be when cognitive decline is already present, an increased AD risk is bad asf
Hi and welcome to the forums. I moved your post to a discussion that has already started on this topic. Please read the full thread to catch up on all the information related to this study and commentary.
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The article mainly refers to people who already have dementia. I am 81+ and have been taking metformin for decades with no adverse side effects. Still
“not crazy after all of these years”
From the article, you refer to:
“The consensus of available preclinical data is that rapamycin could be useful to prevent the onset or early development of AD neuropathology rather than as a treatment for dementia.”
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From 2019:
A just-released study by UT Health San Antonio and collaborating institutions shows age-related decreases in blood flow to the brain and memory loss can be modified with the drug rapamycin.
This finding, if furthered, holds implications for aging in general and perhaps offers an avenue to prevent Alzheimer’s dementia in some people, said research first author Candice Van Skike, Ph.D., of UT Health San Antonio.
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Any chance anyone has access to the following research paper?
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I have requested the full text from the author, I will let you know if I get it
I have it already - here you go. Very technical - a short summary: there are pros and cons to everything. More research needed.
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Sure they do: every aging organism with a brain does. If you have it, aging f#cks it over. Anything reputed to be an anti-aging therapy should blunt or restore age-related cognitive decline.
In this study,
we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats.
we used the Morris water maze to measure hippocampal-dependent spatial learning and memory in adult (16 months old) and aged (34 months old) rats that were either fed either a diet with empty microcapsules or a diet containing microencapsulated rapamycin at 14 parts per million (ppm) for 15 months starting at 19 months of age.
Total distance swam declined progressively throughout the 4 days of training (Figure 1b), indicating effective spatial learning among the groups. However, 34-month-old aged rats had significantly longer path lengths than the 16-month-old adult rats on training days 3 and 4. No significant differences in path length were observed in aged rats treated with rapamycin as compared to adult rats on any training day. Additionally, there were no differences among the groups in the amount of slow swimming below 0.10 m/s during acquisition (Figure 1c).
During a 24-hr probe trial, aged rats made significantly fewer passes over the learned location of the hidden platform as compared to adult rats during a 24-hr recall probe trial (Figure [1]d). Recall of the hidden platform location in aged rats treated with rapamycin, however, was indistinguishable from that of adult rats.
Together, these data indicate that deficits in spatial learning and memory in aged rats can be negated by mTOR attenuation, suggesting that spatial learning and memory impairments in aged rats are at least partially driven by mTOR. Of note, chronic mTOR inhibition did not rescue age-related decreases in swim speed, ruling out an impact of mTOR attenuation on neuromotor pathways or muscle function and activity required for swimming.
Decreased presynaptic density is associated with mild cognitive impairment and AD (Scheff et al., 2015) and with cognitive impairment in rodents (Wang et al., 2014). To define whether changes in synaptic integrity occur during normative aging in rats and understand the role of mTOR, we measured presynaptic density in rats after completion of training and testing in the Morris water maze. Density (Figure 3a and b) and quantity (Figure 3a and c) of synaptophysin-positive synaptic boutons in hippocampal CA1 were decreased with advanced age in rats. Both density and quantity of synaptophysin-positive synaptic elements in aged rats treated with rapamycin to attenuate mTOR, however, were indistinguishable from those of adult animals (Figure 3a–c).
These data indicate that in addition to mediating AD-like cognitive and cerebrovascular deficits in models of AD and atherosclerosis, mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging.
https://onlinelibrary.wiley.com/doi/10.1111/acel.13057
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That would be a huge dose, more than any of us is taking. But that doesn’t mean the paper should be ignored. I restrict calories at the beginning of my rapa cycle to (I’m guessing)) counteract the effects on ADAM10 and TREM2.
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I was in the first stage of the study but was disqualified for having no signs of plaque. I am too a 3/4
I’m jealous. I qualified for the study (which means I do have elevated plaque but normal cognition) but decided not to participate as it is a 4-year study with a 50% chance of placebo and the drug still has some potentially serious side effects. I think that there will be better drugs soon. I’m planning on getting my baseline biomarkers and then going back on Rapamycin. I only took it for about 5 months and I felt better when I was taking it.
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Hello, have you found any new information on whether Rapamycin may lead to increased amyloid in the brain? Would very much appreciate any insights –
Hi Deborah,
Rapamycin in AD is somewhat confusing. Reports suggest that in younger adults, and older people who either don’t have AD, or in its earliest stages, rapamycin is likely to be helpful In later stages of AD, the brain’s lysosomal system is severely damaged and treatment with rapamycin is likely to exacerbate this damage. And I stress, we are still in the early stages of the “rapamycin revolution” so there is much that we still need to study and learn.
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Thank you for your reply. Just sent in an application for the AHEAD Lecanemab study. If I learn that I have plaque I will participate; if I do not have plaque then I will start Rapamycin.
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Aducanumab was discontinued in January 2024 and the FDA put donanemab on hold for further safety review in March 2024. So, I think one should be cautious about lecanemab.
See also in the Journal of Alzheimer’s Disease: The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes 2023
After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab’s efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-β and its derivatives are not the main causative agents of Alzheimer’s disease dementia.
And in Science: Scientists tie third clinical trial death to experimental Alzheimer’s drug 2022
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