#1

This is a really good overview of rapamycin in the context of AD, with many aspects addressed, including ApoE4, metformin, and astaxanthin. I seem to remember some concern expressed in one of the threads about the interaction between asta and rapa, unfortunately I can’t find it atm, but I thought this paper suggests that perhaps asta might ameliorate some negative impacts of rapa. Well worth reading, I think - I searched but couldn’t find if this review has been posted somewhere before:

Quote:

" Inhibiting mTOR signaling with rapamycin not only protects against Aβ and tau pathology but also may prevent memory impairments. Simen et al. 84 evaluated the impact of the rapamycin, an mTOR inhibitor and autophagy stimulator, on the tau‐mediated neurodegeneration and synaptic loss in a mouse model of early‐stage AD‐type tauopathy. The results of the study displayed that intraperitoneal injection of rapamycin can alleviate neuronal, axonal, and synaptic loss in perforant pathway projection and the entorhinal cortex. The perforant starting from layer II of the entorhinal cortex ending in the hippocampal dentate gyrus has a central role in long‐term memory and is precisely delicate to damages caused by tauopathy. 84 , 143

In the study conducted by Wang et al., 144 it was observed that rapamycin not only improved cognitive deficits but also enhanced memory viability, learning, and the expression of synapse proteins in APP/PS1 mice. The authors suggested that cognitive function in the APP/PS1 group showed a direct correlation with autophagy activation and an inverse correlation with mTOR activity and Aβ plaque levels, while the levels of soluble or insoluble Aβ were not significantly associated with cognitive function. These results indicated a significant involvement of mTOR signaling in the cognitive performance of APP/PS1 mice. Similarly, Cassano et al. 72 reported that the administration of everolimus, in their study led to improvements in cognitive functions such as novel object recognition, spatial memory, inhibitory passive avoidance, and depressive‐like phenotype in 3xTg‐AD mice.

On the other hand, given that balanced mTOR activity has a pivotal role in learning and memory, chronic inhibition of mTOR activity by rapamycin or other mTOR inhibitors may harm cognition in the long term. 145 Sui et al. 146 found that systemically administered rapamycin in mice can cause deficits in spatial memory retrieval but not acquisition. 147Moreover, when rapamycin was infused into the basolateral amygdala or dorsal hippocampus of the rat, novel object recognition became impaired. 148 , 149 The study on an 8‐month‐old APP/PS1 transgenic mice model for AD revealed that astaxanthin (Ast), as a carotenoid with potent antioxidant and neuroprotective properties, can activate the mTOR pathway and can ameliorate cognitive impairment, and suggests that the Ast may be beneficial for the treatment of cognitive impairments in AD. The authors suggest that Ast diminishes cognitive deficits of AD by enhancing the mTOR‐dependent mitochondrial dynamics, decreasing Aβ accumulation, and ameliorating synaptic damage."

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Rapamycin as a preventive intervention for Alzheimer’s disease in APOE4 carriers: targeting brain metabolic and vascular restoration
#2

Iranian paper… :grimacing: :grimacing: :grimacing:

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#3

Yes, but a rare good one, and one of the authors is from a German uni.

#4

She’s a student… :man_facepalming:

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#5

That being said, there is a case for mTOR inhibitors, but maybe not rapamycin/sirolimus as it doesn’t engage the brain mTOR pathway:

See also this paper (Chinese + Frontiers so not great but the conclusion is interesting): Pharmacological mTOR inhibitors in ameliorating Alzheimer’s disease: current review and perspectives 2023

mTOR inhibition modulates a plethora of pathologies associated with AD. In sum, it is implicated in successfully elevating the clearance of Aβ fibrils and aggregates through autophagy and elevated blood flow, reduced tau hyperphosphorylation and tau filament removal, lowered neuroinflammation, and blood-brain barrier restoration (Figure 3). However, these successes must be taken with a grain of salt. mTOR inhibitor’s role in Aβ clearance is likely dependent on the time of administration, where a progressed disease state could elevate the level of lysosomal dysfunctions, which makes mTOR inhibitor’s elevated autophagy ineffective. Alternatively, AD models with an intrinsic lysosomal deficiency may also not response to mTOR inhibition intervention. Improved knowledge of the AD etiology concerning neuroinflammation is also necessary. It remains uncertain how microglia and astrocyte proliferation modulate neuronal death and cerebrospinal Aβ aggregates. Experiments that compare mTOR intervention outcomes before, and after, the onset of pathological markers will benefit treatment. This should be conducted in diverse model systems to avoid modelling biases; mice AD models typically have only a few types of AD pathologies. Better cell-type specific understanding of mTOR inhibition functions would clarify the varied outcomes between brain endothelial cells, glial cells, and neurons. In addition, an exploration of non-rapamycin mTOR inhibitors may be useful; current literature revolves around rapamycin when assessing the role of mTOR complexes in AD. These considerations will complement the upcoming findings from the clinical trials administrating rapamycin to MCI Alzheimer’s patients.

All the above has already been discussed:

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#6

Rapamycin’s role in Alzheimer’s is a frustrating one - not because it is ineffective, but because it holds tremendous promise, yet has never been given the light of day for human trials; that sentiment is even echoed by prominent rapamycin researchers [355]. So, why is there a call for rapamycin to be used in the fight against Alzheimer’s?
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Ultimately, it comes down to a mounting pile of pre-clinical data all pointing directly at rapamycin’s benefit. For example, a master protein implicated in many diseases - mTOR - is responsible for the increased production of tau proteins in the neurons (brain cells). Tau, itself, is perfectly normal and helps stabilize the cell’s transportation systems (known as microtubules); however, if tau is hyperphosphorylated (think of it like a tag attached to the protein), the tau protein destabilizes the microtubule network, impairing the cell’s ability to function [356]. Rapamycin is a key molecule in combating this process, because rapamycin is a specific inhibitor of the aforementioned master protein mTOR. So, as mTOR activity is reduced, tau is more readily cleared and less readily formed to be hyperphosphorylated. But, the benefits of rapamycin are believed to extend beyond reduced aberrant tau production.
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In one of several preclinical studies, the researchers gave rapamycin to an Alzheimer’s disease mouse model and showed that multiple markers of autophagy - a cellular clean up system - were elevated [357]. Fascinatingly, the autophagy machinery (a complex group of vesicles that literally engulf components of the cell and destroy them by mass, targeted acidity) was found to be most robustly found around mitochondria (yes, yes, “the Powerhouse of the Cell”) when rapamycin was administered.
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Not only that, rapamycin was able to partially (about 80%) recover the physical and functional integrity of mitochondria (measured by a metric called the ‘membrane potential’). Additionally, rapamycin dramatically reduced the levels of cell death proteins (Bax, for those aware), which stimulate cells to die off - obviously a no-go when discussing brain cells. Above all, however, the mice simply learned better and had better overall cognitive ability compared to similar mice with Alzheimer’s not given rapamycin. Like I mentioned, this isn’t the only signal we’ve received that rapamycin could potently push back Alzheimer’s [356]. So, are we doomed? Is there no way to translate this to humans?
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Well, there are some human studies using rapamycin for other outcomes (organ transplants, safety studies, etc.), but no studies on Alzheimer’s (although one safety study is underway). If it’s worth it to the individual, one could refer to other rapamycin trials and dose accordingly, but the use of rapamycin is different from trial to trial, with some advantages and disadvantages based on protocol used - I put together the protocols, along with the advantages and disadvantages of each as part of my premium research review here, if interested.
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The take-away here is that rapamycin has good evidence behind it being a potent anti-Alzheimer’s molecule, but that evidence is only as strong as the limitations of the studies it’s based on (pre-clinical research). I’m looking forward to when we will have human evidence looking at Alzheimer’s specifically.

No comments on my side. Text says it all: Potent potential anti-Alzheimer. Here the video:

Rapamycin’s Anti-Alzheimer’s Promise: An Autophagy Story