Well this made my day…cognitive is my #1 focus. Thankfully (hopefully) it dosen’t translate well to humans, given the failure of this mouse model in AD translation.
“The experiments were conducted in a specific mouse strain called the 5XFAD, which is used as a model for human Alzheimer’s disease”
This is the problem with ITP…mice don’t get cognitive dysfunction in old age like humans.
There is plenty of literature in support of Rapamycin.
“Our data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.”
Phase 2 clinical trial with 1mg/day Rapamycin underway
The Texas study “mouse model” "at this point is little more than “clickbait” as featured in the Medical express and I am sure it will become fodder for Youtube.
Not sure what to make of that. Definitely a little concerning. Was it a TOR 1 or 2 effect , do you know?
You say it doesn’t translate well into humans?
Not sure either. This same university is publishing this study, yet in Phase 2 clinical trial for 1mg/day Rapamycin and MCI/Alzheimers. Irony.
As for study mechanism, mTOR yes:
“Researchers observed that afterRapamycin treatment, a protein called Trem2 (triggering receptor expressed on myeloid cells 2) is dramatically diminished. Trem2 is present in microglia which are immune cells in the brain and spinal cord. Trem2 is a receptor located on the surface of the microglia, and it enables these cells to engulf and degrade β-amyloid. Loss of Trem2 in microglia impairs the vital function of amyloid degradation, which in turn causes a buildup of β-amyloid plaques. Previous research has shown that loss of Tsc1 leads to activation of the mTOR (mammalian target of rapamycin) signaling pathway. Rapamycin, in contrast, blocks this pathway”
The experiments were conducted in a specific mouse strain called the 5XFAD, which is used as a model for human Alzheimer’s disease
Alzheimer research has used transgenic mouse models to study amyloid therapeutics, because wild type mice don’t get Alzheimers! This mouse model has led to ZERO FDA* approved treatments, zillions of dollars and decades later.
*Aduhelm was approved, but very controversial (scientifically…FDA was bullied), and radically scaled down re clinical use.
This is fascinating. So rapamycin treatment lowers TREM2 and thereby inhibits clearance of tau/amyloid. Guess what else happens when lowering TREM2? Insulin resistance goes up:
There are all kinds of papers on TREM2, these were just a couple I noticed. And I have not read them all, just FYI in case I got any of the above info wrong!
Thanks for posting the links (all mice), haven’t gone down the TREM2 rabbit hole.
Question: with thousands of HUMAN patients around the world over the past decades, getting various chronic dosing regiments of Rapamycin, surely…a cognitive detriment signal would be RESOUNDINGLY observed? Yet I’ve never seen any cognitive secondary outcome commentary?
I know classic sporadic AD is a later stage disease (65+), but either Rapamycin doesn’t cross the BBB into the CNS, or these cohorts never lived long enough to generate a large enough population signal?
I guess so(?) I haven’t seen any studies on a cognitive benefit in humans, either, so maybe nobody has looked at it either way yet. Seems like comparing transplant patients who do or don’t take sirolimus would be fairly straightforward (any higher/lower incidence of Alzheimer’s since the drug has been in use, for instance).
Yes…puzzling outcome. I have not had time to dig into the full text of the study. Need to evaluate the frequency and size of the dose administered. Multiple studies have been published reporting that rapamycin attenuates plaque progression. Stay tuned…
Here’s a study demonstrating the relationship of damaged mitochondria and development of neurodegenerative disorders including AD. Impaired mitophagy seems to be the problem
This study may suggest that rapamycin should be used with caution in AD patients as it may worsen the condition, but perhaps it doesn’t actually induce AD in the healthy.
But as we know, Alzheimer’s starts years (decades?) before there’s enough damage to manifest clinical symptoms. So how do we know who is “healthy”?
Either way, this is more evidence for fasting as being beneficial for cognitive health, since fasting (or CR) appears to activate TREM2. Perhaps regular cycles of fasting (or fasting-mimicking) could both offset any increased risk from rapa while at the same time enhancing rapa’s benefits.
I contacted Alan G about this study and here’s his response
“ the proper interpretation is study proves that amyloid isn’t the cause of AD. Rapamycin prevents the development of AD , but doesn’t increase removal of amyloid. Amyloid is a downstream byproduct of the upstream disease process. The amyloid hypothesis has greatly hindered understanding of AD and this is one more example.”
I know that many neurologists are very skeptical now of the amyloid- AD link.
Mitochondrial dysfunction and the role of autophagy and specifically mitophagy are gaining steam. Here’s a very recent look at this
A narrative review of risk factors and interventions for cancer-related cognitive impairment (2021)
References two studies using everolimus in mice, both showing cognitive improvement.
Rapamycin, Autophagy, and Alzheimer’s Disease
“Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), is believed to be one of such pharmacological agents. It is neuroprotective in neurodegenerative diseases and its primary action is thought to be via enhancement of autophagy, a biological process that not only facilitates the clearance of mutant proteins”
I agree with Dr Green. Amyloid is a downstream marker, not root cause.
Mitchondrial dysfunction as well as impairment of the BBB, are two leading theories.
APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β
“Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer’s mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD.”
Here’s a very comprehensive review of the various theories re AD published in Nature. One leading theory is that mitochondrial dysfunction- perhaps secondary to poor mitophagy- leads to amyloid. This is basically striking the match that leads to tau formation which starts the forest fire of microglial related inflammation. This inflammation may be the real clinical problem and is reduced by TREM2, the fire extinguisher.
Infections, notably herpes simplex, May also strike the match, and there’s quite a bit of supporting evidence for that.
In either case, in the presence of microglial brain inflammation you don’t want to inhibit TREM 2.
That’s not to say that rapamycin is actually involved in the genesis of this process but perhaps pours gas on the fire .
APOE and TREM2 are two high association AD risk genes.
“We included 708 subjects ranging from cognitively normal (CN, n = 221) to mild cognitive impairment (MCI, n = 414) and AD dementia (n = 73) from the Alzheimer’s disease Neuroimaging Initiative. Our results suggest that a higher CSF sTREM2 levels are associated with attenuated ApoE4-related risk for future cognitive decline and AD-typical neurodegeneration. These findings provide further evidence that TREM2 may be protective against the development of AD.”
There are tons of older folks walking around with significant amyloid load, yet are cognitively normal. It’s upstream amyloid.
Maybe the San Antonio Phase 2 Rapamycin/MCI trial (1 mg/day) will shed some further light. Or these participants may be too far gone to impact trajectory?
To qualify to participate in this study, must have:
Minimum Age: 55 Years Maximum Age: 89 Years
Diagnosis of MCI or Alzheimer’s with:
Mini-Mental State Examination of 18 to 30
Clinical Dementia Rating of 0.5 to 1
Presence of amyloid plaques, based on a PET brain scan
Interesting. That study on rapamycin should help.
So let’s say that this is the chain as is suggested by the Nature article:
Impaired autophagy/ mitophagy- mitochondrial dysfunction- amyloid- tau- microglial brain inflammation- further neurodegeneration and clinical symptoms of AD.
The inhibition of TREM 2 exacerbates the inflammation.
If the chain hasn’t already been set in motion, rapamycin may be protective, but otherwise harmful. It’s not very practical since you’d have to PET scan people in their 50’s and start rapamycin on those that are plaque free.
But maybe amyloid and tau have to reach a certain critical mass before brain inflammation is initiated, so then rapamycin would be beneficial in preventing more plaque formation via unregulated mitophagy.
