Rapamycin and Alzheimer Disease: a Hypothesis for the Effective use of Rapamycin

#1

This new paper is from Tim Sargeant’s group out of Australia. Tims one of the leaders in autophagy research. We’ve covered Tim’s work here in the past in these threads:

here: Measuring Autophagy in Body and Brain, Comparing Autophagy Activators
here: What’s autophagy? It’s the ultimate detox that doesn’t yet live up to the hype

In 2019 we summarized work relating to the potential use of rapamycin for treating Alzheimer disease (AD). We considered the commentary necessary because use of rapamycin in people with AD is a very real prospect and we wanted to present a balanced view of the likely consequences of MTOR (mechanistic target of rapamycin kinase) inhibition in the AD brain. We concluded that use of rapamycin, an MTOR inhibitor that increases macroautophagy/autophagy, could hold promise for prevention of AD if used early enough. However, MTOR inhibition appeared ineffectual in resolving existing amyloid pathology in AD mouse models. In this View article, we update these observations with new studies that have used rapamycin in AD models and provide evidence both for and against its use in AD. We also discuss rapamycin in the light of new research that describes rapamycin-induced autophagic stress in the ageing brain and autophagic stress as the origin of the amyloid plaque itself. We conclude that rapamycin will have complex effects on the brain in AD.

Paper (paywalled):

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Predicting Alzheimers
#2

After reading the studies/trials of Rapamycin on mice and the possibility of it causing Alzheimer’s, we are not sure whether we should continue taking Rapamycin and giving it to our dog. I would like to see a study of the people who have been taking Rapam for organ rejection purposes to find out if a number of those people have Alzheimer’s. What are your thoughts ?

#3

I think most of the data suggests that rapamycin is much more likely to prevent alzheimers than cause it.

Have you seen these papers and threads?

Rapamycin and Alzheimer’s disease: Time for a clinical trial? Matt Kaeberlein and Veronica Galvan

Here: Intranasal Rapamycin Lessens Alzheimer-like Cognitive Decline in a Mouse Model of Down Syndrome

Did you listen to the podcast with Arlan Richardson: Intro to Rapamycin, An Interview with Arlan Richardson, Geroscientist

Here is the thread about the one mouse study suggesting increase in plaques: Rapamycin increases Alzheimer's-associated plaques in mice, study finds

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#4

Thank you for the submissions, I think it’s safe to say Rapa is not going to cause Alzheimer’s

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#5

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

Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer’s disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The “Evaluating Rapamycin Treatment in Alzheimer’s Disease using Positron Emission Tomography” (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer’s disease.

Discussion

The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer’s disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer’s disease.

Trial registration

ClinicalTrials.gov ID NCT06022068

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