Rapamycin and Alzheimer disease: a double-edged sword?
Open accessAbstract
Numerous studies have reported that inhibition of MTOR (mechanistic target of rapamycin kinase) clearly reduces Alzheimer disease neuropathological hallmarks in mouse models. This has resulted in calls for the use of the MTOR inhibitor rapamycin for the treatment of dementia in humans. Unfortunately, intervention with rapamycin in these mouse studies commenced before or early in the appearance of these pathological hallmarks. Later in Alzheimer disease, when dementia actually manifests, the brain’s lysosomal system is severely damaged and treatment with rapamycin is likely to exacerbate this damage. We reassess literature described by a recent perspective article calling for the use of MTOR inhibition in dementia and conclude that rapamycin could be useful, but only in people who are in the earliest stages of Alzheimer disease. We contend that our interpretation of preclinical data concerning use of rapamycin in Alzheimer disease models is necessary if we are to avoid another failed Alzheimer disease drug trial.Abbreviations AD: Alzheimer disease; APP: amyloid beta precursor protein; MAPT: microtubule associated protein tau; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1.
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Rapamycin may be beneficial in the early stages of Alzheimer's disease, but it aggravates Alzheimer's disease pathology as the lysosomal degradative capacity of the brain deteriorates.
“Rapamycin may be beneficial in the early stages of AD, but it aggravates AD pathology as the lysosomal degradative capacity of the brain deteriorates.416,417”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [417]
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The Amino Acid-mTORC1 Pathway Mediates APEC TW-XM-Induced Inflammation in bEnd.3 Cells
Zhang, D., Xu, S. C., Wang, Y., Bin, P., & Zhu, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179245 · Cited by 4 · see citing works
Dynamic changes in lysosome‐related pathways in APP/PS1 mice with aging
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Impact of Rapamycin on Longevity: Updated Insights
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Nutrition in Brain Aging: Its Relevance to Age-Associated Neurodegeneration
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İNSÜLİN DİRENCİ VE ALZHEİMER HASTALIĞI ARASINDAKİ PATOJENİK BAĞLANTI: FARMAKOLOJİK MÜDAHALELER
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- Authors
- Carosi, J. M., & Sargeant, T. J.
- Affiliations
- University of South Australia (AU)
- Corresponding author
- Sargeant, Timothy J
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2019-05-22
- Volume
- 15
- Issue
- 8
- Pages
- 1460-1462
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC6613906
- OpenAlex
- W2944447415
- Cited by
- 99
- References
- 15
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 13 · 2023: 15 · 2022: 15 · 2021: 15 · 2020: 13 · 2019: 4
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Funders
- the Hopwood Centre for Neurobiology
- the Australian Government
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- rapamycin, Alzheimer's disease, mTOR inhibition, lysosomal dysfunction, amyloid precursor protein, tau protein, mTORC1, treatment timing, dementia
- MeSH terms
- Alzheimer Disease, Animals, Autophagy, Humans, Amyloid beta-Peptides, Sirolimus, Mice, TOR Serine-Threonine Kinases
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