Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease
Open accessAbstract
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 aging 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. Further, we hypothesize that lysosomal degradative capacity in the brain will likely determine how effective or detrimental rapamycin will be as a treatment of AD.Abbreviations: AD: Alzheimer disease; APP: amyloid beta precursor protein; MAPT/tau: 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 [416]
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Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
- Authors
- Carosi, J. M., & Sargeant, T. J.
- Affiliations
- South Australian Health and Medical Research Institute (AU)
- Corresponding author
- Sargeant, Timothy J
- Venue
- Autophagy
- Publisher
- Informa UK Limited
- Published
- 2023-02-10
- Volume
- 19
- Issue
- 8
- Pages
- 2386-2390
- ISSN
- 1554-8627 (ISSN-L)
- 1554-8635
- PMC
- PMC10351443
- OpenAlex
- W4318921225
- Cited by
- 41
- References
- 41
- Citations by year
- 2026: 6 · 2025: 18 · 2024: 11 · 2023: 6
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Autophagy (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Lysosomal Health in Ageing
- 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, amyloid plaques, lysosomal degradation, neurodegenerative disease treatment, amyloid precursor protein, tau protein, brain aging, AD mouse model
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Alzheimer Disease, Animals, Autophagy, Amyloid beta-Peptides, Neurodegenerative Diseases, Sirolimus, Mice
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