The mTOR pathway: a common link between Alzheimer's disease and Down Syndrome
Open accessAbstract
Down syndrome (DS) is a chromosomal condition that causes many systemic dysregulations, leading to several possible age-related diseases including Alzheimer’s disease (AD). This may be due to the triplication of the Amyloid precursor protein (APP) gene or other alterations in mechanistic pathways, such as the mTOR pathway. Impairments to upstream regulators of mTOR, such as insulin, PI3K/AKT, AMPK, and amino acid signaling, have been linked to amyloid beta plaques (Aβ) and neurofibrillary tangles (NFT), the most common AD pathologies. However, the mechanisms involved in the progression of pathology in human DS-related AD (DS-AD) are not fully investigated to date. Recent advancements in omics platforms are uncovering new insights into neurodegeneration. Genomics, spatial transcriptomics, proteomics, and metabolomics are novel methodologies that provide more data in greater detail than ever before; however, these methods have not been used to analyze the mTOR pathways in connection to DS-AD. Using these new techniques can unveil unexpected insights into pathological cellular mechanisms through an unbiased approach.
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Our findings support a hyperactivated AKT/mTOR/p70S6K axis with IRS1 inhibition in humans with DS-AD.
“Our findings support a hyperactivated AKT/mTOR/p70S6K axis with IRS1 inhibition in humans with DS‐AD. 7 , 9 , 59”
From Disruption of hippocampal upstream regulators of mTOR and insulin pathways in Down syndrome with Alzheimer's disease neuropathology: Preliminary observations (2026) · cites this paper as [7]
Section 2.1 (page unavailable) reports increased IRS-1 phosphorylation and a hyperactivated Akt/mTOR/p70S6K axis in blood-derived exosomes from young children with DS. Section 2.2 (page unavailable) reports PI3K/Akt/mTOR hyperactivation in people with DS with or without AD. The copy does not establish the combined axis hyperactivation and IRS-1 inhibition specifically in humans with DS-AD; it presents the childhood finding as potentially relevant to later AD pathology. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOther factors besides APP contribute to cellular dysfunction in the brains of individuals with DS, including alterations to the mTOR cell signaling pathway.
“other factors contribute to cellular dysfunction in the brains of individuals with this developmental neurodegenerative disorder, including alterations to the mammalian target of rapamycin (mTOR) cell signaling pathway. 7”
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1 of the 119 references couldn’t be matched to a known paper.
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Park, S., Park, M., & Lee, H. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118472 · Cited by 10 · see citing works
Zhang, S., Wang, T., Gu, X. F., Zheng, R., Ding, N., Yang, J., & Zhang, M. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251400667 · Cited by 5 · see citing works
Vertebrate and Invertebrate Animal Models for the Study of Down Syndrome
Granholm, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26168092 · Cited by 3 · see citing works
Self-citationThe Role of Genetic Alterations in the Emergence of Alzheimer's Disease in Down Syndrome: A Review
Robles, C. V., Robles, C. V., Revilla, A. P. A., Suárez‐Valencia, V. D. J., & Salinas-Santander, M. A. (2026) · European Journal of Neuroscience · doi:10.1111/ejn.70623 · Cited by 1 · see citing works
Nordbeck, A. J., Martá‐Ariza, M., Ek Olofsson, H., Kanshin, E., Ueberheide, B., Jones, K., Sanford, B., Hamlett, E. D., Head, E., Mufson, E. J., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71776
“7 The mTOR complex 1 (mTORC1) regulates cell growth, autophagy, and protein synthesis, whereas the mTOR complex 2 (mTORC2) regulates cellular proliferation, migration, and survival.”
Self-citationPolyamine biosynthesis dysregulation in Alzheimer’s disease and Down syndrome cellular modelsPreprint
Sola, A., Sandberg, A., Pham, C., Revier, A., Hebinck, M., Penney, A. L., Caviedes, P. A., Kumar, S., Granholm, A., Linseman, D. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.31.635912
Self-citation
- Authors
- Wohlfert, A. J., Phares, J., & Granholm, A.-C.
- Affiliations
- University of Colorado Anschutz (US)
- Corresponding author
- Granholm, Ann-Charlotte
- Venue
- Journal of Clinical Medicine
- Publisher
- MDPI AG
- Published
- 2024-10-17
- Volume
- 13
- Issue
- 20
- Pages
- 6183
- ISSN
- 2077-0383 (ISSN-L)
- PMC
- PMC11508835
- OpenAlex
- W4403479278
- Cited by
- 6
- References
- 119
- Citations by year
- 2026: 2 · 2025: 4
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- NIH (1R01AG081356, AG071228-02, R01AG070153, R01AG061566, CA2018010)
- BrightFocus Foundation (1R01AG081356, AG071228-02, R01AG070153, R01AG061566, CA2018010)
- LeJeune Foundation (1R01AG081356, AG071228-02, R01AG070153, R01AG061566, CA2018010)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mTOR signaling, Down syndrome, Alzheimer's disease, amyloid precursor protein, amyloid plaques, neurofibrillary tangles, PI3K/Akt signaling, AMPK signaling, insulin signaling, amino acid signaling, neurodegeneration, spatial transcriptomics, proteomics, metabolomics, genomics
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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