INTRODUCTION: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing.

METHODS: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways.

RESULTS: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found.

CONCLUSIONS: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.

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Published in Alzheimer's & Dementia.

© 2021 The Authors

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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This work was supported by Jerome-Lejeune Foundation grant no. 1887-BE2019B to EB and MP; and a Fondi Ateneo grant funded by Sapienza University no. RM11715C77336E99 to EB and no. C26H15JT9X to MP. NIH grants no. R56AG055596 and AG060056 to DAB.

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