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Notably, individuals with DS exhibit significant neuropathological changes for a diagnosis of Alzheimer\u2019s disease (AD), typically by the age of 50\u00a0years. To search for and identify biomarkers crucial for detecting and understanding the mechanisms involved in DS neuropathology, we conducted a protein expression analysis of post-mortem brain samples. We evaluated the frontal cortex of post-mortem brain samples from patients with DS both before and after the onset of AD pathology (DSAD), in comparison with age-matched healthy patients (CTRY and CTRO). Employing a comprehensive label-free shotgun proteomics approach, we sought to gain a deeper understanding of the intricate protein profiles associated with DS and its progression into DSAD. Collected results have been analyzed using specific databases and bioinformatics analysis software to understand relevant pathways, networks, and functions related to the experimental data. Our data support a genotype effect in DS at young and old ages that promotes specific proteome signatures associated with AD development. Notably, the affected signalling pathways encompass energy-related processes, synaptic transmission, and stress response. With aging, the dynamic shift in protein expression contributes to accelerating the neurodegenerative process, culminating in the manifestation of the AD phenotype.<\/jats:p>","DOI":"10.1007\/s12035-025-05432-0","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T07:47:01Z","timestamp":1763711221000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome"],"prefix":"10.1007","volume":"63","author":[{"given":"Fabio","family":"Di Domenico","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Tramutola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Rataj-Baniowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Barone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lanzillotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Pieroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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