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Albeit substantial progress has been made in characterizing AD\u2010associated molecular and cellular events, there is an unmet clinical need for new therapies. In this study, olfactory tract proteotyping performed in controls and AD subjects (<jats:italic>n<\/jats:italic>\u2009=\u200917\/group) showed a Braak stage\u2010dependent proteostatic impairment accompanied by the progressive modulation of amyloid precursor protein and tau functional interactomes. To implement a computational repurposing of drug candidates with the capacity to reverse early AD\u2010related olfactory omics signatures (OMSs), we generated a consensual OMSs database compiling differential omics datasets obtained by mass\u2010spectrometry or RNA\u2010sequencing derived from initial AD across the olfactory axis. Using the Connectivity Map\u2010based drug repurposing approach, PKC, EGFR, Aurora kinase, Glycogen synthase kinase, and CDK inhibitors were the top pharmacologic classes capable to restore multiple OMSs, whereas compounds with targeted activity to inhibit PI3K, Insulin\u2010like growth factor 1 (IGF\u20101), microtubules, and Polo\u2010like kinase (PLK) represented a family of drugs with detrimental potential to induce olfactory AD\u2010associated gene expression changes. To validate the potential therapeutic effects of the proposed drugs, in vitro assays were performed. These validation experiments revealed that pretreatment of human neuron\u2010like SH\u2010SY5Y cells with the EGFR inhibitor AG\u20101478 showed a neuroprotective effect against hydrogen peroxide\u2010induced damage while the pretreatment with the Aurora kinase inhibitor Reversine reduced amyloid\u2010beta (A\u03b2)\u2010induced neurotoxicity. Taken together, our data pointed out that OMSs may be useful as substrates for drug repurposing to propose novel neuroprotective treatments against AD.<\/jats:p>","DOI":"10.1111\/bpa.13252","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T04:25:50Z","timestamp":1709871950000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neuropathological stage\u2010dependent proteome mapping of the olfactory tract in <scp>Alzheimer<\/scp>'s disease: From early olfactory\u2010related omics signatures to computational repurposing of drug candidates"],"prefix":"10.1111","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-7445","authenticated-orcid":false,"given":"Paz","family":"Cartas\u2010Cejudo","sequence":"first","affiliation":[{"name":"Clinical Neuroproteomics Unit, Proteomics Platform, Navarrabiomed, Hospitalario Universitario de Navarra (HUN), Universidad P\u00fablica de 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