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Understanding changes in protein sequences due to amino acid substitutions (AASs) may be important for uncovering molecular mechanisms of this disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The study aimed at developing a bioinformatic pipeline for searching AASs in proteomic data and revealing the AD-specific ones, highlighting potential biomarkers and\/or therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The developed pipeline integrates peptide\n                      <jats:italic toggle=\"yes\">de novo<\/jats:italic>\n                      sequencing approach, database searches, and retention time prediction. It was applied to a large collection of AD proteomic data from global consortium studies obtained for post-mortem brain tissue samples.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Proteins with identified AASs were clustered by functionality. Proteins heavily enriched with AASs were the ones associated with ion transport activity, ATP binding, and G-protein signaling, aligning with known AD mechanisms. Further we classified the identified AASs by their origin (tRNA misacylation, post-translational modifications, single nucleotide polymorphisms) and by Braak stage and sex. Pathogenicity analysis, cross-referenced with clinical information, identified pathogenic mutations in HBD (W38S), GFAP (N77D), and NEFL (N98D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The developed pipeline successfully maps disease-relevant protein variants by uncovering novel molecular features of a disease with biomarker and therapeutic potential. AASs identified in the work for AD samples reveal specific pathogenic mutations and implicate important biological processes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251414414","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T13:50:14Z","timestamp":1770126614000},"page":"242-257","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping protein variants associated with Alzheimer's disease by mass-spectrometry based\n                    <i>de novo<\/i>\n                    sequencing assisted strategy"],"prefix":"10.1177","volume":"110","author":[{"given":"Daria D.","family":"Emekeeva","sequence":"first","affiliation":[{"name":"V.L. Talrose Institute for Energy Problems of Chemical Physics, N.N. 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