{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T09:15:01Z","timestamp":1775034901247,"version":"3.50.1"},"reference-count":86,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T00:00:00Z","timestamp":1748908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["NeuroSci"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder, heterogeneous at the molecular level and characterized by diverse and complex pathological features. Such features are known to accumulate silently in the brain over years or even decades before the onset of detectable symptoms. Despite long years of intense research activities, the disease remains orphaned of either disease-modifying therapies or a specific blood test capable of predicting the disease in the pre-symptomatic stages. This disappointing outcome of such efforts can be attributed to a number of factors. One of these factors is the failure of earlier research to capture the heterogeneity of the disease. Such failure has the direct consequence of poor patient stratification, which in turn impacts negatively on the development of specific and effective therapy. The second factor is the absence of detailed and accurate information on proteins and associated post-translational modifications, which may influence the initiation and progress of the disease. Recent studies have demonstrated that the quantification of various isoforms of phosphorylated tau protein in plasma and other biofluids can be considered as potential biomarkers for the early detection of Alzheimer\u2019s disease. Mass spectrometry-based proteomics and immunoassay-based multiplex proteomics are the two technologies in current use for probing the human proteome, both in tissues and biofluids. In the present review, we discuss the contribution of MS-based proteomics to efforts aimed at the identification and eventual characterization of the heterogeneity of the disease, and the key role of the same technique in the analysis of protein post-translational modifications associated with the disease is also discussed.<\/jats:p>","DOI":"10.3390\/neurosci6020050","type":"journal-article","created":{"date-parts":[[2025,6,3]],"date-time":"2025-06-03T06:21:51Z","timestamp":1748931711000},"page":"50","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Isoforms of Phosphorylated Tau as Potential Biomarkers for Alzheimer\u2019s Disease: The Contribution of Mass Spectrometry-Based Proteomics"],"prefix":"10.3390","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7578-1233","authenticated-orcid":false,"given":"Marco","family":"Agostini","sequence":"first","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, Corso Stati Uniti 4, 35100 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7568-3614","authenticated-orcid":false,"given":"Pietro","family":"Traldi","sequence":"additional","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, Corso Stati Uniti 4, 35100 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmoud","family":"Hamdan","sequence":"additional","affiliation":[{"name":"Istituto di Ricerca Pediatrica Citt\u00e0 della Speranza, Corso Stati Uniti 4, 35100 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/s41593-021-00999-y","article-title":"Large-scale deep multi-layer analysis of Alzheimer\u2019s disease brain reveals strong proteomic disease-related changes not observed at the RNA level","volume":"25","author":"Johnson","year":"2022","journal-title":"Nat. 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