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An in-depth understanding of the pathogenesis and neuropathology of AD is essential for the development of effective treatments and early diagnosis techniques. The neuropathological signature of AD involves two hallmark lesions: intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau aggregates and extracellular senile plaques containing amyloid-\u03b2 (A\u03b2) peptide depositions. Although A\u03b2-centric research has dominated AD investigations over the past three decades, pharmacological interventions targeting A\u03b2 pathology have failed to demonstrate clinical efficacy. Tau, a microtubule-associated protein predominantly localized to neuronal axons, orchestrates microtubule stabilization and axonal transport through dynamic tubulin interactions under physiological conditions. In AD pathogenesis, however, tau undergoes pathogenic post-translational modifications (PTMs), encompassing hyperphosphorylation, lysine acetylation, methylation, ubiquitination, and glycosylation. These PTM-driven alterations induce microtubule network disintegration, mitochondrial dysfunction, synaptic impairment, and neuroinflammatory cascades, ultimately culminating in irreversible neurodegeneration and progressive cognitive decline. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a framework for biomarker discovery, targeted therapeutic development, and precision medicine approaches in tauopathies. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a solid theoretical and experimental basis for the early diagnosis of neurodegenerative diseases, the discovery of therapeutic targets, and the development of novel therapeutic strategies.<\/jats:p>","DOI":"10.3390\/biom15060824","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T11:04:06Z","timestamp":1749121446000},"page":"824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["The Role and Pathogenesis of Tau Protein in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3690-411X","authenticated-orcid":false,"given":"Xiaoyue","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Hubei Provincial Clinical Research Center for Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linshu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Lei","sequence":"additional","affiliation":[{"name":"Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Hubei Provincial Clinical Research Center for Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengliu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9997-3109","authenticated-orcid":false,"given":"Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Guerreiro, R.J., Schymick, J.C., Crews, C., Singleton, A., Hardy, J., and Traynor, B.J. 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