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While the presence of large, insoluble neurofibrillary tangles has long been the primary focus of this research, a paradigm shift in the field now highlights smaller, soluble oligomers as the more neurotoxic Tau species leading to neuronal death and cognitive decline. This leaves the important and ill\u2010understood question of what molecular events lead to the conversion of healthy, functional Tau into these toxic oligomers. This review addresses the knowledge gap by investigating existing literature on the upstream mechanisms responsible for the onset of neurodegeneration and connecting it to disease pathogenesis. By synthesizing evidence from molecular biophysics, cellular biology, and neuropathology, this review summarizes the most recent understanding of factors contributing to pathological Tau aggregation, including post\u2010translational modifications, lipids, and metal ions, among others. This review also discusses how neurotoxic Tau aggregates contribute to the onset of AD. By connecting these factors with findings from mammalian brain studies, this review establishes a comprehensive timeline of pathology that demystifies the transition from physiological Tau to toxic oligomers and links specific molecular triggers to the onset of neurodegeneration.<\/jats:p>","DOI":"10.1002\/pro.70635","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T04:15:31Z","timestamp":1779855331000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Biophysical assessment of the molecular mechanisms of Tau aggregation and its role in Alzheimer's disease"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2658-1707","authenticated-orcid":false,"given":"Joshua T.","family":"Skrehot","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Kurouski","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics Texas A&amp;M University  College Station Texas USA"},{"name":"Department of Chemistry Texas A&amp;M University  College Station Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2019.02.007"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-022-01230-7"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01575-4"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.274329"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5078"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.16294"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpclett.4c01718"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.595532"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2194"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-021-00732-z"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.07.018"},{"key":"e_1_2_15_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2007.06.004"},{"key":"e_1_2_15_14_1","doi-asserted-by":"crossref","unstructured":"Bell\u2010SimonsM BuchholzS KlimekJ ZempelH.Axonal Tau sorting depends on the PRR2 domain and 0N4R\u2010specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity. 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