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Here, we reinvestigated detergent\u2010insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)\u2010mass spectrometry (MS)\u2010MS\u2010based proteomics, we robustly identified 125 proteins in the detergent\u2010insoluble fraction of late\u2010onset AD (LOAD) temporal cortex that included several proteins critical to A\u03b2 production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot. Following multiple analyses, we estimated that these represent \u223c80% of detergent\u2010insoluble proteins in LOAD detectable by our method. A\u03b2, tau, and 7 of 8 other newly identified detergent\u2010insoluble proteins were disproportionately increased in temporal cortex from patients with LOAD and AD derived from mutations in\n                    <jats:italic>PSEN1<\/jats:italic>\n                    and\n                    <jats:italic>PSEN2;<\/jats:italic>\n                    all of these except tau were elevated in individuals with prodromal dementia, while none except A\u03b2 were elevated in aged\n                    <jats:italic>APPswe<\/jats:italic>\n                    mice. These results are consistent with the amyloid hypothesis of AD and extend it to include widespread protein insolubility, not exclusively A\u03b2 insolubility, early in AD pathogenesis even before the onset of clinical dementia.\n                  <\/jats:p>","DOI":"10.1096\/fj.05-4263fje","type":"journal-article","created":{"date-parts":[[2005,8,29]],"date-time":"2005-08-29T20:13:07Z","timestamp":1125346387000},"page":"1923-1925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Proteomic determination of widespread detergent insolubility, including A\u03b2 but not tau, early in the pathogenesis of Alzheimer's disease"],"prefix":"10.1096","volume":"19","author":[{"given":"Randall L.","family":"Woltjer","sequence":"first","affiliation":[{"name":"Department of Pathology Division of Neuropathology University of Washington  Seattle WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. 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