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Increasing evidence suggests that aggregating A\u03b2 drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely, there is a realization that non\u2010fibrillar (oligomeric) forms of A\u03b2 mediate toxicity in AD. Fibrillar (filamentous) aggregates of proteins across the spectrum of the primary and secondary tauopathies were the focus of recent structural studies with a filament structure\u2010based nosologic classification, but less emphasis was given to non\u2010filamentous co\u2010aggregates of insoluble proteins in the fractions derived from post\u2010mortem human brains. Here, we revisited sarkosyl\u2010soluble and \u2010insoluble extracts to characterize tau and A\u03b2 species by quantitative targeted mass spectrometric proteomics, biochemical assays, and electron microscopy. AD brain sarkosyl\u2010insoluble pellets were greatly enriched with A\u03b2<jats:sub>42<\/jats:sub> at almost equimolar levels to N\u2010terminal truncated microtubule\u2010binding region (MTBR) isoforms of tau with multiple site\u2010specific post\u2010translational modifications (PTMs). MTBR R3 and R4 tau peptides were most abundant in the sarkosyl\u2010insoluble materials with a 10\u2010fold higher concentration than N\u2010terminal tau peptides. This indicates that the major proportion of the enriched tau was the aggregation\u2010prone N\u2010terminal and proline\u2010rich region (PRR) of truncated mixed 4R and 3R tau with more 4R than 3R isoforms. High concentration and occupancies of site\u2010specific phosphorylation pT<jats:sub>181<\/jats:sub> (~22%) and pT<jats:sub>217<\/jats:sub> (~16%) (key biomarkers of AD) along with other PTMs in the PRR and MTBR indicated a regional susceptibility of PTMs in aggregated tau. Immunogold labelling revealed that tau may exist in globular non\u2010filamentous form (N\u2010terminal intact tau) co\u2010localized with A\u03b2 in the sarkosyl\u2010insoluble pellets along with tau filaments (N\u2010truncated MTBR tau). Our results suggest a model that A\u03b2 and tau interact forming globular aggregates, from which filamentous tau and A\u03b2 emerge. These characterizations contribute towards unravelling the sequence of events which lead to end\u2010stage AD changes.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15713-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15713","type":"journal-article","created":{"date-parts":[[2022,10,22]],"date-time":"2022-10-22T06:53:45Z","timestamp":1666421625000},"page":"529-552","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Quantitative proteomics of tau and A\u03b2 in detergent fractions from Alzheimer's disease 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