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Fluid AD biomarker studies highlight an increase in several phosphorylated tau (p-tau) epitopes in DS. However, neuropathological measures of p-tau epitopes in DS have not been examined. Therefore, our main objective was to characterize p-tau epitope burdens across the DS lifespan at autopsy. We analyzed postmortem brain samples of 98 individuals with late-onset AD (LOAD), DS with AD neuropathology (DSAD), young DS (below 40\u00a0years of age), and age-matched neurotypical controls, ranging from 1 to 96\u00a0years of age. Immunohistochemical and digital pathology measures of p-tau epitopes at threonine 181 (pThr181), threonine 217 (pThr217), and threonine 231 (pThr231) burdens in the frontal cortex were compared across groups. We observed similar pThr181, pThr217, and pThr231 burdens between DSAD and LOAD, despite DSAD cases being younger on average. Observed pThr181, pThr217, and pThr231 burdens were higher in DSAD compared to young DS and neurotypical controls. Generalized additive models (GAMs) were used to model the cross-sectional trajectory of p-tau epitope burdens across the DS lifespan. Estimated age breakpoints revealed a significant rise in frontal cortex pThr231 at age 40, followed by pThr181 and pThr217 at age 42. In summary, our findings revealed an age-associated increase in p-tau epitopes across the DS lifespan. Our results have the potential to inform future associations between neuropathological and biofluid and neuroimaging biomarker measures of p-tau epitopes.<\/jats:p>","DOI":"10.1007\/s00401-026-02994-8","type":"journal-article","created":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T10:57:45Z","timestamp":1774177065000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuropathological measures of increased tau phosphorylation across the Down syndrome lifespan"],"prefix":"10.1007","volume":"151","author":[{"given":"Jesse R.","family":"Pascual","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Halyma","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phong 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