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We assessed the associations of five cerebrospinal fluid (CSF) (A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    , p-tau\n                    <jats:sub>181<\/jats:sub>\n                    , p-tau\n                    <jats:sub>217<\/jats:sub>\n                    , A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/p-tau\n                    <jats:sub>181<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/p-tau\n                    <jats:sub>217<\/jats:sub>\n                    ) and three plasma (p-tau\n                    <jats:sub>217<\/jats:sub>\n                    , p-tau\n                    <jats:sub>217<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    ) biomarkers with post-mortem A\u03b2 and tau pathology burden in 250 participants with ante-mortem CSF (\n                    <jats:italic>n=<\/jats:italic>\n                    230) and\/or plasma (\n                    <jats:italic>n=<\/jats:italic>\n                    101), affected by prion (\n                    <jats:italic>n=<\/jats:italic>\n                    162) or non-prion diseases (\n                    <jats:italic>n=<\/jats:italic>\n                    88). A\u03b2 and tau burden were scored across nine and six brain areas, respectively. We assessed the earliest biomarker changes across quartiles of A\u03b2 and tau pathology burden and the discriminatory performance at progressively higher pathology thresholds using multivariable linear regression and sequential ROC analyses. Analyses on p-tau markers were restricted to non-prion participants. The median sampling-death interval was 1.5\u00a0months for CSF and 1\u00a0month for plasma. CSF A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    decreased at the second quartile of A\u03b2 burden (\n                    <jats:italic>p&lt;<\/jats:italic>\n                    0.001), whereas p-tau\n                    <jats:sub>181<\/jats:sub>\n                    (\n                    <jats:italic>p&lt;<\/jats:italic>\n                    0.01) and p-tau\n                    <jats:sub>217<\/jats:sub>\n                    (\n                    <jats:italic>p&lt;<\/jats:italic>\n                    0.001) increased only from the third quartile. CSF A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    achieved its highest accuracy at low\/intermediate A\u03b2 burden (AUC 0.984), while CSF p-tau and derived ratios performed best at advanced A\u03b2 (AUCs 0.889 to 0.980) and intermediate tau pathology stages (AUCs 0.949 to 0.995). CSF p-tau\n                    <jats:sub>217<\/jats:sub>\n                    and A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/p-tau\n                    <jats:sub>217<\/jats:sub>\n                    consistently showed higher accuracy than their p-tau\n                    <jats:sub>181<\/jats:sub>\n                    counterparts across A\u03b2 and tau pathology scores. Plasma p-tau\n                    <jats:sub>217<\/jats:sub>\n                    and p-tau\n                    <jats:sub>217<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    significantly increased in the highest A\u03b2 and tau burden quartiles, where they achieved their best performance (AUCs 0.893 to 0.928). These findings support a sequential model of biomarker changes across the Alzheimer\u2019s disease neuropathological continuum. CSF A\u03b2\n                    <jats:sub>42<\/jats:sub>\n                    \/A\u03b2\n                    <jats:sub>40<\/jats:sub>\n                    best reflects low\/intermediate A\u03b2 burden, while CSF p-tau markers are more closely related to high A\u03b2 and intermediate tau load. Plasma markers primarily identify advanced A\u03b2 and tau pathology burden. Notably, current fluid biomarkers do not capture the earliest phases of A\u03b2 deposition.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03076-5","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:05:12Z","timestamp":1788437112000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Changes in five cerebrospinal fluid and three plasma Alzheimer\u2019s disease biomarkers across increasing brain amyloid-beta and tau pathology burden"],"prefix":"10.1007","volume":"152","author":[{"given":"Andrea","family":"Mastrangelo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Baiardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Ruggeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Mario","family":"Bentivenga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Marina","family":"Vargiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sbriccoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Polischi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Carl\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Capellari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-9524","authenticated-orcid":false,"given":"Piero","family":"Parchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"3076_CR1","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1111\/j.1750-3639.2008.00147.x","volume":"18","author":"I Alafuzoff","year":"2008","unstructured":"Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer\u2019s disease: a study of the BrainNet Europe Consortium. 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