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We evaluated correspondence of core AD-relevant biomarkers pTau217, pTau181, A\u03b242\/A\u03b240, pTau217\/A\u03b242, GFAP, and NfL measured using multiplex NULISAseq and single-plex Lumipulse immunoassays. ROC curve analyses compared performance for detecting amyloid-positivity (A+) (a) across platforms in SAMS and (b) across brain-derived (BD) and total-pTau assays in AMASS, leveraging novel NULISAseq immunoassays. Linear models were applied across all NULISAseq CNS proteins to explore proteomic abundance patterns associated with age, sex,\n                      <jats:italic>APOE-<\/jats:italic>\n                      \u03b54, amyloid burden (CSF A\u03b242\/A\u03b240, amyloid PET), and tau burden (CSF pTau181, PI-2620 tau PET) using an FDR-corrected\n                      <jats:italic>p<\/jats:italic>\n                      -value of &lt;\u20090.05 to identify significant targets.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In SAMS, moderate to high correlations were observed between NULISAseq and Lumipulse plasma biomarkers. NULISAseq pTau217\/A\u03b242 (AUC: 0.940) and pTau217 (AUC: 0.879) performed as well as corresponding single-plex Lumipulse assays (pTau217\/A\u03b242, AUC: 0.907; pTau217, AUC: 0.838) for detecting CSF A+\u2009in SAMS. In AMASS, BD-pTau217 (AUC: 0.920) and BD-pTau181 (AUC: 0.920) exhibited the highest performance in discriminating PET A+, providing significant performance gains compared to total-pTau measures (pTau217, AUC: 0.861; pTau181, AUC: 0.763). Exploratory proteomic abundance analyses across NULISA CNS targets revealed pTau isoforms as most differentially expressed with amyloid burden across cohorts, together with upregulation of GFAP and downregulation of A\u03b242 in SAMS. Tau burden was associated with upregulation of plasma pTau217, independent of amyloid burden, together with proteins related to astrocyte activation, inflammation, and synaptic integrity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>NULISAseq multiplex immunoassays, including novel BD-pTau assays, accurately detect AD pathology among CU older adults and identify multiple biological pathways related to aging and early biomarker abnormality that may become dysregulated in preclinical AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-026-00941-5","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T06:46:29Z","timestamp":1777013189000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Plasma proteomic signatures of preclinical Alzheimer\u2019s disease in clinically unimpaired older adults"],"prefix":"10.1186","volume":"21","author":[{"given":"Alexandra N.","family":"Trelle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karly A.","family":"Cody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran T.","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Winer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skylar","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isha","family":"Sai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Channappa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Mendiola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Al-Rajhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keerthana","family":"Raghuraman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon J.","family":"Sha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward N.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Wyss-Coray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holden T.","family":"Maecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony D.","family":"Wagner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Mormino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"issue":"4","key":"941_CR1","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1002\/alz.12748","volume":"19","author":"MS Rafii","year":"2023","unstructured":"Rafii MS, Sperling RA, Donohue MC, et al. 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