{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:17:00Z","timestamp":1783070220979,"version":"3.54.6"},"posted":{"date-parts":[[2026,6,30]]},"group-title":"Neurology","reference-count":26,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["National Institutes of Health Grant U19 AG024904"],"award-info":[{"award-number":["National Institutes of Health Grant U19 AG024904"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Plasma brain-derived pTau217 (BD-pTau217) may provide a Alzheimer\u2019s disease-specific plasma tau measure than total pTau217, but its prognostic value is unclear. We compared BD-pTau217 and total plasma pTau217 for predicting clinical and amyloid PET progression in cognitively unimpaired (CU) ADNI participants.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Plasma NULISAseq biomarkers were measured in 1,427 ADNI participants, including 529 CU individuals. Amyloid PET progression was assessed in baseline CU amyloid-negative participants (Centiloid \u226524.1) with longitudinal PET imaging; clinical progression was assessed in all baseline CU participants. Associations were evaluated using Cox models and time-dependent AUC.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>BD-pTau217 did not clearly outperform total pTau217 for predicting progression to mild cognitive impairment or dementia. However, among baseline amyloid-negative participants (N=175), BD-pTau217 better predicted amyloid PET positivity at 2.5 years (tdAUC 0.82 vs 0.69; HR=10.54, p=0.00015) and 4 years (tdAUC 0.77 vs 0.64; HR=7.03, p=0.00055).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>BD-pTau217 improved prediction of near-term amyloid PET progression, with less clear advantage for clinical progression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:p>\n                    <jats:list list-type=\"bullet\">\n                      <jats:list-item>\n                        <jats:p>BD-pTau217 predicted amyloid PET progression in CU ADNI participants.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>BD-pTau217 outperformed total pTau217 at the CL \u226524.1 threshold.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>BD-pTau217 and total pTau217 performed similarly for clinical progression.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Prognostic performance varied across amyloid PET thresholds.<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>BD-pTau217 may support risk stratification in prevention trials.<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESEARCH IN CONTEXT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Systematic review<\/jats:title>\n                    <jats:p>Plasma pTau217 biomarkers show strong cross-sectional associations with amyloid and tau pathology and are increasingly used to support Alzheimer\u2019s disease diagnosis and trial screening. Recent assay designs selectively measuring brain-derived pTau217 may reduce peripheral contributions to total pTau217 measurements, but their longitudinal prognostic value relative to total pTau217 remains less well established.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>In cognitively unimpaired ADNI participants, plasma BD-pTau217 showed stronger prognostic performance than total pTau217 for progression from amyloid PET negative to amyloid PET positive status, particularly at the primary CL \u226524.1 threshold. In contrast, BD-pTau217 and total pTau217 showed more similar performance for predicting clinical progression to MCI or dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Future directions<\/jats:title>\n                    <jats:p>These findings support further evaluation of BD-pTau217 for biological risk stratification and prevention trial enrichment. Validation is needed in more diverse cohorts, longer follow-up intervals, and across clinical-grade assay platforms.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.26.26356597","type":"posted-content","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T21:15:46Z","timestamp":1782854146000},"source":"Crossref","is-referenced-by-count":0,"title":["Prognostic value of plasma brain-derived pTau"],"prefix":"10.64898","author":[{"given":"Valentina","family":"Ghisays","sequence":"first","affiliation":[{"name":"Banner Alzheimer\u2019s Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa N.","family":"Denkinger","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute, Sun City, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alpana","family":"Singh","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute, 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