{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T11:11:52Z","timestamp":1788606712408,"version":"build-2803163510"},"posted":{"date-parts":[[2026,2,9]]},"group-title":"Neurology","reference-count":57,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Plasma p-Tau217 leaves 30-50% of patients in an indeterminate \u201cgray zone\u201d often requiring A\u03b2-PET. We developed GRAD (Gatekeeper-Reflex for Alzheimer\u2019s Disease), a two-stage A\u03b2+ prediction model to improve classification while reserving A\u03b2-PET for residual uncertainty.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>GRAD was developed in 145 cognitively impaired ADNI participants and externally validated in 1,644 cognitively unimpaired A4\/LEARN participants. Stage 1 used p-Tau217 alone; probabilities between 0.25-0.75 were considered indeterminate. Stage 2 used L2-regularized logistic regression combining plasma-biomarkers, genetic and demographic features. A\u03b2-PET served as the reference standard (ADNI florbetapir SUVR&gt;1.11; A4 Centiloid\u226520).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Full model AUC was 0.915 (95% CI, 0.859-0.961) internally and 0.879 (95% CI, 0.861-0.895) externally. In the external gray zone (\n                    <jats:italic>n<\/jats:italic>\n                    =630), Stage 2 improved discrimination over p-Tau217 alone (AUC 0.793 vs 0.719; P&lt;.001), increased correct classification without PET from 41.4% to 56.2% and reduced PET referral from 35.9% to 24.3%. In the p-Tau181 subset (\n                    <jats:italic>n<\/jats:italic>\n                    =256), Stage 2 outperformed p-Tau181 (AUC 0.799 vs 0.597; P&lt;.001). Overall, 89.0% of ADNI and 90.7% of A4\/LEARN participants were classified without PET; modeled testing costs were 44-52% lower than p-Tau217 screening with PET confirmation of the gray zone.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>Reflex multimarker testing improves indeterminate p-Tau217 classification while retaining A\u03b2-PET for residual uncertainty. GRAD may reduce PET use and testing costs in memory-clinic triage, prevention-trial enrichment, and disease-modifying therapy workup.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.03.26345302","type":"posted-content","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T17:10:11Z","timestamp":1770657011000},"source":"Crossref","is-referenced-by-count":0,"title":["A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2796-1436","authenticated-orcid":false,"given":"Harthik","family":"Parankusham","sequence":"first","affiliation":[{"name":"Department of Physiology & Neurobiology, UConn Computational Biology Core, University of Connecticut, Storrs, CT 06269-3125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8233-5829","authenticated-orcid":false,"given":"Casey","family":"Vanderlip","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, 1424 Biological Sciences III Irvine, University of California Irvine, Irvine, CA, 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7212-7700","authenticated-orcid":false,"given":"Colin","family":"Birkenbihl","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8435-6123","authenticated-orcid":false,"given":"Eashwar","family":"Krishna","sequence":"additional","affiliation":[{"name":"Department of Molecular & Cell Biology, University of Connecticut, 91 North Eagleville Road, Unit 3125, Storrs, CT 06269-3125, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8665-0464","authenticated-orcid":false,"given":"Chizobam","family":"Ugboaja","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, Yale New Haven Health, 333 Cedar Street, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2913-0015","authenticated-orcid":false,"given":"Andrew","family":"Budson","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System, Boston, MA, USA; Alzheimer\u2019s Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-9074","authenticated-orcid":false,"given":"Brandon","family":"Frank","sequence":"additional","affiliation":[{"name":"VA Boston Healthcare System, Boston, MA, USA; Alzheimer\u2019s Disease Research Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026090503200461000_2026.02.03.26345302v3.1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"2026090503200461000_2026.02.03.26345302v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.02.018"},{"key":"2026090503200461000_2026.02.03.26345302v3.3","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70535.PMC12306682"},{"key":"2026090503200461000_2026.02.03.26345302v3.4","doi-asserted-by":"publisher","DOI":"10.1001\/JAMA.2020.12134"},{"key":"2026090503200461000_2026.02.03.26345302v3.5","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1001\/jamaneurol.2023.5319","article-title":"Diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay for Alzheimer disease pathology","volume":"81","year":"2024","journal-title":"JAMA Neurol"},{"key":"2026090503200461000_2026.02.03.26345302v3.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02869-z"},{"key":"2026090503200461000_2026.02.03.26345302v3.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-025-03622-w.PMC12176611"},{"key":"2026090503200461000_2026.02.03.26345302v3.8","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae346.PMC11788211"},{"key":"2026090503200461000_2026.02.03.26345302v3.9","doi-asserted-by":"crossref","unstructured":"Therriault J , Ashton NJ , Pola I , et al. 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