{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T22:43:45Z","timestamp":1789425825363,"version":"build-2803163510"},"posted":{"date-parts":[[2025,9,19]]},"group-title":"Neurology","reference-count":37,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>Biological Staging for Alzheimer\u2019s disease (AD) in clinically unimpaired (CU) individuals is critical for early detection efforts. In this study, we evaluated whether Core 1 biomarkers (plasma ptau-217 and amyloid-PET) within Biological Stage A, the earliest biological stage of AD, predicts progression of downstream biomarkers and cognition.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We used baseline plasma ptau-217 and amyloid-PET, and longitudinal tau-PET, atrophy, and cognition data from the recently completed Anti-Amyloid Treatment in Asymptomatic Alzheimer\u2019s (A4) Study. PET data were used to identify participants within AD Biological Stage A (amyloid-PET positive and medial temporal tau-PET negative). Within these Stage A participants, linear mixed effects models were used to examine associations between continuous baseline levels of plasma p-tau217 and amyloid-PET burden with longitudinal regional tau-PET, atrophy, and cognition. We additionally evaluated whether continuous p-tau217 and amyloid-PET burden within this group was associated with higher risk of progression to Biological Stage B+ (tau-PET positive in the medial temporal lobe). In our statistical models, we included covariates for age, sex, and APOE4 carriage.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Of 335 A4 participants with complete biomarker data, 222 were identified as being in Biological Stage A. Among Biological Stage A CU, continuous baseline plasma p-tau217 and amyloid-PET burden were independently associated with faster tau-PET accumulation and atrophy in AD-relevant regions (mean follow-up time for both tau-PET and MRI: 4.2 years), as well as faster cognitive decline (mean follow-up time for PACC: 5.7 years) (all p&lt;0.05). Plasma p-tau217 and amyloid-PET burden were independently associated with higher risk of progression to Biological Stage B+.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>In CU individuals, early changing AD biomarkers during the initial stage of AD (Biological Stage A) provide prognostic information of downstream markers of disease. Evaluation of the utility of these continuous measures in a real-world setting is warranted.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Clinical Trial Information<\/jats:title>\n                  <jats:p>\n                    The A4 study was submitted for registration to clinicaltrials.gov on December 6th, 2023. The study is registered with ID\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02008357\">NCT02008357<\/jats:ext-link>\n                    . Screening and data collection for the study began in April 2014.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.17.25336007","type":"posted-content","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T16:35:17Z","timestamp":1758299717000},"source":"Crossref","is-referenced-by-count":2,"title":["Continuum of Core 1 Biomarkers in Preclinical Alzheimer\u2019s Disease"],"prefix":"10.64898","author":[{"given":"Leonardino A.","family":"Digma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina B.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Winer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karly A.","family":"Cody","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyan","family":"Younes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip S.","family":"Insel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Rissman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reisa","family":"Sperling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Mormino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092204050617000_2025.09.17.25336007v1.1","first-page":"1","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: a practical approach","volume":"123","year":"2012","journal-title":"Acta Neuropathol. 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