{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:19:06Z","timestamp":1768569546728,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Neurology","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and Objectives<\/jats:title>\n                  <jats:p>Although amyloid positron emission tomography (PET) and Cerebrospinal fluid (CSF) biomarkers remain the standard for confirming Alzheimer\u2019s disease (AD) pathology, their use is impractical for screening or routine prognostic assessment. Plasma phosphorylated tau 217 (p-tau217), subjective cognitive concerns, and computerized cognitive testing are non-invasive, scalable, and feasible to implement in large populations. We tested whether these measures independently predict the onset of cognitive impairment and whether combining them improves prognostic accuracy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed 1,071 cognitively unimpaired adults aged 65\u201385 years from the Anti-Amyloid Treatment in Asymptomatic Alzheimer\u2019s Disease (A4) trial (amyloid-positive; solanezumab or placebo arms) and the parallel Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) cohort (amyloid-negative). At baseline, participants completed plasma p-tau217 measurement, the Cognitive Function Index (CFI), and the Cogstate Computerized Battery (CCB). Over 240 weeks of follow-up, incident impairment was defined as conversion from a Global Clinical Dementia Rating Score (CDR-GS) of 0 to 0.5 or higher. The predictive value of each measure for subsequent decline was examined after adjustment for demographic and genetic covariates.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>During the follow-up, 365 of 1,071 participants (34.1%) developed cognitive impairment. Higher plasma p-tau217 (per\u2013standard-deviation increase) was associated with higher odds of converting to CDR-GS&gt;0 across all cohorts: A4-Placebo (HR=1.56; 95% CI, 1.37-1.78), A4-Solanezumab (HR=1.46; 95% CI, 1.29-1.65), LEARN (HR=1.25; 95% CI, 1.05-1.48). Similarly, higher CFI predicted incident impairment: A4-Placebo (HR=1.59; 95% CI, 1.42-1.79), A4-Solanezumab (HR=1.67; 95% CI, 1.47-1.91), LEARN (HR=1.37; 95% CI, 1.12-1.68). Lower CCB also conferred higher risk: A4-Placebo (HR=0.76; 95% CI, 0.65-0.91), A4-Solanezumab (HR=0.73; 95% CI, 0.62-0.87), LEARN (HR=0.68; 95% CI, 0.53-0.87). In models including all three predictors, each remained independently associated with progression.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Plasma p-tau217, subjective cognitive concerns, and computerized cognitive testing each independently predicted progression to cognitive impairment in cognitively unimpaired older adults. Together, these non-invasive and scalable measures provide practical tools for risk stratification years before clinical diagnosis. Combining biological, subjective, and digital markers may support earlier detection in clinical care and enhance efficiency in prevention trial enrollment.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.14.25338009","type":"posted-content","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:15:24Z","timestamp":1760591724000},"source":"Crossref","is-referenced-by-count":0,"title":["Scalable Markers for Early Cognitive Decline: Plasma p-tau217, Subjective Cognitive Concerns, and Digital Testing: Results from the A4\/LEARN studies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1585-3909","authenticated-orcid":false,"given":"Babak","family":"Khorsand","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin","family":"Teichrow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elham","family":"Ghanbarian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lukai","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Ahmad","family":"Sajjadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crystal M","family":"Glover","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua D.","family":"Grill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura A.","family":"Rabin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Ezzati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"5","key":"2025101804350534000_2025.10.14.25338009v1.1","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1038\/s43587-023-00410-4","article-title":"Detection and treatment of Alzheimer\u2019s disease in its preclinical stage","volume":"3","year":"2023","journal-title":"Nature aging"},{"issue":"5","key":"2025101804350534000_2025.10.14.25338009v1.2","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1097\/CM9.0000000000002566","article-title":"Progress in blood biomarkers of subjective cognitive decline in preclinical Alzheimer\u2019s disease","volume":"136","year":"2023","journal-title":"Chinese Medical Journal"},{"issue":"1","key":"2025101804350534000_2025.10.14.25338009v1.3","doi-asserted-by":"crossref","first-page":"e213769","DOI":"10.1212\/WNL.0000000000213769","article-title":"Association of Plasma Phosphorylated Tau 217 With Clinical Deterioration Across Alzheimer Disease Stages","volume":"105","year":"2025","journal-title":"Neurology"},{"issue":"2","key":"2025101804350534000_2025.10.14.25338009v1.4","first-page":"e70128","article-title":"Association of item-level responses to cognitive function index with tau pathology and hippocampal volume in the A4 Study","volume":"17","year":"2025","journal-title":"Alzheimer\u2019s & Dementia: Diagnosis, Assessment & Disease Monitoring"},{"issue":"1","key":"2025101804350534000_2025.10.14.25338009v1.5","first-page":"e12217","article-title":"Current advances in digital cognitive assessment for preclinical Alzheimer\u2019s disease","volume":"13","year":"2021","journal-title":"Alzheimer\u2019s & Dementia: Diagnosis, Assessment & Disease Monitoring"},{"key":"2025101804350534000_2025.10.14.25338009v1.6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2305032"},{"issue":"4","key":"2025101804350534000_2025.10.14.25338009v1.7","doi-asserted-by":"crossref","first-page":"823","DOI":"10.14283\/jpad.2024.134","article-title":"Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer\u2019s Disease","volume":"11","year":"2024","journal-title":"The Journal of Prevention of Alzheimer\u2019s Disease"},{"issue":"3","key":"2025101804350534000_2025.10.14.25338009v1.8","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1080\/13854046.2016.1256435","article-title":"Reliability and validity of the CogState computerized battery in patients with seizure disorders and healthy young adults: comparison with standard neuropsychological tests","volume":"31","year":"2017","journal-title":"The Clinical Neuropsychologist"},{"issue":"4","key":"2025101804350534000_2025.10.14.25338009v1.9","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1001\/jamaneurol.2014.3375","article-title":"Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer\u2019s Disease Cooperative Study Cognitive Function Instrument","volume":"72","year":"2015","journal-title":"JAMA neurology"},{"issue":"4","key":"2025101804350534000_2025.10.14.25338009v1.10","doi-asserted-by":"crossref","first-page":"814","DOI":"10.14283\/jpad.2024.123","article-title":"Characterizing clinical progression in cognitively unimpaired older individuals with brain amyloid: results from the A4 study","volume":"11","year":"2024","journal-title":"The journal of prevention of Alzheimer\u2019s disease"},{"issue":"8","key":"2025101804350534000_2025.10.14.25338009v1.11","doi-asserted-by":"crossref","first-page":"e70182","DOI":"10.1111\/jnc.70182","article-title":"Profiling Plasma Biomarkers, Particularly pTau217 and pTau217\/A\u03b242, and Their Relation to Cognition in Memory Clinic Patients","volume":"169","year":"2025","journal-title":"Journal of Neurochemistry"},{"key":"2025101804350534000_2025.10.14.25338009v1.12","doi-asserted-by":"crossref","unstructured":"Feizpour A , Doecke JD , Dor\u00e9 V , Krishnadas N , Huang K , Bourgeat P , et al. Detection and staging of Alzheimer\u2019s disease by plasma pTau217 on a high throughput immunoassay platform. EBioMedicine. 2024;109.","DOI":"10.1016\/j.ebiom.2024.105405"},{"key":"2025101804350534000_2025.10.14.25338009v1.13","doi-asserted-by":"crossref","unstructured":"Shin D , Jang H , Yoo H , Kim K , Zetterberg H , Blennow K , et al. Potential utility of plasma pTau217 for assessing amyloid and tau biomarker profiles. 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tau181 as predictors of longitudinal tau accumulation: implications for clinical trial design","volume":"18","year":"2022","journal-title":"Alzheimer\u2019s & Dementia"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.14.25338009","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:48:47Z","timestamp":1768510127000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.10.14.25338009"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,15]]},"references-count":27,"URL":"https:\/\/doi.org\/10.1101\/2025.10.14.25338009","relation":{},"subject":[],"published":{"date-parts":[[2025,10,15]]},"subtype":"preprint"}}