{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T07:56:16Z","timestamp":1777190176915,"version":"3.51.4"},"posted":{"date-parts":[[2025,7,14]]},"group-title":"Neurology","reference-count":48,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"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":[[2025,7,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>\n                    Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes leading to Alzheimer\u2019s disease (AD). While\n                    <jats:italic>APOE<\/jats:italic>\n                    is a major genetic factor, the contribution of other variants to Core-1 biomarkers remains unclear. The goal of this study is to determine whether genetic regulators of Core-1 biomarker levels predict AD pathology better than genetic regulators of clinical AD.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>METHODS<\/jats:title>\n                  <jats:p>Among 955 non-Hispanic white individuals, PGSs were built using GWAS of amyloid PET, plasma P-tau181, CSF P-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma P-tau181 and clinical AD GWAS. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>The Core-1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGS in both populations.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>DISCUSSION<\/jats:title>\n                  <jats:p>The Core-1 PGS show improved predictive value for AD-related plasma biomarkers and early cognitive changes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>HIGHLIGHTS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        <jats:italic>APOE<\/jats:italic>\n                        -\u03b54 explained more variance in plasma P-tau217 than in plasma P-tau181.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>PGSs based on Core-1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in white non-Hispanic and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>While the variance in P-tau181 and P-tau217 explained by individual Core-1 PGSs remains limited, the distinct genetic signals captured by the best-performing PGSs across different Core-1 biomarkers may provide an opportunity for developing an integrative Core-1 PGS that more effectively predicts plasma P-tau181 and P-tau217 levels than AD-based PGS.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\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>Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes in Alzheimer\u2019s disease (AD). The authors reviewed the literature on the association between core-1 biomarker-based polygenic scores (PGS) and plasma biomarkers using traditional sources (e.g., PubMed), meeting abstracts, and presentations. While several studies examined the association between PGS and plasma P-tau181 and P-tau217, most PGSs were based on AD genetic studies and performed poorly in predicting these biomarkers\u2014especially in asymptomatic individuals. No studies have comprehensively assessed Core-1 biomarker-based PGSs in relation to P-tau181, P-tau217, other plasma biomarkers, and cognitive change.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>INTERPRETATION<\/jats:title>\n                    <jats:p>Our findings show that Core-1 biomarker-based PGSs outperform AD PGSs in predicting early changes in plasma P-tau181, P-tau217, other non-tau plasma biomarkers, and cognition in asymptomatic White and Caribbean Hispanic individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUTURE DIRECTIONS<\/jats:title>\n                    <jats:p>The Core-1 PGS offers improved predictive value for AD-related plasma biomarkers and early cognitive changes. Future research should validate these findings using larger genome-wide association studies and explore integrated Core-1 PGSs for P-tau217 and P-tau181, especially as more Core-1 biomarker genetic data become available.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.12.25331438","type":"posted-content","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:50:16Z","timestamp":1752540616000},"source":"Crossref","is-referenced-by-count":1,"title":["Polygenic Scores of Core-1 Alzheimer\u2019s Disease Biomarkers Predict Early Cognitive and Pathological Change"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2732-7199","authenticated-orcid":false,"given":"Yuexuan","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamil 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