{"doi":"10.1002/alz.70937","title":"Polygenic scores of Core 1 Alzheimer's disease biomarkers predict early cognitive and pathological change","abstract":"INTRODUCTION: Core 1 biomarkers, such as amyloid positron emission tomography, capture the earliest biological changes leading to Alzheimer's disease (AD). While APOE is a major genetic factor, the contribution of other variants to Core 1 biomarkers remains unclear. The goal of this study was to determine whether genetic regulators of Core 1 biomarker levels predicted AD pathology better than genetic regulators of clinical AD. METHODS: Among 955 non-Hispanic White individuals, polygenic scores (PGSs) were built using genome-wide association studies (GWASs) of amyloid PET, plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and clinical AD. Hispanic-specific PGSs were constructed in 515 individuals using plasma p-tau181 and clinical AD GWASs. Baseline and longitudinal associations with plasma biomarkers and cognition were assessed, and replication was conducted in separate cohorts. RESULTS: The Core 1 biomarker PGSs predicted AD pathology and associated cognitive performance better than the AD PGSs in both populations. DISCUSSION: The Core 1 PGSs show improved predictive value for AD-related plasma biomarkers and early cognitive changes. HIGHLIGHTS: APOE ε4 explained more variance in plasma p-tau217 than in plasma p-tau181. PGSs based on Core 1 biomarkers outperformed AD PGSs in predicting plasma biomarkers and cognitive decline among asymptomatic individuals in non-Hispanic White and Hispanic individuals. However, the improvement in predictive power was modest and may vary by age. 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.","journal":"Alzheimer s & Dementia","year":2025,"id":548968,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9653,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1127985,"name":"Min Qiao","orcid":"0000-0002-5823-4892","position":1,"is_corresponding":false},{"id":686606,"name":"Tamil Iniyan Gunasekaran","orcid":"0000-0002-8639-5060","position":2,"is_corresponding":false},{"id":268543,"name":"Yian Gu","orcid":"0000-0002-4297-1548","position":3,"is_corresponding":false},{"id":413237,"name":"Dolly Reyes‐Dumeyer","orcid":"0000-0003-3572-8248","position":4,"is_corresponding":false},{"id":892515,"name":"Angel Piriz","orcid":null,"position":5,"is_corresponding":false},{"id":932098,"name":"Danurys Sanchez","orcid":"0000-0001-8273-0952","position":6,"is_corresponding":false},{"id":1037663,"name":"Belisa Soriano","orcid":null,"position":7,"is_corresponding":false},{"id":855732,"name":"Yahaira Franco","orcid":null,"position":8,"is_corresponding":false},{"id":1037664,"name":"Zoraida Dominguez Coronado","orcid":null,"position":9,"is_corresponding":false},{"id":1037220,"name":"Patricia Recio","orcid":"0000-0002-0530-4404","position":10,"is_corresponding":false},{"id":1037221,"name":"Diones Rivera Mejía","orcid":"0000-0001-5935-8005","position":11,"is_corresponding":false},{"id":413239,"name":"Martin Medrano","orcid":"0000-0003-3673-9088","position":12,"is_corresponding":false},{"id":413238,"name":"Rafael Lantigua","orcid":"0000-0003-4854-7331","position":13,"is_corresponding":false},{"id":108602,"name":"Lawrence S. Honig","orcid":"0000-0002-9703-2265","position":14,"is_corresponding":false},{"id":1160542,"name":"Rachael Wilson","orcid":null,"position":15,"is_corresponding":false},{"id":49960,"name":"Jennifer J. Manly","orcid":"0000-0002-9481-7497","position":16,"is_corresponding":false},{"id":270469,"name":"Adam M. Brickman","orcid":"0000-0002-5125-8226","position":17,"is_corresponding":false},{"id":261840,"name":"Corinne D. Engelman","orcid":"0000-0003-4750-5607","position":18,"is_corresponding":false},{"id":230038,"name":"Sterling C. Johnson","orcid":"0000-0002-8501-545X","position":19,"is_corresponding":false},{"id":289695,"name":"Sanjay Asthana","orcid":"0000-0002-3998-4479","position":20,"is_corresponding":false},{"id":63303,"name":"Badri N. Vardarajan","orcid":"0000-0002-5560-4085","position":21,"is_corresponding":false},{"id":27608,"name":"Richard Mayeux","orcid":"0000-0001-6519-9696","position":22,"is_corresponding":false},{"id":1080030,"name":"Yuexuan Xu","orcid":"0000-0002-2732-7199","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:54:03.053965Z","pmid":"41307156","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}