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Polygenic scores (PGS) capture little of this complexity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>We conducted genome\u2010, transcriptome\u2010, and proteome\u2010wide association studies (G\/T\/PWAS) on 15,480 individuals from the Alzheimer's Disease Sequencing Project R4 (ADSP) to identify AD\u2010associated signals, followed by pathway enrichment analysis. Integrative risk models (IRMs) were developed using genetically regulated components of gene and protein expression and clinical covariates. Elastic\u2010net logistic regression and random forest classifiers were evaluated using standard metrics and compared against baseline PGS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>Known and novel signals were identified via G\/T\/PWAS. Enrichment analyses highlighted cholesterol and immune signaling pathways. The best\u2010performing IRM, random forest with transcriptomic and covariate features, achieved area under the receiver operating characteristic (AUROC) of 0.703 and area under the precision\u2010recall curve (AUPRC) of 0.622, significantly outperforming PGS and baseline models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>Integrating univariate discovery approaches with multivariate modeling enhances AD risk prediction and offers novel insights into underlying biological processes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Identified novel contributions to Alzheimer's disease (AD) from a multi\u2010omics perspective.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Integrated genome\u2010wide association studies (GWAS), transcriptome\u2010wide association studies (TWAS), and proteome\u2010wide association studies (PWAS) in a unified association study framework.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Developed a method for predicting heritable risk of late\u2010onset AD.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Demonstrated that ancestry\u2010aware modeling improves AD risk prediction accuracy.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  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