Integrative multi-omics approaches identify molecular pathways and improve Alzheimer's Disease risk prediction.

Alzheimer's Disease (AD) is the most prevalent condition that impacts the aging population, with no effective treatment or singular underlying causal factor identified. As a complex disease, characterizing the genetic risk of developing AD has proven to be difficult; polygenic scores (PGS) exclusively use common variants which fail to fully capture disease heterogeneity. This study used univariate and multivariate approaches to characterize AD risk. Genome-, transcriptome-, and proteome-wide association studies (GWAS, TWAS, and PWAS) were conducted on 15,480 individuals from the Alzheimer's Disease Sequencing Project (ADSP) R4 release to identify AD-associated 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-net logistic regression and random forest classifiers were evaluated using area under the receiver operating characteristic (AUROC), area under the precision-recall curve (AUPRC), F1-score, and balanced accuracy. These IRMs were compared against baseline PGS and covariate models. We identified 104 genomic, 319 transcriptomic, and 17 proteomic associations with AD under significant thresholds. Putatively novel associations were enriched in signaling, myeloid differentiation, and immune pathways. The best-performing IRM, random forest with transcriptomic and covariate features, achieved an AUROC of 0.703 and AUPRC of 0.622, significantly outperforming PGS and baseline models. Integrating univariate discovery approaches with multivariate modeling enhances AD risk prediction and offers insights into underlying biological processes.