Integrative prediction of Alzheimer's disease and related dementias using multi-omics aging clocks and genetic data.

<h4>Introduction</h4>We tested whether combining Alzheimer's disease and related dementias (ADRD) polygenic risk scores (PRS) with biological aging markers improves ADRD risk prediction.<h4>Methods</h4>In 16,215 UK Biobank (UKB) participants free of ADRD at baseline (median follow-up: 10.08 years), 397 incident diagnoses were identified. Biological aging measures included clinical, telomere(definition), proteomic, and metabolomic aging markers. External validation/replication was performed in TwinGene (N = 3772; 331 cases).<h4>Results</h4>The fully integrated model achieved area under the curve (AUC) = 0.90 and area under the precision-recall curve (AUPRC) = 0.24 in the UKB held-out test set. PRS was the strongest predictor (subdistribution hazard ratio [sHR] = 2.24, 95% CI: 2.02-2.48), followed by ProtAge (sHR = 2.01, 95% CI: 1.13-3.58). The top predicted-risk quartile showed higher ADRD incidence (sHR = 16.73, 95% CI: 6.49-43.11). TwinGene showed moderate transportability (AUC = 0.757; AUPRC = 0.223) and preserved risk stratification (sHR = 4.02, 95% CI: 3.25-5.02).<h4>Discussion</h4>Integrating PRS and biological aging measures improved ADRD risk stratification.