Blood transcriptomic signatures of vascular risk in Alzheimer's disease

INTRODUCTION: Lifestyle and environmental factors contributing to cardiovascular risk are components of the exposome, yet molecular signatures associated with cumulative cardiovascular risk in Alzheimer's disease (AD) remain incompletely understood. METHODS: We analyzed blood-based transcriptomics data from two independent cohorts: Seoul National University Bundang Hospital (SNUBH; N = 148, Korean) and Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 743, predominantly European ancestry). Framingham cardiovascular risk score (FRS)-associated co-expression network modules were identified, followed by pathway-based enrichment, hub gene-based participant stratification, and bidirectional cross-cohort discovery-replication analyses. RESULTS: Two co-expression modules were associated with FRS in SNUBH, and six in ADNI. Bidirectional analyses identified two preserved modules with consistent module-FRS associations across cohorts, enriched in pathways implicated in cellular responses to exposure, including RNA-protein homeostasis, mitochondrial function, and hematopoietic processes. Hub genes in the two modules stratified participants into molecularly distinct subgroups concordant with clinical FRS categories. DISCUSSION: FRS-associated molecular pathways were identified and warrant further investigation as potential targets for risk modification.