Blood transcriptomic signatures of vascular risk in Alzheimer's disease
Sang‐Won Han, Young Ho Park, Jung‐Min Pyun, Jiyun Hwang, Jeong Su Park, SangYun Kim, Kwangsik NhoAbstract
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.