Blood co-expression modules tied to Framingham cardiovascular risk score were identified in two independent cohorts, and two preserved modules enriched in RNA-protein homeostasis, mitochondrial function, and hematopoietic pathways showed consistent FRS associations across cohorts and stratified participants in line with clinical FRS categories.
Key Findings
Methods
Blood-based transcriptomic analysis was performed in two independent cohorts of different ancestry to identify molecular signatures of cumulative cardiovascular risk (Framingham risk score, FRS) in Alzheimer's disease research populations.
Seoul National University Bundang Hospital (SNUBH) cohort: N = 148, Korean.
Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort: N = 743, predominantly European ancestry.
Methods included FRS-associated co-expression network module identification, pathway enrichment, hub gene-based participant stratification, and bidirectional cross-cohort discovery-replication analyses.
Results
Co-expression modules associated with FRS were found in both cohorts, with more modules identified in the larger ADNI cohort.
Two co-expression modules were associated with FRS in SNUBH.
Six co-expression modules were associated with FRS in ADNI.
Results
Bidirectional cross-cohort analyses identified two preserved modules showing consistent module-FRS associations in both cohorts.
Discovery-replication analyses were run in both directions between SNUBH and ADNI.
The two preserved modules had consistent module-FRS associations across the two cohorts.
Results
The two preserved FRS-associated modules were enriched in pathways related to cellular responses to exposure.
Enriched pathways included RNA-protein homeostasis, mitochondrial function, and hematopoietic processes.
The authors frame these as pathways implicated in cellular responses to exposure, relating to the exposome.
Results
Hub genes in the two preserved modules stratified participants into molecularly distinct subgroups that were concordant with clinical FRS categories.
Stratification was based on hub genes from the two preserved modules.
Resulting subgroups aligned with clinical FRS categories.
Conclusions
The authors conclude that FRS-associated molecular pathways were identified and warrant further investigation as potential targets for risk modification.
The findings are presented as hypothesis-generating regarding targets for modifying cardiovascular risk in AD.
What This Means
This study looked at gene activity in blood samples from two groups of people: 148 Korean participants and 743 participants in a U.S. Alzheimer's research study who were mostly of European ancestry. The researchers asked whether patterns of gene activity track with the Framingham risk score, a common measure of a person's overall cardiovascular risk based on factors such as age, blood pressure, and cholesterol.
They found groups of genes whose activity moves together and relates to cardiovascular risk: two such groups in the Korean cohort and six in the larger cohort. Two of these gene groups showed the same relationship with cardiovascular risk in both cohorts. These groups were tied to basic cell processes, including how cells manage RNA and proteins, how mitochondria (the cell's energy producers) work, and how blood cells are produced. Key genes in these groups could also sort participants into subgroups that matched their clinical cardiovascular risk categories.
This research suggests that cardiovascular risk leaves a measurable molecular signature in blood that holds up across different populations. The authors say these pathways deserve further study as possible targets for reducing risk. The findings show associations only and do not show that these pathways cause Alzheimer's disease or that changing them would help.
Han S, Park Y, Pyun J, Hwang J, Park J, Kim S, et al.. (2026). Blood transcriptomic signatures of vascular risk in Alzheimer's disease.. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1002/alz.71930