Blood-Brain Network-Based Polygenic Risk Scores Reveal Biomarker Signatures and the Progression of Alzheimer's Disease.

Résumé

Polygenic risk scores for Alzheimer's disease (AD), organized by gene networks shared between the blood and brain, may provide insights into underlying disease mechanisms common to both tissues. We derived a blood-brain network-based polygenic risk score (nbPRS) from AD-associated genetic variants for three blood-brain networks, selected by the preservation of blood and brain gene co-expression networks, and AD association. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1109), Framingham Heart Study (FHS, n = 8310), the Religious Orders Study Memory Aging Project (ROSMAP, n = 1215), and Mount Sinai Brain Bank (MSBB, n = 323) were stratified into low- and high-nbPRS subgroups, then profiled using longitudinal and cross-sectional data. We compared the conversion from normal cognition to AD between nbPRS subgroups. Genes differentially expressed among low- and high-nbPRS individuals were profiled with classical neuropathological markers and we investigated potential biologically relevant pathways for the genes significantly expressed in high-risk individuals. Individuals with high nbPRS in three AD-associated networks (M2, M6, M14) demonstrated significant impairment in executive function and memory performance, whereas high-risk individuals in networks M2 and M14 had significantly reduced hippocampal volume. We observed high-risk individuals in M2 and M14 developed AD at twice the rate of low-risk individuals in these networks. genes were differentially expressed with transcriptome-wide significance among low- and high-nbPRS individuals in M14 and associated with neuroinflammatory and tau pathology. Polygenic risk scores derived from blood and brain networks can differentiate individuals with a high risk of AD conversion.