APOE4 Genotype is Associated with Reduced Cortical VEGFR2 ( KDR ) Transcript Levels Independent of Endothelial Abundance: An AMP-AD RNA-seq Pilot Study

Abstract Background Apolipoprotein E4 ( APOE4 ) is the strongest common genetic risk factor for late-onset Alzheimer’s disease and has been implicated in cerebrovascular dysfunction. Vascular endothelial growth factor receptor 2 (VEGFR2), encoded by the gene KDR , is a key regulator of endothelial integrity and blood-brain barrier (BBB) maintenance; however, its relationship to APOE4 status in human brain tissue remains unclear. Methods Bulk RNA-sequencing data from 162 donors (n = 633 cortical samples) from the AMP-AD MSSB cohort were analysed using linear mixed-effects models with donor-level random intercepts. Models were adjusted for tissue region, age at death, sex, RNA integrity (RIN), and post-mortem interval. An endothelial composite score derived from key endothelial markers ( PECAM1, VWF, CLDN5, FLT1, TEK ) was included to account for endothelial signal abundance. Interaction models assessed modification by cortical region and neuropathological burden (Braak stage, CERAD score, plaque mean). A candidate panel of endothelial/BBB transcripts ( KDR, CAV1, MFSD2A, CLDN5, SLC2A1, OCLN, TJP1 ) were also assessed in relation to APOE genotype. Results Bulk KDR expression varied significantly across cortical regions (p < 2×10 −16 ) and was strongly correlated with endothelial signal abundance (r = 0.57, p < 2×10 −16 ). APOE4 status was not associated with endothelial composite score (p = 0.78). In models adjusting for tissue and technical covariates, but not endothelial signal, APOE4 carriers showed a non-significant trend toward reduced KDR expression (β = −0.16, p = 0.064). After inclusion of the endothelial composite score, APOE4 carrier status was significantly associated with reduced KDR expression (β = −0.17, p = 0.029), corresponding to an estimated 10-15% decrease in transcript levels. The direction of effect was consistent across cortical regions, with no evidence of APOE4 × region interaction. No significant APOE4 × neuropathology interactions were observed. Among candidate transcripts, only KDR and TJP1 showed reduced expression, suggesting a selective rather than global transcriptional effect. Conclusions Bulk KDR transcript levels are strongly influenced by endothelial signal abundance; however, APOE4 is associated with a modest but consistent reduction in VEGFR2 expression independent of endothelial signal abundance and neuropathological severity. These findings support a model in which APOE4 contributes to vascular dysfunction through targeted endothelial alterations, rather than merely reflecting changes in endothelial cell proportion.