APOE ε4-specific associations of VEGF gene family expression with cognitive aging and Alzheimer's disease

Abstract

Literature suggests vascular endothelial growth factor A (VEGFA) is protective among those at highest risk for Alzheimer's disease (AD). Apolipoprotein E (APOE) ε4 allele carriers represent a highly susceptible population for cognitive decline, and VEGF may confer distinct protection among APOE-ε4 carriers. We evaluated interactions between cortical expression of 10 VEGF gene family members and APOE-ε4 genotype to clarify which VEGF genes modify the association between APOE-ε4 and cognitive decline. Data were obtained from the Religious Orders Study and Rush Memory and Aging Project (N = 531). Linear regression assessed interactions on global cognition. VEGF genes NRP1 and VEGFA interacted with APOE-ε4 on cognitive performance (p.fdr < 0.05). Higher NRP1 expression correlated with worse outcomes among ε4 carriers but better outcomes among ε4 noncarriers, suggesting NRP1 modifies the risk for poor cognitive scores based on APOE-ε4 status. NRP1 regulates angiogenesis, and literature suggests vessels in APOE-ε4 brains are more prone to leaking, perhaps placing young vessels at risk for ischemia. Results suggest that future therapeutics targeting brain angiogenesis should also consider ε4 allele status.

Keywords: APOE-ε4; Aging; Cognition; Gene expression; Vascular endothelial growth factor (VEGF).

Figure 1.

(A) NRP1 expression associations with global cognitive performance at the final neuropsychological assessment, stratified by APOE-ε4 allele status. Overall interaction: NRP1 × APOE-ε4, β=−0.28, p.fdr=0.007; APOE-ε4 carriers, β=−0.17, p=0.038; APOE-ε4 non-carriers, β=0.11, p=0.004. (B) VEGFA expression associations with global cognitive performance at the final neuropsychological assessment, stratified by APOE-ε4 allele status. Overall interaction: VEGFA × APOE-ε4, β=−0.03, p.fdr=0.026; APOE-ε4 carriers, β=−0.03, p=0.019; APOE-ε4 non-carriers, β=0.004, p=0.4.