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

• Published in: Neurobiology of aging Vol. 87; pp. 18 - 25
• Main Authors: Moore, Annah M., Mahoney, Emily, Dumitrescu, Logan, De Jager, Philip L., Koran, Mary Ellen I., Petyuk, Vladislav A., Robinson, Renã AS, Ruderfer, Douglas M., Cox, Nancy J., Schneider, Julie A., Bennett, David A., Jefferson, Angela L., Hohman, Timothy J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2020
• Subjects: Aged; Aged, 80 and over; Aging; Aging - genetics; APOE-ε4; Apolipoprotein E4 - genetics; Cognition; Cognitive Aging; Cognitive Dysfunction - genetics; Female; Gene Expression; Genetic Association Studies; Genetic Predisposition to Disease - genetics; Genotype; Humans; Male; Neovascularization, Physiologic - genetics; Neuropilin-1 - genetics; Neuropilin-1 - physiology; Vascular endothelial growth factor (VEGF); Vascular Endothelial Growth Factor A - genetics; Aging; Cognition; Gene expression; APOE-ε4; Vascular endothelial growth factor (VEGF)
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2019.10.021

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. •Evaluated interactions between VEGF expression and APOE-ε4 allele on cognition.•VEGF genes NRP1 and VEGFA interacted with APOE-ε4 on cognitive performance.•Among ε4 carriers, higher NRP1 expression correlated with worse outcomes.•Among ε4 noncarriers, higher NRP1 expression correlated with better outcomes.•Associations of angiogenic-relevant VEGF genes appear to depend on APOE genotype.