Effect of APOE ε4 Gene on Perihematomal Edema in Intracerebral Hemorrhage: A Prospective Study.

Abstract

Background: Intracerebral hemorrhage (ICH) leads to perihematomal edema (PHE), exacerbating brain swelling and functional deterioration. Blood-brain barrier disruption has been observed in carriers of the apolipoprotein E (APOE) ε4 genotype. The study focused on the impact of APOE ε4 in PHE and its underlying molecular mechanisms.

Methods: This study was a single-center, prospective, and nested cohort study involving patients with ICH admitted to the emergency department of the Affiliated Hospital of Guizhou Medical University between April 2023 and October 2024. We included patients who underwent surgery within 24 h of onset. APOE ε4 and APOE ε3 groups were formed based on hemorrhage location, age, and hemorrhage volume using a 1:1 stratified matching method. We analyzed the initial cranial computed tomography scans taken within 24 h after onset; we measured hematoma volume and edema volume (EV) and calculated the combined edema and hematoma volume, the preoperative edema coefficient (PEC), and the edema expansion distance (EED). In addition, cerebrospinal fluid samples from the hematoma cavity were collected during surgery, and enzyme-linked immunosorbent assays were used to measure the expression levels of APOE, low-density lipoprotein receptor-related protein 1 (LRP1), cyclophilin A (CypA), nuclear factor κB (NF-κB), matrix metalloproteinase 9 (MMP-9), occludin, and ZO-1.

Results: Among 48 patients (24 per group), APOE ε4 carriers exhibited greater PHE than APOE ε3 carriers, reflected by increased EV, PEC, and EED. After adjusting for hematoma volume, linear regression showed APOE ε4, MMP-9, and occludin were positively associated with PEC, whereas LRP1 had an inverse relationship (β =  - 0.2, p = 0.008). Mediation analysis revealed APOE ε4 influenced PEC indirectly via MMP-9 (effect size = 0.38, p < 0.001), accounting for 32.84% of the total effect.

Conclusions: The APOE ε4 genotype in patients with ICH may encode an APOE isoform with a lower affinity for LRP1, which decreases the inhibitory effect of LRP1 on MMP-9 activity, leading to blood-brain barrier disruption and the exacerbation of PHE, as indicated by increased EV, PEC, and EED.