Objective: To explore the impact of the apolipoprotein E (APOE) E4 allele in the gender-specific aging process in glaucoma by illustrating the interaction between risk factors, including the APOE E4 allele, gender, and intraocular pressure (IOP), for age at diagnosis (AAD) of glaucoma. Design: A cross-sectional study included UK Biobank participants with complete data (2006-2010) for analysis. Data were analyzed in December 2023. Participants: Two thousand two hundred thirty-six glaucoma patients and 103 232 controls. Methods: We evaluated multivariable-adjusted associations of AAD of glaucoma, APOE E4 allele (0: absence; 1: presence), and IOP using linear mixed model (LMM) analyses across groups stratified by AAD of mean age of menopause (50 years) and gender. Main outcomes measures: Age at diagnosis of glaucoma, APOE E4 allele, and IOP. Results: Patients with glaucoma were older and had a higher percentage of males and a higher mean IOP compared to controls (all P < 0.001). Further stratifying the patients with glaucoma by AAD of 50 and gender, lower IOP (model 1 adjusted by age, beta(IOP) = -0.096 +/- 0.041, P = 0.019), and positive APOE E4 allele (model 2 adjusted by age and IOP, beta(e4) = 1.093 +/- 0.488, P = 0.026) were associated with an older AAD in females with an AAD <50 years under univariate LMM. In multivariate LMM adjusted by age (model 3), the effect size of both factors increased in the multivariate model as the beta-value increased (beta(IOP) = -0.111 +/- 0.040, P = 0.007; beta(e4) = 1.235 +/- 0.485, P = 0.012) (model 1 vs. model 3: P = 0.011). In females with an AAD >= 50 years, only positive APOE E4 allele (adjusted by age and IOP, beta(e4) = -1.121 +/- 0.412, P = 0.007) was associated with a younger AAD. In males, only higher IOP was associated with an older AAD in those with an AAD >= 50 years (beta(IOP) = 0.088 +/- 0.032, P = 0.006). Conclusions: Apolipoprotein E E4 allele may initially delay and later accelerate the development of glaucoma in females around the transition period of 50 years, which is the mean age of menopause, and importantly, this is independent of IOP. Understanding the specific transition states and modifiable factors within each age phase is crucial for developing interventions or strategies that promote healthy aging. Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.