The Role of Menopause and Its Association with the Apolipoprotein E4 Allele for Age at Diagnosis of Glaucoma in Women

Abstract

Objective: To explore the impact of menopause for age at diagnosis (AAD) of glaucoma in women and illustrate its interaction with the apolipoprotein E (APOE) E4 allele.

Design: A retrospective, case-only analysis using the UK Biobank participants with complete data (2006-2010) for analysis.

Participants: One thousand three hundred fifty-eight female glaucoma patients.

Methods: Multivariable-adjusted associations of AAD of glaucoma, APOE E4 allele, age of menopause, and hormone replacement therapy (HRT) were analyzed by linear mixed model (LMM) analyses across groups stratified by whether glaucoma developed before or after menopause and whether or not HRT was used.

Main outcome measures: Age at diagnosis of glaucoma, age of menopause, APOE E4 allele, and HRT information.

Results: The age-adjusted univariate LMM showed that later menopause was significantly associated with an older AAD of glaucoma in both the overall cohort and subgroups where glaucoma developed before or after menopause (model 1, all P < 0.05). The age-adjusted multivariate LMM found that carrying the APOE E4 allele combined with later menopause significantly increased the AAD of glaucoma in patients diagnosed before menopause (model 3: β_{age of menopause} = 0.711 ± 0.074, P < 0.001; β_e4 = 1.406 ± 0.596, P = 0.019; model 1 vs. model 3: P = 0.018). No similar association was observed in patients diagnosed after menopause (P > 0.05). Additionally, the age-adjusted univariate LMM showed that HRT was associated with an older AAD of glaucoma (model 4: β_HRT = 1.239 ± 0.368, P = 0.001), with this effect being more pronounced in patients with later menopause (model 5: β_HRT = 1.625 ± 0.356, P < 0.001; β_{age of menopause} = 0.301 ± 0.033, P < 0.001; model 4 vs. model 5: P < 0.001).

Conclusions: Later menopause was associated with an older AAD of glaucoma, with the APOE E4 allele providing increased protection against glaucoma in those diagnosed before, but not after, menopause. The protective effect of later menopause was also enhanced by HRT use after menopause. These findings underscore the interaction of hormonal status and APOE genotype in glaucoma onset, potentially guiding the prevention or management of glaucoma and other age-related health conditions in women.

Financial disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Keywords: APOE E4 allele; Age at diagnosis of glaucoma; Alzheimer's disease; Menopause; UK Biobank.

Figure 1

Cohort selection diagram illustrating the stratification of the UK Biobank dataset into subsets to analyze female-specific risk factors for glaucoma. Menopause status and age at glaucoma diagnosis were selected. The diagram depicts the grouping of female participants into those who had glaucoma before or after menopause, further stratified by whether they received hormone replacement therapy (HRT) and the timing relative to menopause onset when HRT was received. APOE = apolipoprotein E.