Menopausal hormone therapy has beneficial effects on cognitive trajectories among homozygous carriers of the APOE‐ε4 allele: Biomarkers (non‐neuroimaging) / Longitudinal change over time. (7th December 2020)

• Record Type: Journal Article
• Authors: Mahoney, Emily R.; Dumitrescu, Logan; Maki, Pauline M.; Rapp, Stephen R.; Keene, C. Dirk; Corrada, Maria M.M.; Hayden, Kathleen M.; Baker, Laura D.; Espeland, Mark A.; Resnick, Susan M.; Hohman, Timothy J.
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 5
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.041482
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Two‐thirds of Alzheimer's disease (AD) cases are females and increasing evidence suggests the greatest genetic risk factor for AD, the APOE ‐ε4 allele, has a stronger association among females compared to males. Estrogen changes after menopause may contribute to cognitive decline, particularly among those at highest genetic risk for AD. While estrogen treatment has not shown a consistent association with reducing cognitive decline in late‐life, the modifying role of APOE on the cognitive consequences of menopausal hormone therapy (MHT) is not well‐characterized. We used a pharmacogenomic approach to evaluate the interaction between MHT and APOE on longitudinal cognitive change leveraging data from the Women's Health Initiative (WHI). Method: We evaluated data from 4, 128 WHI participants who were randomized to receive conjugated equine estrogens with or without medroxyprogesterone acetate (n=2, 030) or matching placebo (n=2, 098). Cognition was measured biennially with the Modified Mini‐Mental Status Exam (3MSE). At baseline, average age was 70±4, average 3MSE was 96±3 and 25% of participants were APOE‐ ε4 carriers. Mixed‐effects regression using a three‐way interaction ( APOE x years from baseline x treatment group) assessed the potential modifying role of APOE on the cognitive consequences of MHT. Separate sensitivity analyses were run in the estrogen and estrogen+progestin treatment groups. Result: APOE genotype significantly interacted with MHT on change in 3MSE scores (Figure 1, p=0.01), whereby homozygous ε4 carriers showed a benefit of MHT (p=0.01), while heterozygotes and non‐ε4 carriers showed none (p>0.07). This interaction was consistent between the estrogen‐alone and estrogen+progestin treatment groups. Conclusion: MHT may have cognitive benefits among women who are at high genetic risk for AD. Literature on the cognitive effects of MHT among APOE ‐ε4 carriers remains mixed, but this analysis of a large sample from a randomized trial of MHT adds critical information to the field. Additional work is needed to better understand how age, timing of MHT initiation, treatment duration and form, or other health conditions may contribute to the observed effect of MHT among APOE‐ ε4 homozygotes. Regardless, these findings underscore the potential benefit of a precision medicine approach that integrates genetic modifiers of treatment response into clinical decision‐making.