Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort

Abstract

Background The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT. Methods The analysis used baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes. Results APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6–10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized β= −0.555, p=0.035) and left hippocampal volumes (standardized β= −0.577, p=0.028) only in APOE4 carriers. Conclusion HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

Benefits for cardiovascular system, bone density, and quality of life of a long-term hormone therapy in hysterectomized women: a 20-year follow-up study

“…After long-term HT, we observed a beneficial increase in bone density. Interestingly, HT has been recently associated with improved delayed memory, mitigating the higher life-time risk of Alzheimer disease 26 . Altogether, these results are contrary to the main findings of the WHI study.…”

“…Interestingly, HT has been recently associated with improved delayed memory, mitigating the higher life-time risk of Alzheimer disease. 26 Altogether, these results are contrary to the main findings of the WHI study. The administration of conjugated equine estrogen in WHI cohort versus transdermal estradiol in our study may have an impact on these differences.…”

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

“…For example, results of the Phase 3 Lecanemab trial revealed that females and APOE4 homozygotes did not show improved cognition in response to Lecanemab treatment, while males and APOE4 carriers showed significant improvement (66). Additionally, hormone replacement therapy was shown to interact with APOE genotype to yield different efficacies in AD risk prevention in post-menopausal women (67). Since APOE signals through TREM2 (50), the sex biases observed in TREM2 signaling pathways in aged microglia may be contributing to the differential response to AD treatment.…”

Counseling in menopausal women: How to address the benefits and risks of menopause hormone therapy. A FIGO position paper

“…61 In addition, in women who are APOE4 carriers and therefore at high risk for Alzheimer's disease, early MHT may represent an effective targeted strategy to mitigate their higher lifetime risk of Alzheimer's disease. 63,64 Further investigation in this area is still warranted, as data from the literature are somewhat contradictory. Indeed, recent North European Finnish/Danish case-control studies, based on national registries, have pointed towards a relationship between MHT and the risk of developing Alzheimer's disease and/or late-onset dementia.…”