First to Know

Members of The Menopause Society receive a subscription to this e-mail newsletter featuring the latest research news and menopause information, along with expert commentary that places the news into perspective. The Society requests commentary from experts in the clinical practice and research communities on subjects of interest to its members. Editor of First to Know is The Society’s medical director, Stephanie S Faubion, MD, MBA, FACP, MSCP, IF. Opinions expressed in the commentaries are those of the authors and are not necessarily endorsed by The Society or by Dr. Faubion. 

Sample Issue

February 16, 2023 

Experts Respond to Article on Hormone Therapy and Improved Cognition and Larger Brain Volumes 

“We want to make you aware of a study by Saleh and colleagues published in Alzheimer’s Research & Therapy,” says Dr. Faubion. “The study suggests that hormone therapy (HT) is associated with improved cognition and larger brain volumes in at-risk APOE ε4 women. 

“It is important that we have experts on the topic to provide commentary on the significance of these findings, so I invited my esteemed colleague and expert in the field, Dr. Kenjal Kentarci, to provide expert commentary to help put this new study into perspective.” 

Summary 

The risk of dementia is higher in women than in men. The decline of estrogen during the menopause transition is theorized to accelerate development of neuropathology in women. The use of HT in the prevention of cognitive decline has shown conflicting results. This study aimed to investigate the modulating role of the APOE ε4 genotype and age at HT initiation on the heterogeneity in cognitive response to HT. The study was an analysis based on data from participants in the European Prevention of Alzheimer’s Dementia cohort (N=1,906; women=1,178, 61.8%). Analysis of covariate models were employed to test the independent and interactive effect of the APOE ε4 genotype and HT on select cognitive tests, together with volumes of the medial temporal lobe regions by magnetic resonance imaging (MRI). Multiple linear regression models were used to examine the effect of age of HT initiation according to APOE ε4 carrier status on these cognitive and MRI outcomes. Results showed that APOE ε4 HT users had the highest delayed memory index score compared with APOE ε4 nonusers and to non-APOE ε4 carriers, with 6% to 10% larger entorhinal (left) and amygdala (right and left) volumes. Earlier introduction of HT was associated with larger right and left hippocampal volumes only in APOE ε4 carriers. The authors concluded that HT use is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE ε4 genotype carriers only. They suggest that HT may represent an effective targeted strategy to mitigate the higher lifetime risk of Alzheimer disease (AD) in this large at-risk population subgroup. 

Commentary 

In this publication from Alzheimer’s Research & Therapy, Saleh and colleagues describe findings from a cross-sectional investigation of cognitive outcomes in women who were HT users and nonusers in the European Prevention of Alzheimer’s Dementia cohort. They further stratify this cohort by APOE ε4 carrier status as carriers and noncarriers, because APOE ε4 carriers have a higher risk for AD than noncarriers. 

In general, the sample size was quite large, comprised of 1,074 women, but the APOE ε4 carrier HT users, in whom the main effects were seen, was relatively small (n=29-31). The cohort was aged, on average, 65 years at the time of evaluation, with most of the users (91%) continuing to use HT at that age. Of interest to The Menopause Society community, the authors report better delayed memory function on objective measures in APOE ε4 carrier HT users. They further demonstrate that medial temporal structures that are responsible for memory function, such as the hippocampus and entorhinal cortex, have larger volumes in APOE ε4 carrier HT users than APOE ε4 carrier HT nonusers, particularly if they started HT at an earlier age. 

There is significant interest in investigating risks and benefits of HT on cognitive health, and the current study is another addition to a large body of observational studies that have shown conflicting findings of either benefit or no benefit. Lately, the APOE ε4 genotype has emerged as a modifier of the HT effects on the brain, with APOE ε4 carriers showing a better response, as demonstrated in the current study. Although this may be a pharmacogenomic effect in persons with the APO ε4 genotype, another explanation is that APOE ε4 carriers tend to accumulate AD pathology at an earlier age, increasing the power to detect an effect at an average age of 65 years. 

As the authors point out, a causal relationship cannot be established in a cross-sectional study. Furthermore, “healthy-user bias” is a concern in observational studies, because the choice to use HT is made by the participant, not through randomization. Furthermore, HT formulations and the route of administration may have varying effects on outcomes. So far, cognitive effects have not been demonstrated in the Early Versus Late Intervention Trial With Estradiol and the Kronos Early Estrogen Prevention Study that tested the “critical window” hypothesis for early initiation of HT in postmenopausal women. 

We also need to consider the broader implications of this work. The APOE ε4 genotype, which increases the risk of AD, appears to be an important modifier of HT effects on the brain. Understanding who may be at risk for AD because of menopause-related factors needs further investigation. The current study provides further evidence that the APOE ε4 genotype may be an important factor.