My Friends!
I'm very excited about this post today because it speaks to the incredibly important issue of cognitive function and Alzheimer's Disease risk and how hormone therapy (HT) fits into this equation. 
Enjoy!
-Carla DiGirolamo, MD

The question of how hormone therapy (HT) impacts cognition has been a subject of intense debate with conflicting results in the medical literature.

A recent open-access article was published in January 2023 by RNM Saleh et al from Norwich Medical School in the UK entitled 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. Their findings make a valuable contribution to this debate.

Today’s post will summarize this study and include the official response from the North American Menopause Society (NAMS) as well as my own commentary.

____________________________________________________________________________________

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

Rasha N. M. Saleh, Michael Hornberger, Craig W. Ritchie, and Anne Marie Minihane

Alzheimer’s Research & Therapy (2023) 15:10

Goal of the Study

Investigate the role of APOE gene variant carrier status and age at HT initiation in the cognitive response to HT.

Background

• More than 2/3 of Alzheimer’s Disease (AD) patients are women and the hormonal changes of the menopause transition are emerging as a potential contributing factor.

• The APOE gene codes for the production of a special protein that combines with fat creating a lipoprotein. Lipoproteins aid in the transport of cholesterol throughout the body.

• A variant of the APOE gene called APOE4 has been associated with an increased risk of AD and cognitive decline. The risk of cognitive decline / AD has been reported to be greater in women who possess the APOE4 variant as compared to men with this same variant.

• The results of studies investigating the impact of HT on cognitive decline and AD risk have been mixed. However, there are trends suggesting that there may be a “window” of time during the menopause transition / early menopause where HT use may benefit cognitive function. Likewise, potentially harmful effects on cognitive function have been seen in women initiating HT later in menopause and at an older age. More investigation into these observations is needed.

Study Methods

• Data analysis of participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort.

• Participants: 1,906 of whom 1,178 (61%) were women.

• Statistical modeling (ANCOVA test) was used to test the independent and interactive impact of the APOE gene variants and HT on various cognitive performance tests and brain MRI findings.

• Additional statistical modeling (Multiple Linear Regression) was used to examine the impact of age of HT initiation in women possessing the APOE4 variant on cognitive testing and MRI findings.

Results

• Women possessing the APOE4 variant who were HT users had significantly higher memory scores (RBANS delayed memory index) compared with non-APOE4 carriers and non-users of HT.

• APOE4 / HT users also had greater maintenance of tissue volume in areas of the brain responsible for memory and cognition by MRI.

• Initiation of HT at a younger age was associated with greater maintenance of tissue volume in the memory/cognition areas of the brain in APOE4 carriers ONLY. This difference was not seen in APOE4 non-carriers.

Author’s Conclusions

• HT use is associated with improved memory scores and maintenance of tissue volume in areas of the brain responsible for memory and cognition in women who possess the APOE4 gene variant. This effect is not seen in women who do not carry the APOE4 variant.

• The presence of the APOE4 variant and the age of HT initiation are important modulators of the effect of HT on cognition. Consideration of these two factors may be an effective, targeted strategy to mitigate AD risk in this at-risk population of APOE4 variant carriers.

Study Limitations

• This study was a cross-sectional analysis that reveals associations among variables. This type of study cannot prove a cause-effect relationship.

• The small sample size of the APOE4 /HT user group did not allow stratification by type and dose of HT used (ie estrogen alone, estrogen plus progesterone, specific formulation, etc.).

NAMS Response

Because HT and cognition have been the subject of intense study with conflicting results, NAMS released an official commentary on the findings of this study and its significance within the existing medical literature. The main points of their response are below:

• The reviewers note that the APOE4 carrier/HT user population is small (29-31 participants).

• The average age of this patient group was 65 years. 91% were continuing the use of HT.

• The authors effectively demonstrated improved memory function using objective measures in APOE4 carrier HT users. They further demonstrate greater tissue volume in areas of the brain responsible for memory and cognition, particularly if HT was started at an earlier age.

• A causal relationship cannot be established in this type of study (cross-sectional). “Healthy user bias” is also a concern in observational studies where participants have chosen to use HT as compared to a study where the use of HT is randomized.

• So far, cognitive effects have not been demonstrated in two large randomized trials: the Early Versus Late Intervention Trial with Estradiol (ELITE) and the Kronos Early Estrogen Prevention Study (KEEPS).

• The APOE4 carrier status appears to be associated with an increased risk of AD and appears to be an important modifier of HT effects on the brain. An understanding of who is at risk for AD because of menopause-related factors needs further investigation. This study provides further evidence that APOE4 carrier status is an important factor.

In my humble opinion….

This study is an important contribution to the literature and provides a direction for further study. However, we must be cautious because there are studies that have shown harmful cognitive effects of HT in the same age group as the small number of APOE4 HT users in this study.

The author’s points are well-taken with respect to the “window” of therapeutic benefit for HT use. This has been a pattern seen in the study of the favorable effects of HT on cardiovascular disease risk and all-cause mortality in HT users within 10 years of menopause younger than 60 years old.

Although no cognitive effects have been observed thus far in the ELITE and KEEPS trials, these studies are not designed to stratify based on APOE4 carrier status. If the relationship between APOE4 and AD risk is significant as the literature currently suggests, the benefit for this population may not be appreciated in these larger trials designed to evaluate the effect of HT use in the general population.

All in all, this is great stuff! The area of personalized medicine and risk assessment based on genetics is growing rapidly. My colleagues at Wild Health are among the pioneers in this area and APOE genetic carrier status is part of their comprehensive genetic analysis. I have worked closely with the Wild Health physicians and coaches and they are top-notch!