HRT May Prevent Alzheimer’s in High-Risk Women

Hormone replacement therapy (HRT) introduced early during the menopausal transition may protect against Alzheimer’s dementia in women carrying the APOE4 gene, new research suggests.

Results from a cohort study of almost 1200 women showed that use of HRT was associated with higher delayed memory scores and larger entorhinal and hippocampal brain volumes ― areas that are affected early by Alzheimer’s disease (AD) pathology.

HRT was also found to be most effective, as seen by larger hippocampal volume, when introduced during early perimenopause.

“Clinicians are very much aware of the susceptibility of women to cognitive disturbances during menopause,” lead author Rasha Saleh, MD, senior research associate, Norwich Medical School, University of East Anglia, United Kingdom, told Medscape Medical News.

“Identifying the at-risk APOE4 women and early HRT introduction can be of benefit. Confirming our findings in a clinical trial would be the next step forward,” Saleh said.

The findings were published online January 9 in Alzheimer’s Research and Therapy.

Personalized Approaches

Saleh noted that estrogen receptors are localized in various areas of the brain, including cognition-related areas. Estrogen regulates such things as neuroinflammatory status, glucose utilization, and lipid metabolism.

“The decline of estrogen during menopause can lead to disturbance in these functions, which can accelerate AD-related pathology,” she said.

HRT during the menopausal transition and afterward is “being considered as a strategy to mitigate cognitive decline,” the investigators write. Early observational studies have suggested that oral estrogen “may be protective against dementia,” but results of clinical trials have been inconsistent, and some have even shown “harmful effects,” they add.

The current researchers were “interested in the personalized approaches in the prevention of AD,” Saleh said. Preclinical and pilot data from her group have shown that women with APOE4 have “better cognitive test scores with nutritional and hormonal interventions.”

This led Saleh to hypothesize that HRT would be of more cognitive benefit for those with vs without APOE4, particularly when introduced early during the menopausal transition.

To investigate this hypothesis, the researchers analyzed baseline data from participants in the European Prevention of Alzheimer’s Dementia (EPAD) cohort. This project was initiated in 2015 with the aim of developing longitudinal models over the entire course of AD prior to dementia clinical diagnosis.

Participants were recruited from 10 European countries. All were required to be at least 50 years old, to have not been diagnosed with dementia at baseline, and to have no medical or psychiatric illness that could potentially exclude them from further research.

The current study included 1178 women (mean age, 65.1 years), who were divided by genotype into non-APOE4 and APOE4 groups. HRT treatment for current or previous users included estrogen alone or estrogen plus progestogens via oral or transdermal administration routes, and at different doses.

The four tests used to assess cognition were the Mini-Mental State Examination dot counting to evaluate verbal working memory, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score, the Four Mountain Test, and the supermarket trolley virtual reality test.

Brain MRI data were collected. The researchers focused on the medial temporal lobe as the “main brain region regulating cognition and memory processing.” This lobe includes the hippocampus, the parahippocampus, the entorhinal cortex, and the amygdala.

“Critical Window”

The researchers found a “trend” toward an APOE-HRT interaction (P-interaction = .097) for the total RBANS score. In particular, it was significant for the RBANS delayed memory index, where scores were consistently higher for women with APOE4 who had received HRT compared with all other groups (P-interaction = .009).

Within-genotype group comparisons showed that HRT users had a higher RBANS total scale score and delayed memory index (P = .045 and P = .002, respectively), but only among APOE4 carriers. Effect size analyses showed a large effect of HRT use on the Four Mountain Test score and the supermarket trolley virtual reality test score (Cohen’s d =.988 and 1.2, respectively).

“This large effect was found only in APOE4 carriers,” the investigators note.

Similarly, a moderate to large effect of HRT on the left entorhinal volume was observed in APOE4 carriers (Cohen’s d = .63).

In members of the APOE4 group who received HRT, the left entorhinal and left and right amygdala volumes were larger compared with both no-APOE4 and non-HRT users (P-interaction = .002, .003, and .005, respectively). Similar trends were observed for the right entorhinal volume (P = .074).

In addition, among HRT users, the left entorhinal volume was larger (P = .03); the right and left anterior cingulate gyrus volumes were smaller (P = .003 and .062, respectively); and the left superior frontal gyrus volume was larger (P = .009) in comparison with women who did not receive HRT, independently of their APOE genotype.

Early use of HRT among APOE4 carriers was associated with larger right and left hippocampal volume (P = .035 and P = .028, respectively) ― an association not found in non-APOE4 carriers. The association was also not significant when participants were not stratified by APOE genotype.

“The key important point here is the timing, or the ‘critical window,’ when HRT can be of most benefit,” Saleh said. “This is most beneficial when introduced early, before the neuropathology becomes irreversible.”

Study limitations include its cross-sectional design, which precludes the establishment of a causal relationship, and the fact that information regarding the type and dose of estrogen was not available for all participants.

HRT is not without risk, Saleh noted. She recommended that clinicians “carry out various screening tests to make sure that a woman is eligible for HRT and not at risk of hypercoagulability, for instance.”

Risk-Benefit Ratio

Commenting for Medscape Medical News, Howard Fillit, MD, cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation, called the study “exactly the kind of work that needs to be done.”

Fillit, who was not involved with the current research, is a clinical professor of geriatric medicine, palliative care medicine, and neuroscience at Mount Sinai Hospital, New York City.

He compared the process to that of osteoporosis. “We know that if women are treated [with HRT] at the time of the menopause, you can prevent the rapid bone loss that occurs with rapid estrogen loss. But if you wait 5, 10 years out, once the bone loss has occurred, the HRT doesn’t really have any impact on osteoporosis risk because the horse is already out of the barn,” he said.

Although HRT carries risks, “they can clearly be managed; and if it’s proven that estrogen or hormone replacement around the time of the menopause can be protective [against AD], the risk-benefit ratio of HRT could be in favor of treatment,” Fillit added.

The study was conducted as part of the Medical Research Council (MRC, UK) NuBrain Consortium. The investigators and Fillit have reported no relevant financial relationships.

Alzheimers Res Ther. Published online January 9, 2023. Full article

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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