Hormone replacement therapy (HRT) introduced at the start of the menopausal transition may protect against Alzheimer’s dementia in women with the disease. APOE4 gene, new research suggests.
Results from a cohort study of almost 1,200 women showed that HRT use was associated with higher delayed memory scores and larger entorhinal and hippocampal brain volumes – areas that are affected precociously by the pathology of Alzheimer’s disease (AD).
HRT was also found to be most effective, as evidenced by the larger hippocampal volume, when introduced at the onset of perimenopause.
“Clinicians are very aware of women’s susceptibility to cognitive impairment during menopause,” said lead author Rasha Saleh, MD, Senior Research Associate, Norwich Medical School, University of East Anglia, UK. Medscape Medical News.
“Identify people at risk APOE4 women and early introduction of HRT may be beneficial. Confirming our findings in a clinical trial would be the next step,” Saleh said.
The results were published online on January 9 in Alzheimer’s research and therapy.
Saleh noted that estrogen receptors are located in various areas of the brain, including areas related to cognition. Estrogen regulates things like neuro-inflammatory state, glucose utilization, and lipid metabolism.
“The decline in estrogen during menopause can lead to disruption of these functions, which can accelerate AD-related pathology,” she said.
HRT during the menopausal transition and after is “considered a strategy to mitigate cognitive decline”, write the researchers. Early observational studies suggested that oral estrogen “may protect against dementia,” but results from clinical trials have been inconsistent, and some have even shown “harmful effects,” they add.
The current researchers were “interested in 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 more cognitively beneficial for people with or without APOE4especially when introduced early in the menopausal transition.
To investigate this hypothesis, the researchers analyzed baseline data from participants in the European Alzheimer’s Dementia Prevention (EPAD) cohort. This project was launched in 2015 with the aim of developing longitudinal models of the entire AD pathway before the clinical diagnosis of dementia.
Participants were recruited from 10 European countries. All had to be at least 50 years old, not initially diagnosed with dementia, and had no medical or psychiatric illness that would 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 former users included estrogen alone or estrogen plus progestin either orally or transdermally, and at varying doses.
The four tests used to assess cognition were the Mini-Mental State Examination score count to assess verbal working memory, the Repeatable Battery Total Score for Assessment of Neuropsychological Status (RBANS), the four mountains test and the shopping cart virtual reality test.
Brain MRI data was collected. The researchers focused on the medial temporal lobe as the “primary region of the brain regulating cognition and memory processing.” This lobe includes the hippocampus, parahippocampus, entorhinal cortex, and amygdala.
The researchers discovered a “trend” towards a APOE-THS interaction (P-interaction = 0.097) 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 received HRT compared with all other groups (P-interaction = .009).
Comparisons within genotype groups showed that HRT users had a higher RBANS total score and delayed memory index (P = 0.045 and P = 0.002, respectively), but only among APOE4 carriers. Effect size analyzes showed a large effect of HRT use on the Four Mountain test score and the virtual reality shopping cart test score (Cohen’s D =.988 and 1.2, respectively).
“This great effect was only found in APOE4 carriers,” the investigators note.
Similarly, a moderate to large effect of HRT on left entorhinal volume was observed in APOE4 porters (from Cohen D = 0.63).
Among the members of the APOE4 group that received HRT, left entorhinal and left and right amygdala volumes were larger compared to the two non-APOE4 and non-users of HRT (P-interaction = 0.002, 0.003 and 0.005, respectively). Similar trends were observed for right entorhinal volume (P = 0.074).
Additionally, among HRT users, left entorhinal volume was greater (P = 0.03); the volumes of the right and left anterior cingulate gyrus were smaller (P = 0.003 and 0.062, respectively); and the left superior frontal gyrus volume was larger (P = 0.009) compared to women who did not receive HRT, regardless of their APOE genotype.
Early use of HRT in APOE4 carriers was associated with greater right and left hippocampal volume (P = 0.035 and P = 0.028, respectively) ― an association not found in theAPOE4 carriers. The association was also not significant when participants were not stratified by APOE genotype.
“The important point here is when, or the ‘critical window,’ when HRT can be most beneficial,” Saleh said. “This is most beneficial when introduced early, before the neuropathology becomes irreversible.”
Limitations of the study include its cross-sectional design, which precludes establishing a causal relationship, and the fact that information regarding estrogen type and dose was not available for all participants.
HRT is not without risk, Saleh noted. She recommended that clinicians “perform various screening tests to ensure that a woman is eligible for HRT and that she is not at risk of hypercoagulability, for example”.
Commenting for Medscape Medical NewsHoward Fillit, MD, co-founder and chief scientific officer of the Alzheimer’s Drug Discovery Foundation, called the study “exactly the kind of work that needs to be done.”
Fillit, who was not involved in the current research, is a clinical professor of geriatric medicine, palliative care medicine and neuroscience at Mount Sinai Hospital in New York.
He compared the process to that of osteoporosis. “We know that if women are treated [with HRT] at the time of menopause, you can prevent the rapid bone loss that occurs with the rapid loss of estrogen. But if you wait 5, 10 years, once the bone loss has happened, HRT doesn’t really have an impact on the risk of osteoporosis because the horse is already out of the stable.” he declared.
Although HRT has risks, “these can clearly be managed; and if there is evidence that replacing estrogen or hormones around the time of menopause can be protective [against AD]the benefit/risk ratio of HRT might be in favor of the treatment,” added Fillit.
The study was conducted as part of the NuBrain consortium of the Medical Research Council (MRC, UK). Investigators and Fillit have not reported any relevant financial relationship.
Alzheimer Res Ther. Published online January 9, 2023. Full article
Batya Swift Yasgur MA, LSW is a freelance writer with a consulting practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-focused health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoirs of two brave Afghan sisters who told her their stories).
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