Hormone Replacement Therapy Could Ward off Alzheimer’s Among At-Risk Women

Summary: Hormone replacement therapy (HRT) use was associated with better cognition, memory, and larger brain volume in women who carry the Alzheimer’s associated APOE4 genetic variant.

Source: University of East Anglia

Hormone Replacement Therapy (HRT) could help prevent Alzheimer’s Dementia among women at risk of developing the disease—according to University of East Anglia research.

The study shows that HRT use is associated with better memory, cognition and larger brain volumes in later life among women carrying the APOE4 gene—the strongest risk factor gene for Alzheimer’s disease.

The research team found that HRT was most effective when introduced early in the menopause journey during perimenopause.

Prof Anne-Marie Minihane, from UEA’s Norwich Medical School and director of the Norwich Institute for Healthy Aging at UEA, led the study in collaboration with Prof Craig Ritchie at the University of Edinburgh.

Prof Minihane said, “We know that 25 percent of women in the UK are carriers of the APOE4 gene and that almost two thirds of Alzheimer’s patients are women.

“In addition to living longer, the reason behind the higher female prevalence is thought to be related to the effects of menopause and the impact of the APOE4 genetic risk factor being greater in women.

“We wanted to find out whether HRT could prevent cognitive decline in at-risk APOE4 carriers.”

The research team studied data from 1,178 women participating in the European Prevention of Alzheimer’s Dementia initiative—which was set up to study participants’ brain health over time.

The project spanned 10 countries and tracked participants’ brains from ‘healthy’ to a diagnosis of dementia in some. Participants were included if they were over 50 and dementia-free.

The research team studied their results to analyse the impact of HRT on women carrying the APOE4 genotype.

Dr. Rasha Saleh, also from UEA’s Norwich Medical School, said, “We found that HRT use is associated with better memory and larger brain volumes among at-risk APOE4 gene carriers. The associations were particularly evident when HRT was introduced early—during the transition to menopause, known as perimenopause.

“This is really important because there have been very limited drug options for Alzheimer’s disease for 20 years and there is an urgent need for new treatments.

“The effects of HRT in this observation study, if confirmed in an intervention trial, would equate to a brain age that is several years younger.”

This shows a woman
The study shows that HRT use is associated with better memory, cognition and larger brain volumes in later life among women carrying the APOE4 gene—the strongest risk factor gene for Alzheimer’s disease. Image is in the public domain

Prof Anne Marie Minihane said, “Our research looked at associations with cognition and brain volumes using MRI scans. We did not look at dementia cases, but cognitive performance and lower brain volumes are predictive of future dementia risk.

Prof Michael Hornberger, from UEA’s Norwich Medical School, said, : “It’s too early to say for sure that HRT reduces dementia risk in women, but our results highlight the potential importance of HRT and personalised medicine in reducing Alzheimer’s risk.

“The next stage of this research will be to carry out an intervention trial to confirm the impact of starting HRT early on cognition and brain health. It will also be important to analyse which types of HRT are most beneficial,” he added.

Prof Craig Ritchie, from the University of Edinburgh, said, “This important finding from the EPAD Cohort highlights the need to challenge many assumptions about early Alzheimer’s disease and its treatment, especially when considering women’s brain health.

“An effect on both cognition and brain changes on MRI supports the notion that HRT has tangible benefit. These initial findings need replication however in other populations.”

About this genetics and Alzheimer’s disease research news

Author: Press Office
Source: University of East Anglia
Contact: Press Office – University of East Anglia
Image: The image is in the public domain

Original Research: Open access.
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” by Anne Marie Minihane et al. Alzheimer’s Research & Therapy


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


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.


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.


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.


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.

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  1. This study was not a clinical trial so it proves nothing. The WHI showed that estrogen, with or without progestin, increased the risk of Alzheimer’s and atrophied the hippocampus and frontal lobe. KEEPS also showed HRT in newly menopausal women also caused greater brain atrophy, ventricular expansion, and white matter hyperintensities. So while these women were too young to show increased dementia risk, they did experience impaired verbal learning (Premarin) or impaired event recall and greater subjective memory complaints (estradiol). Moreover, a study last year of APOE carriers found they have greater levels of ER alpha in their hippocampi, which theoretically would make exogenous estrogen particularly risky.
    Bottom line – HRT does not prevent dementia, it CAUSES it.

    1. Are you pertaining to estrogen or estradiol? Progesterone or progestin… they are not the same. Estradiol has shown in several clinical studies to prevent disease same for progesterone. When making claims please make sure are not pertaining to synthetics produced by big Pharma.

      1. Estradiol and micronized progesterone have never been evaluated in a large randomized trial like the WHI to see if the hormones prevent heart disease or dementia. There are only surrogate marker trials (like KEEPS and ELITE) and secondary prevention trials.

        Estradiol triples the risk of fatal stroke in women who have already had a stroke (WEST). Transdermal estradiol was shown in KEEPS to reduce brain volume, enlarge ventricles, and increase white matter hyperintensities in newly menopausal women. Although Premarin was worse, estradiol did cause more memory impairment. ELITE tested oral estradiol – there was no difference in memory or cognitive function vs placebo.

        Bioidentical hormones may seem like an attractive alternative to “synthetics,” but studies to date have not been positive. And the argument is just a rehash of the ones made prior to WHI – that HRT is an elixir that will keep you young and prevent age-related disease, including Alzheimer’s. It does not. On the contrary, there is actually a new clinical trial out of SUNY testing the aromatase inhibitor letrozole (an antiestrogen used to treat and prevent breast cancer) to see if it will slow Alzheimer’s progression. I suspect THIS will actually work.

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