Hormone replacement therapy may ward off Alzheimer’s disease among at-risk women

Overview: The use of hormone replacement therapy (HRT) was associated with better cognition, memory and larger brain volume in women carrying the Alzheimer’s-associated APOE4 genetic variant.

Source: University of East Anglia

Hormone replacement therapy (HRT) could help prevent Alzheimer’s dementia in women at risk of developing the disease, according to research from the University of East Anglia.

The study shows that HRT use is associated with better memory, cognition and larger brain volumes later in life in women who carry 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 menopause 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 from the University of Edinburgh.

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

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

“We wanted to know if HRT could prevent cognitive decline in high-risk APOE4 carriers.”

The research team studied data from 1,178 women who took part in the European Alzheimer’s Dementia Prevention 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 older than 50 and free of dementia.

The research team studied their results to analyze the impact of HRT on HRT carriers APOE4 genotype.

Dr. Rasha Saleh, also from UEA’s Norwich Medical School, said: “We found that use of HRT is associated with better memory and larger brain volumes in APOE4 gene carriers at risk. The associations were particularly apparent when HRT was introduced early – during the transition to menopause, also 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 observational study, if confirmed in an intervention trial, would be equivalent to a brain age several years younger.”

This shows a woman
The study shows that HRT use is associated with better memory, cognition and larger brain volumes later in life in women who carry the APOE4 gene – the strongest risk factor gene for Alzheimer’s disease. The 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 didn’t look at cases of dementia, but cognitive performance and lower brain volumes are predictive of future risk of dementia.

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

“The next phase of this research will be to conduct an intervention study to confirm the impact of starting HRT early on cognition and brain health. It will also be important to analyze which types of HRT are most beneficial,” he added.

Professor Craig Ritchie, from the University of Edinburgh, said: “This important finding from the EPAD cohort highlights the need to challenge many assumptions about early-stage Alzheimer’s disease and its treatment, particularly when it comes to women’s brain health.

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This shows a brain

“An effect on both cognition and brain changes on MRI supports the idea that HRT has tangible benefits. However, these initial findings need to be replicated in other populations.”

About this news about genetics and Alzheimer’s disease

Writer: Press Office
Source: University of East Anglia
Contact: Press Service – 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 APOE4 At Risk Women: Results From The European Alzheimer’s Disease Prevention Cohort (EPAD)” by Anne Marie Minihane et al. Alzheimer’s Research & Therapy


Hormone replacement therapy is associated with improved cognition and larger brain volumes in APOE4-at-risk women: results from the European Alzheimer’s Disease Prevention Cohort (EPAD)


The risk of dementia is higher in women than in men. The metabolic consequences of estrogen decline at menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in preventing cognitive decline has produced conflicting results. Here we investigate its modulatory role APOE genotype and age at onset of HRT on 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 used to test the independent and interactive impact of APOE genotype and HRT on selected cognitive tests, such as MMSE, RBANS, point count, Four Mountain Test (FMT), and the supermarket trolley test (SMT), along 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*HST 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 (Pinteraction = 0.002, 0.003 and 0.005 respectively). Earlier introduction of HST was accompanied by greater rights (standardised b= −0.555, p=0.035) and left hippocampal volumes (standardized b= −0.577, p=0.028) only APOE4 carriers.


HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may be an effective, targeted strategy to reduce the higher lifetime risk of AD in this high-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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