April 3, 2023

expert reaction to association between age of menopause and use of hormone therapy with tau and β-Amyloid in the brain

A study published in JAMA Neurology looks at age at menopause and hormone therapy use, and tau and β-Amyloid in the brain.

Dr Sara Imarisio, Head of Research at Alzheimer’s Research UK said:

“While we understand that news like this can seem concerning, this study doesn’t show that hormone therapy causes Alzheimer’s. The researchers didn’t look at whether the participants went on to develop symptoms of dementia and we can’t be sure of cause and effect in this kind of research.

“It’s important that people are empowered with evidence-based advice that allows them to make informed decisions about their health. But there’s a lot more to understand about how menopause and HRT influence dementia risk. We need to see larger studies and controlled clinical trials to better understand this complex area of research and make sense of conflicting findings that have emerged in recent years.

“Some past research has highlighted potential cognitive benefits of hormone therapy, while other studies point to an increased risk of memory and thinking problems. While this study contributes valuable new data to this topic, we still aren’t able to point to a definitive link between hormone therapy and Alzheimer’s or dementia.

“Hormone therapy provides important benefits to many women, helping to combat the symptoms that menopause can bring. Women who take, or are thinking of taking, hormone therapy should not be put off by these results, and anyone concerned about the effects of this treatment should speak to their doctor.”

Prof Annice Mukherjee, Consultant Endocrinologist and Honorary Professor, Centre for Intelligent Healthcare, Coventry University, said:

“This cross sectional study investigates potential biological mechanisms associated with high tau, deposition in female individuals, and risk of Alzheimer’s disease, particularly in the setting of high beta amyloid.

“Female sex, earlier age at Menopause and Menopause hormone therapy (HT) use were associated with higher regional tau PET in individuals with elevated AB, compared with male sex, late age of menopause, and HT non-use. The study also found a late initiation of HT was associated with higher tau, PET compared with earlier initiation.

“The authors identified this excess risk to relate to late initiation rather than early initiation or overall use of HT. Overall numbers in the subgroups were small.

“This cross sectional study adds to the existing conflicting body of observational evidence around the impact of Menopause and HT on Alzheimer’s risk, with overall pooled existing data suggesting a null effect of HT. The need for larger, appropriately powered RCTs are reiterated. Inference around existing conflicting data need to be viewed with caution.”

Prof Tara Spires-Jones, Professor of Neurodegeneration and deputy director of the Centre for Discovery Brain Sciences at the University of Edinburgh, and BNA President-Elect, said:

“This study by Buckley and team at Massachusetts General Hospital examined brain scans of people with normal cognitive function for Alzheimer’s disease amyloid and tau pathology. 193 women and 99 men participated in the study. The scientists found that women had more tau pathology in several parts of the brain than men of a similar age. Further, females had higher tau burden than males when they also have amyloid pathology in the brain – this is important as both types of pathology together are required to develop Alzheimer’s disease.  Early age of menopause and use of hormone replacement therapy in females was associated with more tau pathology in people who already have amyloid in their brains but not in people without amyloid. These data indicate that female sex, earlier age at menopause, and hormone replacement therapy may be important risks for developing Alzheimer’s disease pathology in the brain. While this is a well-conducted study, it does have several limitations  including mostly white participants and not having data about whether these people go on to develop Alzheimer’s disease.  Even with the limitations, this study is important as more research is needed to understand why women are more susceptible to Alzheimer’s disease than men.”

Dr Liz Coulthard, Associate Professor in Dementia Neurology, University of Bristol, said:

“Life expectancy does not explain why more women than men have Alzheimer’s disease. It is important to try and understand the link between female sex hormones and menopause. This is a well-designed, scientifically sophisticated study using state-of-the-art neuroimaging and detailed participant testing. However, there are a few drawbacks which mean we still do not know what to advise women about HRT and dementia risk.

“The participant numbers are too small and there aren’t enough people in the study at increased genetic risk of Alzheimer’s. Recently we found out that HRT might have different effects in people at high genetic risk (apoE4 gene positive), but this is not featured here. Furthermore, there aren’t enough people with early menopause in the study, there were more menopause-related sleep problems in the HRT group (and we know poor sleep in itself may be a dementia risk), and there were years between the amyloid and tau scans for many individuals. Plus this study is in people without any symptoms of dementia – so we do not know how this relates to dementia itself.

“The results here are scientifically interesting. But research into the relationship between HRT, menopause and Alzheimer’s is beset by multiple small studies, all confounded by the different reasons people are prescribed HRT and accuracy of memory for menopause age and HRT use. As a result, women are receiving conflicting or poorly justified advice as to whether HRT use may be helpful or not for future brain health. Important questions including whether there is a critical time period where HRT might be particularly helpful or harmful are not being effectively answered – there is just a hint here that starting HRT more than 5 years after menopause might worsen brain health. A balanced, well-powered trial of HRT over many years is the only way we will really understand whether HRT is harmful to brain health.”

‘Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography’ by Gillian T. Coughlan et al. was published in JAMA Neurology at 16:00 UK time on Monday 3 April.

DOI: 10.1001/jamaneurol.2023.0455

Declared interests

Prof Tara Spires-Jones: “I have no conflicts of interest with this study.”

Dr Liz Coulthard: “I am not funded to research this area. I am funded by or do consultancy for NIHR, BRACE, Rosetrees, Above and Beyond, MRC, Biogen, Eisai, Lilly.”

For all other experts, no reply to our request for DOIs was received.