An early menopause has been linked to a heightened risk of women developing Alzheimer’s disease dementia.
Taking hormone replacement therapy (HRT) appeared to help reduce the risk US-based researchers said – but only if it’s taken near to the age of diagnosis.
Women who begin HRT treatment five or six years after the start of the menopause were found to have higher levels of two key proteins involved in dementia, tau and beta-amyloid, according to the study published in JAMA Neurology.
The researchers admit more studies are needed to determine how the menopause and HRT affect the brain. But these early findings suggest starting HRT as soon as the first menopausal symptoms appear may be better not only for brain health but in helping reduce heart disease and other medical symptoms associated with the change of life.
“When it comes to hormone therapy, timing is everything,” said Dr JoAnn Manson, a co-author of the study conducted by the Mass General Brigham hospital based in Boston, Massachusetts.
Dr Manson, who is chief of the Division of Preventative Medicine at Brigham and Women’s Hospital and one of the lead investigators of the Women’s Health Initiative (WHI), added: “Our previous findings from the WHI suggested that starting HT early in menopause, rather than late initiation, provides better outcomes for heart disease, cognitive function, and all-cause mortality, and this study suggests that the same is true for tau deposition.”
Using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), one of the few longitudinal studies on AD dementia that includes detailed information on menopause and HT, the researchers analysed PET scans from 193 women and 99 men who were cognitively unimpaired to map the levels of beta-amyloid and tau in seven regions of the brain.
Alzheimer’s is the most common type of dementia with women more likely to develop it than men.
As expected, the scans showed more tau present in women than men of the same age, particularly in cases where they also had increased beta-amyloid.
The tau levels were high in the parts of the brain close to the memory-centre and areas that are already known to be involved in the progression of AD dementia.
The study showed that the women at greatest risk of Alzheimer’s were those who reported premature menopause, defined as under the age of 45, than women overall.
Given that many women who go through the menopause early use HRT, the researchers also looked at whether its use was linked to the two proteins beta-amyloid and tau.
Interestingly, a higher risk was seen – but only associated with those women who had a long gap between the onset of their menopause and HRT. 
Rachel Buckley of the Department of Neurology at Massachusetts General Hospital said: “HT is the most reliable way to ameliorate severe menopause symptoms, but over the last few decades, there has been a lack of clarity on how HT affects the brain.
“We found that the highest levels of tau, a protein involved in Alzheimer’s disease, were only observed in hormone therapy users who reported a long delay between age at menopause onset and their initiation of hormone therapy.
“The idea that tau deposition may underlie the association between late hormone therapy intervention and Alzheimer’s disease dementia was a huge finding, something that hadn’t been seen before.”
Gillian Coughlan, an author of the study at Massachusetts General Hospital, added: “These observational findings support clinical guidelines that state hormone therapy should be administered close to menopause onset, but not several years after.”
Going forward, the researchers are continuing to study sex-specific risk factors for AD dementia by analysing biological signatures, including sex hormones, in blood plasma and on the X-chromosome.
They are also continuing to engage in efforts to understand the unique role that tau plays in women compared to men, its impact on the brain, and why earlier menopause and the late HT initiation may be associated with increased tau, even in cognitively unimpaired women.
Experts have given a cautious welcome to the study, but point out its limitations. 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: “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.”
However, she added: “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 at the University of Bristol, commented: “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 five 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.”
