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Women are more likely to develop Alzheimer’s disease compared to men as women make up two-thirds of the population suffering from the disease. Mass General Brigham researchers conducted a study on the relationship between the risk of Alzheimer’s disease, the age of menopause and the use of hormone therapy.
The study, published in JAMA Neurology, indicated that early menopause might be a risk factor for developing Alzheimer’s disease dementia, but the women who were prescribed hormone therapy around the age of menopause onset did not show an increased risk.
Neuroscientist, researcher, author and the founding member of the Mass General Brigham healthcare system, Rachel Buckley, said that hormone therapy “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,” she added.
Premature menopause, defined as menopause occurring spontaneously before the age of 40 or due to a surgical intervention before the age of 45, has been associated with an increased risk of Alzheimer’s disease dementia. Notably, hormone therapy improves severe symptoms related to menopause and has been hypothesized to also prevent cognitive impairment.
However, two decades ago, the seminal Women’s Health Initiative (WHI) study found that hormone therapy use was associated with a nearly two-fold higher incidence of dementia compared to placebo among women aged 65 years and older, possibly due to the initiation of hormone therapy many years after menopause onset.
Rachel Buckley and her colleagues used positron emission tomography (PET) neuroimaging to study how the presence of two proteins involved in AD dementia, amyloid and tau, related to age at menopause and hormone therapy use. While previous studies examined symptoms of cognitive decline in menopausal women, few investigations analysed the biological factors underlying these changes, which may be at play in determining the risk of Alzheimer’s disease.
Professor of Medicine, at Harvard Medical School and a founding member of the Mass General Brigham healthcare system, JoAnn Manson said, “When it comes to hormone therapy, timing is everything.” She added, “Our previous findings from the WHI suggested that starting hormone therapy 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.”
The researchers used 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 hormone therapy use as well as PET neuroimaging.
They analysed PET scans from 292 cognitively unimpaired adults to determine levels of amyloid and tau in seven regions of the brain. Tau, which is known to be present in greater quantities in women compared to men in these brain regions, was the primary focus of the investigation, as its presence may offer insight into the sex-specific aspects of AD dementia and the risks that post-menopausal women may experience, even before they begin to display symptoms of cognitive decline.
The women had greater levels of tau compared to men of the same age, especially in cases where they also had elevated amyloid. The researchers also found that the association between abnormal levels of amyloid and tau was much stronger in women who had earlier menopause onset, even after adjusting for known causes of premature menopause, such as smoking and oophorectomy, and even genetic risk factors for Alzheimer’s disease dementia.
It is pertinent to note that tau levels were high in the entorhinal and inferior temporal regions, which are located close to the memory center of the brain and are known to be involved in the progression of Alzheimer’s disease dementia. Given that many women who undergo premature menopause use hormone therapy, the researchers examined whether hormone therapy use was associated with amyloid and tau. While they did confirm this association, they observed that late initiation of hormone therapy — five years or more after menopause — drove this relationship. Many women in the late-hormone therapy-initiation group began hormone therapy close to a decade after menopause.
Furthermore, 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 late hormone therapy initiation may be associated with increased tau, even in cognitively unimpaired women.
Author and Research Fellow in Neurology, Massachusetts General Hospital, Gillian Coughlan said, “Up to 10 percent of women experience premature or early menopause, and our findings suggest that earlier age at menopause may be a risk factor for Alzheimer’s disease dementia.” She added, “Hormone therapy can have negative effects on cognition, but only if initiated several years after the age at menopause. These observational findings support clinical guidelines that state hormone therapy should be administered close to menopause onset, but not several years after.”
[with inputs from ANI]
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