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Women are more likely than men to develop Alzheimer’s disease (AD), and a new study by researchers at Mass General Brigham has now shed light on the relationship between the risk of AD, age of menopause, and use of hormone therapy (HT). Findings from the cross-sectional study indicated that early age at menopause may be a risk factor for AD dementia, but also suggested that women who were prescribed HT around the age of menopause onset did not show increased risk.

“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,” said corresponding author Rachel Buckley, PhD, of the department of neurology at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system. “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.”

Buckley is corresponding author of the team’s published paper in JAMA Neurology, titled “Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography.”

Approximately 6.2 million people in the United States have a clinical diagnosis of AD, and in general, about two-thirds of individuals who have the neurodegenerative disorder are women. “In the context of high β-amyloid (Aβ), substantial evidence suggests that female individuals exhibit greater AD-related neurofibrillary tau tangles than males,” the authors wrote. Premature menopause, defined as menopause that occurs spontaneously before the age of 40 or due to surgical intervention before the age of 45, has been associated with increased risk of AD dementia.

Some previous studies have found that HT improves many severe symptoms associated with menopause and has been hypothesized to also prevent cognitive impairment. “Early trials and observational studies suggested that use of exogenous hormones, via HT, may ameliorate cognitive impairment in menopausal or postmenopausal individuals,” the team continued. However, two decades ago, the Women’s Health Initiative (WHI) study found that HT 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 HT many years after menopause onset. And as the investigators further noted, after this study, “Follow-up randomized clinical trials and observational studies revealed that HT postmenopause was associated with increased risk of probable dementia relative to initiation of HT proximal to menopause onset.”

To try and better understand these findings, Buckley and colleagues used positron emission tomography (PET) neuroimaging to study the presence of β-amyloid and tau, which are the two proteins involved in AD dementia, in relation to age at menopause and HT use. Prior studies examined symptoms of cognitive decline in menopausal women, but few investigations analyzed the biological factors underlying these changes, which may play a role in determining risk of AD. “Using PET neuroimaging markers of tau deposition, we hypothesized that female sex and younger age at menopause would be associated with greater regional tau PET signal than male sex and older age at menopause, at a given level of neocortical Aβ,” the investigators wrote. “We further hypothesized that female individuals with a late initiation of HT would show a greater regional tau PET signal than those with early initiation.”

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 HT use as well as PET neuroimaging. They analyzed PET scans from 292 cognitively unimpaired adults—193 females and 99 males—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.

As expected, women had greater levels of tau compared to men of the same age, especially in cases where they also had elevated β-amyloid. “… females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aβ,” the authors noted. But the researchers also found that the association between abnormal levels of β-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 AD dementia.

Notably, 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 AD dementia. Given that many women who undergo premature menopause use HT, the researchers examined whether HT use was associated with β-amyloid and tau. They did confirm this association, but also observed that late initiation of HT—five years or more after menopause—drove this relationship. “Female individuals with late initiation of menopausal HT, more than five years after age at menopause, showed higher levels of tau, relative to those who initiated near their age at menopause,” the authors stated. In fact, many women in the late-HT-initiation group began HT close to a decade after menopause. “To our knowledge, this is the first study to show that tau deposition may underlie the preestablished association between late HT intervention and AD dementia,” they wrote.

Going forward, the researchers are continuing to study sex-specific risk factors for AD dementia by analyzing 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 HT initiation may be associated with increased tau, even in cognitively unimpaired women. ”Approximately a quarter of postmenopausal female individuals (70 years and older) have a history of HT use and have now entered a critical age of AD risk,” the scientists commented. These findings may help inform AD diagnostic  treatment plans for postmenopausal individuals with a history of postmenopausal HT use.”

They say clinical trials will be needed to investigate the potential implications of HT timing on tau deposition in women who undergo menopause at a relatively young age. “Female individuals who experience younger age at menopause may represent a subgroup for priority inclusion in AD prevention trials.”

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