Starting hormone therapy too late during menopause could lead to Alzheimer’s disease

BOSTON — Early menopause and a later start to hormone therapy could increase the risk that women develop Alzheimer’s disease, a new study finds. The research shows that it is much safer for women to begin hormone therapy closer to the time they start going through the menopause than leaving it until later.

Women normally hit menopause between the ages of 45 and 55, when hormone levels begin to drop and their periods stop. A variety of symptoms come with the change, including a rise in anxiety, mood swings, and hot flushes.

Hormone therapy is a common treatment women use to help ease severe symptoms. Two decades ago, however, the Women’s Health Initiative study found that women going through HT were more than twice as likely to suffer from dementia than those who were not among women 65 and older. Researchers from Massachusetts General Hospital suggest that this could be due to starting HT many years after menopause begins rather than straight away.

To collect their data, the team used positron emission tomography (PET) neuroimaging to study how the presence of two proteins involved in AD dementia related to age at menopause and HT use. These two proteins were beta-amyloid and tau.

The researchers used data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), one of the few longitudinal studies on AD dementia. It included detailed information on menopause and HT use as well as PET neuroimaging. Study authors analyzed PET scans from 292 cognitively unimpaired adults to determine levels of beta-amyloid and tau in seven regions of the brain.

How soon should hormone therapy start?

As expected, women were found to have greater levels of tau compared to men of the same age, especially in cases where they had elevated β-amyloid. In general, women have larger amounts of tau in these brain regions compared to men. The amount of tau levels were high in the entorhinal and inferior temporal regions. These areas are located close to the memory center of the brain and are involved in the progression of Alzheimer’s — the most common form of dementia.

Given that many women who undergo premature menopause use HT, the researchers also looked at how HT use tied to beta-amyloid and tau formation. They found that women who began HT five years or later after menopause began were more likely to have high levels of both these proteins. The team also discovered that the large quantities of β-amyloid and tau were much stronger in women who had earlier menopause onset, meaning they were more at risk of AD dementia.

“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,” says 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, in a media release.

Middle-aged woman feeling sad or depressed, or having menopause symptoms
(© digitalskillet1 –

“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.”

“When it comes to hormone therapy, timing is everything,” adds co-author JoAnn Manson, MD, MPH, DrPH, one of the lead investigators of the WHI and chief of the Division of Preventive Medicine at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system.

“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.”

The researchers plan to continue looking into sex-specific risk factors for Alzheimer’s. They also hope to find out more about the unique role tau plays in women compared to men, its impact on the brain, and why earlier menopause and late HT intuition may have a link to this increase of tau.

“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 AD dementia,” says first author Gillian Coughlan, PhD, of the MGH Department of Neurology. “Hormone therapy can have negative effects on cognition, but only if initiated several years after 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.”

The study is published in JAMA Neurology.

South West News Service writer Alice Clifford contributed to this report.

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