Link between premature menopause, later hormone therapy and Alzheimer’s disease

Researchers are investigating the role of tau in the link between early menopause, delayed hormone therapy and Alzheimer’s disease

Women are more likely than men to develop Alzheimer’s disease (AD). Mass General Brigham researchers had led a study exploring the relationship between age on menopause, the use of hormone therapy and Alzheimer’s disease. Results suggest that early age at menopause may be a risk factor for AD dementia.

What is premature menopause?

The NHS defines premature menopause as, “Premature menopause, or premature ovarian insufficiency (POI), is defined as being menopause that happens before the age of 40. Premature menopause is estimated to affect 1% of women under the age of 40 years and 0.1% of women under the age of 30 years.”

Essentially, it is when menopause occurs spontaneously before the age of 40. It can also be due to surgical intervention before the age of 45. Premature menopause has been associated with an increased risk of Alzheimer’s disease dementia.

How does HT impact menopause?

Though HT improves many severe symptoms related to menopause and can possibly prevent cognitive impairment, a study by the Women’s Health Initiative (WHI) found that, when compared to a placebo, HT use was associated with a nearly two-fold higher increase in dementia.

Corresponding author Rachel Buckley, PhD, of the Department of Neurology at Massachusetts General Hospital (MGH) and colleagues, used positron emission tomography (PET) neuroimaging to understand these results further. They planned to study how the presence of two proteins involved in AD dementia, amyloid-β and tau, related to age at menopause and HT use.

‘When it comes to hormone therapy, timing is everything’

“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.

“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 analyzed PET scans from 292 cognitively unimpaired adults and data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) to determine levels of amyloid-β and tau in seven brain regions.

Tau, which is present in greater quantities in women than men in these brain regions, was the primary focus of the investigation. This is because tau can help us to explore the sex-specific aspects of AD dementia.

The link between delayed hormone therapy and Alzheimer’s disease dementia

Buckley explains: “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.”

Women have greater levels of tau compared to men of the same age

Women had greater levels of tau compared to men of the same age, but this is to be expected. This was especially true in cases with elevated amyloid-β.

Researchers found that an association between abnormal levels of amyloid-β and tau was much stronger in women who had earlier menopause onset.

Tau levels were high in the entorhinal and inferior temporal regions. This is located close to the memory centre of the brain. It is known to be involved in the progression of AD dementia.

Many women who experience premature menopause use HT, and so the team wanted to see if HT use was associated with amyloid-β and tau. They observed that late initiation of HT, a minimum of five years after menopause, drove this relationship.

The future of researching the link between hormone therapy and Alzheimer’s disease

Researchers plan further to study the sex-specific risk factors for AD dementia. This means analyzing biological signatures, including:

• Sex hormones
• Blood plasma
• X-chromosome

Understanding tau’s role in women and its impact on the brain is also vital. Earlier menopause and late HT initiation may be associated with increased tau, even in cognitively unimpaired women.

“Up to 10% of women experience premature or early menopause, and our findings suggest that earlier age at menopause may be a risk factor for AD dementia,” said 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.”