A new study, led by Massachusetts General Brigham researchers, explored the relationship between the risk of Alzheimer’s disease (AD), age of menopause, and use of hormone therapy (HT).  The results, just published in JAMA Neurology, indicate that early age at menopause may be a risk factor for AD dementia, but that women who were prescribed HT around the age of menopause onset did not show increased risk.  Importantly, the higher risk was only associated with those women who had a long gap between their menopause onset and HT initiation.

Alzheimer’s afflicts more women

The NIH’s National Institute on Aging currently ranks Alzheimer’s disease as the seventh leading cause of death in the United States.  Postmenopausal females represent ~70% of all individuals with AD making the disease almost twice as common in women compared to men.  At the age of 65, women have a 1 in 5 chance of developing Alzheimer’s, compared to a 1 in 11 chance for men.  But why?

In part, women live longer.  According to Alzheimer’s Association, the chief risk factors for late-onset Alzheimer’s are older age, genetics, and having a family history of Alzheimer’s.  Of these 3, age is the greatest risk factor.  Further, the percentage of people with Alzheimer’s dementia increases dramatically with age (2023 Alzheimer’s Disease Facts and Figures. Alzheimers Dement., 2023).  Five percent of people aged 65 to 74, 13.1% of people aged 75 to 84, and 33.3% of people aged 85 or older have Alzheimer’s dementia.

Seeking the elusive

According to the Alzheimer’s Association, emerging evidence suggests that Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors.

Tau helps stabilize the internal skeleton of nerve cells (neurons) in the brain.  It appears that abnormal tau accumulates in specific brain regions involved in memory.  Beta-amyloid clumps into plaques between neurons.  As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout 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 researchers who hypothesized that 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.

 Previous literature had shown elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high beta-amyloid.  Yet the biological mechanisms associated with higher tau deposition in female individuals remain elusive.

Building on WHI’s dementia findings

Premature menopause—which can be either spontaneous or the result of surgical intervention before age 40 or 45, respectively—occurs in 1% to 10% of women and has been associated with increased risk of AD dementia.

HT improves many severe symptoms related to menopause and has been hypothesized to also prevent cognitive impairment.  However, 2 decades ago, the seminal Women’s Health Initiative (WHI) study found that HT use was associated with a nearly 2-fold higher incidence of dementia compared to a placebo among women aged 65 years and older, possibly due to the initiation of HT many years after menopause onset.

To further explore these findings, the Massachusetts General Brigham investigators used positron emission tomography (PET) neuroimaging to study how the presence of beta-amyloid and tau related to age at menopause and HT use.  The objective of the study was to examine the extent to which sex, age at menopause, and HT use are associated with regional tau at a given level of beta-amyloid.

Participant particulars

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.  They then analyzed PET scans of 292 cognitively unimpaired adults (193 women and 99 men) to determine beta-amyloid and tau levels in 7 regions of the brain.

Mean age of the study participants was 67.4 at tau scan; 52 participants had abnormal beta-amyloid, and 106 were APOE4 carriers—the strongest risk factor gene for AD.  A total of 98 women were past or current hormone therapy users.  Data were collected between November 2006 and May 2021.  Age at menopause and use of hormone therapy were self-reported.

Associations with higher tau

As expected, women in the study had greater levels of tau compared to men of the same age, especially in cases where they also had elevated beta-amyloid.  However, the researchers also found that the association between abnormal levels of beta-amyloid and tau was much stronger in women who had earlier menopause onset.  Overall findings remained even after adjusting for years of education, APOE4, cardiovascular disease risk, menopause symptom severity, and menopause-related sleep problems.

The highest levels of tau were seen in hormone therapy users who had a delay of more than 5 years between menopause onset and the start of hormone therapy.

Key points for women’s health providers

“When it comes to hormone therapy, timing is everything,” co-author JoAnn Manson, MD, DrPH, who also served as a lead investigator on the WHI, said in a statement released with publication of the study.  “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.”

“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,” added 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.”

Read more about the study and its implications for your patients, “Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography.”

Clinicians’ Bonus:  More To Know

Resources for you and your patients

 For You

For the latest in clinical practice guidelines, be sure to refer to 2022 hormone therapy position statement published by The North American Menopause Society.  This update from its 2017 position statement evaluates new literature, assesses the evidence, and reaches consensus on recommendations, using the level of evidence to identify the strength of recommendations and the quality of the evidence.  The Cognition section discusses later initiation of hormone therapy, Alzheimer disease, and all-cause dementia, highlighting 4 key points on HRT with corresponding evidence Levels I and II.

For Your Patients

The UK-based Alzheimer’s Society walks patients through a well-referenced, comprehensive online Q&A on Hormones and Dementia, including medical, lifestyle, and environmental factors for the disease, and why women are more likely to develop Alzheimer’s than men.

The contents of this feature are not provided or reviewed by NPWH.