Do Women Who Experience Early Menopause and Start Hormone Therapy Later Have an Increased Risk of Alzheimer’s?

Women are more likely than men to develop Alzheimer’s disease. In addition to the longer life expectancy, hormonal differences also play a role. While women have some protection due to estrogen, they often experience memory problems during menopause when this important hormone begins to decrease. In the long term, these hormonal changes can increase the risk of developing Alzheimer’s. A new study led by Mass General Brigham researchers sheds light on the relationship between the risk of developing Alzheimer’s and age at menopause as well as the use of hormone therapy. The results, published in JAMA Neurology, indicate that early menopausal age may be a risk factor for Alzheimer’s dementia, but that women prescribed such therapy at normal menopausal age were not at increased risk.

How Menopausal Age, Hormone Therapy and Alzheimer’s are Related

Hormone therapy is the most reliable way to relieve severe menopause symptoms, but for the last few decades there has been some confusion about how this type of therapy affects the brain. The researchers found that the highest levels of tau, a protein implicated in Alzheimer’s disease, were observed only in women using hormone therapy who had a long delay between the age at which they entered menopause and their reported initiation of hormone therapy. Premature menopause, defined as menopause that occurs before age 40 or before age 45 due to surgery, has been associated with an increased risk of Alzheimer’s dementia. Hormone therapy improves many severe symptoms associated with menopause and has been hypothesized to prevent cognitive impairment as well.

Two decades ago, however, the landmark Women’s Health Initiative (WHI) study found that use in women ages 65 and older was associated with a nearly two-fold higher incidence of dementia compared to placebo, possibly due to the initiation of HRT many years after the onset of menopause. To better understand these findings, Buckley and colleagues used positron emission tomography (PET) neuroimaging to study how the presence of two proteins implicated in Alzheimer’s dementia, β-amyloid and tau, is linked to menopause age and hormone therapy. While previous studies have examined symptoms of cognitive decline in postmenopausal women, few studies have analyzed the biological factors underlying these changes that may play a role in determining Alzheimer’s risk.

When it comes to hormone therapies, the right timing is important. Previous results suggest that early initiation of hormone therapy during menopause is better than late initiation and is associated with better outcomes in terms of heart disease, cognitive function, and all-cause mortality, and the current study suggests the same for tau depostion. The researchers used data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), one of the few longitudinal studies of Alzheimer’s dementia that includes detailed information on menopause and HRT use, as well as PET neuroimaging. They analyzed PET scans of 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 higher amounts in these brain regions in women compared to men, was the focus of the investigation as its presence could offer insight into the gender-specific aspects of Alzheimer’s dementia and the risks postmenopausal women experience before they show symptoms of cognitive decline.

Increased Tau Levels

As expected, females had higher levels of tau compared to males of the same age, particularly in cases where they also had elevated β-amyloid. But the researchers also found that the association between abnormal levels of β-amyloid and tau was much stronger in women who had entered menopause earlier, even after accounting for known causes of premature menopause, such as smoking and oophorectomy, and even genetic risk factors for Alzheimer’s dementia. Notably, tau levels were high in the entorhinal and inferior temporal regions, which are located near the brain’s memory center and are known to be involved in the progression of Alzheimer’s dementia. Given that many women who experience premature menopause receive hormone replacement therapy, the researchers investigated whether this therapy is associated with β-amyloid and tau. While confirming this association, they observed that late initiation of hormone therapy; five years or more after menopause, this relationship drives forward. Many women in the late hormone therapy group began treatment nearly a decade after menopause.

Going forward, researchers will continue to study gender-specific risk factors for Alzheimer’s dementia by analyzing biological signatures, including sex hormones, in blood plasma and on the X chromosome. They also continue to strive to understand the unique role tau plays in women compared to men, its effects on the brain, and why earlier menopause and late onset of hormone therapy may be associated with elevated tau, even in women who are cognitively not impaired.

Up to 10 percent of all women experience premature or early menopause, and the results suggest that earlier menopausal age may be a risk factor for Alzheimer’s dementia. Hormone therapy can have negative effects on cognition, but only when administered a few years after the onset of menopause. These observational results support clinical guidelines that state that hormone therapy should be administered shortly before the onset of menopause, but not several years later.