Clinical Context

Women vs men with high β-amyloid have greater AD-related neurofibrillary tau tangles, with unclear underlying mechanisms. Premature or early menopause, spontaneous or surgical, occurs in 1% to 10% of women and has been linked to poor outcomes from AD dementia.

Early studies suggested that hormone therapy (HT) use may mitigate cognitive impairment in menopausal or postmenopausal women, but the Women’s Health Initiative (WHI) found that HT use vs placebo was associated with doubled incidence of probable dementia. Subsequent studies of HT have yielded conflicting results.

Study Synopsis and Perspective

Early menopause and delayed initiation of HT have been linked to an increase in Alzheimer’s disease (AD) pathology in women, a new imaging study shows.

Investigators found elevated levels of tau protein in the brains of women who initiated HT more than 5 years after menopause onset, whereas those who started the therapy earlier had normal levels.

Tau levels were also higher in women who started menopause before age 45 years, either naturally or after surgery, but only in those who already had high levels of beta-amyloid.

The findings were published online April 3 in JAMA Neurology.^[1]

Hotly Debated

Previous research has suggested the timing of menopause and HT initiation may be associated with AD. However, the current research is the first to suggest that tau deposition may explain that link.

“There have been a lot of conflicting findings around whether HT induces risk for Alzheimer’s disease dementia or not, and at least in our hands, our observational evidence suggests that any risk is fairly limited to those rarer cases when women might delay their initiation of HT considerably,” senior investigator Rachel Buckley, PhD, assistant investigator in neurology at Massachusetts General Hospital and an assistant professor of neurology at Harvard Medical School, told Medscape Medical News.

The link between HT, dementia, and cognitive decline has been hotly debated since the initial release of findings from the Women’s Health Initiative Memory Study, reported 20 years ago.^[2]

Since then, dozens of studies have yielded conflicting evidence about HT and AD risk, with some showing a protective effect and others showing that the treatment may increase AD risk.^[3,4]

For this study, researchers analyzed data from 292 cognitively unimpaired participants (66.1% women) in the Wisconsin Registry for Alzheimer Prevention. About half of the women had received HT.

Women had higher levels of tau measured on positron emission tomography (PET) imaging than age-matched men, even after adjusting for APOE status and other potential confounders.

Higher tau levels were found in those with an earlier age at menopause (P<.001) and HT use (P=.008) compared with men, those with later menopause onset, or those with HT nonuse, but only in patients who also had a higher beta-amyloid burden.

Late initiation of HT (>5 years after age at menopause) was associated with higher tau compared with early initiation (P=.001), regardless of amyloid levels.

Surprising Finding

Although researchers expected to find that surgical history (specifically oophorectomy) might have a greater effect on risk, that was not the case.

“Given that bilateral oophorectomy involves the removal of both ovaries, and the immediate ceasing of estrogen production, I had expected this to be the primary driver of higher tau levels,” Dr Buckley said. “But early age at menopause, regardless of whether the genesis was natural or surgical, seemed to have similar impacts.”

These findings are the latest from Buckley’s group that indicate that women tend to have higher levels of tau than men, regardless of preexisting amyloid burden in the brain.

“We see this in healthy older women, women with dementia and even in postmortem cases,” Dr Buckley said. “It really remains to be seen whether women tend to accumulate tau faster in the brain than men, or whether this is simply a 1-shot phenomenon that we see in observational studies at the baseline.”

“One could really flip this finding on its head and suggest that women are truly resilient to the disease,” she continued. “That is, they can hold much more tau in their brain and remain well enough to be studied, unlike men.”

Among the study’s limitations is that the data were collected at a single point and did not include information on subsequent Alzheimer’s diagnosis or cognitive decline.

“It is important to remember that the participants in this study were not as representative of the general population in the United States, so we cannot extrapolate our findings to women from a range of socioeconomic, racial and ethnic backgrounds or education levels,” she said.

The study’s observational design left researchers unable to demonstrate causation. What is more, the findings also do not support the assertion that hormone therapy may protect against AD, Dr Buckley added.

“I would more confidently say that evidence from our work, and that of many others, seems to suggest that HT initiated around the time of menopause may be benign, not providing benefit or risk, at least in the context of Alzheimer’s disease risk,” she said.

Another important takeaway from the study, Dr Buckley said, is that not all women are at high risk for AD.

“Often the headlines might make you think that most women are destined to progress to dementia, but this simply is not the case,” Dr Buckley said. “We are now starting to really drill down on what might elevate risk for AD in women and use this information to better inform clinical trials and doctors on how best to think about treating these higher-risk groups.”

New Mechanism?

Commenting on the findings for Medscape Medical News, Pauline Maki, PhD, professor of psychiatry, psychology and obstetrics and gynecology at the University of Illinois at Chicago, called the study “interesting.”

“It identifies a new mechanism in humans that could underlie a possible link between sex hormones and dementia,” Dr Maki said.

However, Dr Maki noted that the study was not randomized and that information about menopause onset was self-reported.

“We must remember that many of the hypotheses about hormone therapy and brain health that came from observational studies were not validated in randomized trials, including the hypothesis that hormone therapy prevents dementia,” she said.

The findings do not resolve the debate over hormone therapy and AD risk and point to the need for randomized, prospective studies on the topic, Dr Maki added. Still, she said, they underscore the gender disparity in AD risk.

“It’s a good reminder to clinicians that women have a higher lifetime risk of [AD] and should be advised on factors that might lower their risk,” she said.

The study was funded by the National Institutes of Health. Dr Buckley has disclosed no relevant financial relationships. Dr Maki serves on the advisory boards for Astellas, Bayer, Johnson and Johnson; consults for Pfizer and Mithra; and has equity in Estrigenix, Midi-Health, and Alloy.

JAMA Neuro. Published online April 3, 2023.

Clinical Implications

• Among women, earlier age at natural or surgical menopause, HT use, and late HT initiation were associated with increased tau vulnerability, especially when neocortical β-amyloid was elevated.
• These may be important sex-specific risk factors underlying sex differences in tau deposition.
• Implications for the Health Care Team: The findings may inform AD risk discussions regarding female reproductive health and treatment.

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