Age at Menopause, Hormone Therapy Initiation Tied to Tau Vulnerability in Women

Increased tau vulnerability in women is associated with younger age at menopause onset and hormone therapy initiation after more than 5 years.

Earlier age at menopause and late initiation of hormone therapy are associated with increased tau vulnerability in women, particularly when neocortical β-amyloid
(Aβ) levels are elevated, according to findings from a cross-sectional study published in JAMA Neurology.

Evidence has shown that “female individuals exhibit greater AD [Alzheimer disease]-related neurofibrillary tau tangles than males.” The biologic mechanisms that might be driving tau deposition among women, however, remain to be elucidated. It is known that premature or early menopause — that is, menopause that occurs spontaneously or is surgically induced prior to 40 or 45 years of age — is reported in 1%-10% of women. The occurrence of early menopause has been linked to adverse AD dementia–related clinical outcomes.

For the study, researchers analyzed the extent to which sex, age at menopause, and use of hormone therapy are linked to regional tau at a particular Aβ level, based on positron emission tomography (PET) measurements.

The current study comprised men and women who were enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). All data were obtained from November 2006 through May 2021. WRAP is an ongoing longitudinal study in which more than 1700 middle-aged, cognitively unimpaired individuals with a parental history of AD have been enrolled.

Female individuals who experience younger age at menopause may represent a subgroup for priority inclusion in AD prevention trials.

All participants completed a neuropsychological battery at multiple visits, including a Preclinical Alzheimer Cognitive Composite (PACC) that calculated the mean of 3 summary tests of memory and executive function. PACC scores were obtained from evaluations that were administered closest to the tau PET scan visit.

A total of 292 participants were enrolled in the study — 193 of whom were women and 99 of whom were men. The mean participant age was 67.4 years (range, 49-80 years). Overall, 98 of women were prior or current hormone therapy users. In all, 106 of the participants were Apolipoprotein E4 (APOEε4) carriers; abnormal Aβ levels were detected in 52 individuals.

Researchers found that the following factors were associated with significantly higher regional tau PET among participants with elevated Aβ levels compared with male sex, later age at menopause, and hormone therapy use:

  • Female sex: standardized β, –0.41; 95% CI, –0.97 to –0.32; P <. 001
  • Earlier age at menopause: standardized β, –0.38; 95% CI, –0.14 to –0.09; P <. 001
  • Hormone therapy use: standardized β, –0.31; 95% CI, 0.40-1.20; P =.008

Additionally, initiation of hormone therapy at a later age (ie, more than 5 years after age at menopause) was associated with significantly higher tau vulnerability on PET compared with early initiation of hormone therapy (β, 0.49; 95% CI, 0.27-0.43; P =.001).

Women participants had significantly higher PACC scores compared with age-matched men (β, –0.42; 95% CI, –0.61 to –0.22; P <.001). Further, significant associations were shown between earlier age at menopause and lower PACC scores (β, –0.03; 95% CI, 0-0.05; P =.02), which was intensified in the setting of higher Aβ burden (interaction:
β, –0.12; 95% CI, 0.02-0.23; P =.02). Of note, women participants who reported late initiation of hormone therapy performed subtly lower on the PACC compared with those who reported early initiation of hormone therapy.

A key limitation of the present study is that although the researchers accounted for potential impacts of medical and menopausal-linked psychiatric factors, information on precipitating factors in premature/early menopause and the reason for the selection of hormone therapy in women were not included in the study. In addition, the study sample included predominantly non-Hispanic White individuals, along with a small group of Black participants, which limits the generalizability of the study’s findings.

Researchers acknowledged that “The findings of the present study may inform AD risk discussions relating to female reproductive health and treatment. “Female individuals who experience younger age at menopause may represent a subgroup for priority inclusion in AD prevention trials. Clinical trials to assess the potential implications of HT [hormone therapy] timing on tau deposition are also warranted,” they concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Coughlan GT, Betthauser TJ, Boyle R, et al. Association of age at menopause and hormone therapy use with tau and β-amyloid positron emission tomography. JAMA Neurol. Published online April 3, 2023. doi:10.1001/jamaneurol.2023.0455