Menopause Status Moderates Sex Differences in Tau Burden: A Framingham PET Study

Abstract

Objective: Women have a higher lifetime risk of Alzheimer's disease (AD) than men. Among cognitively normal (CN) older adults, women exhibit elevated tau positron emission tomography (PET) signal compared with men. We explored whether menopause exacerbates sex differences in tau deposition in middle-aged adults. Methods: 328 CN participants from the Framingham Study (mean age = 57 years (AE10 years), 161 women, of whom, 104 were post-menopausal) underwent tau and β-amyloid (Aβ)-PET neuroimaging. We examined global Aβ-PET, and tau-PET signal in 5 regions identified a priori as demonstrating significant sex differences in older adults (in temporal, inferior parietal, middle frontal, and lateral occipital regions). We examined sex and menopause status-related differences in each region-of-interest, using linear regressions, as well as interactions with Aβ and APOEε4 genotype. Results: Women exhibited higher tau-PET signal (p < 0.002), and global Aβ-PET (p = 0.010), than men in inferior parietal, rostral middle frontal, and lateral occipital regions. Compared with age-matched men, post-menopausal women showed significantly higher tau-PET signal in parieto-occipital regions (p < 0.0001). By contrast, no differences in tau-PET signal existed between pre-menopausal women and men. Aβ-PET was not associated with menopausal status or age. Neither Aβ-PET nor APOEε4 status moderated sex or menopause associations with tau-PET. Interpretation: Clear divergence in tauopathy between the sexes are apparent approximately 20 years earlier than previously reported. Menopause status moderated sex differences in Aβ and tau-PET burden, with tau first appearing post-menopause. Sex and menopause differences consistently appeared in middle frontal and parieto-occipital regions but were not moderated by Aβ burden or APOEε4, suggesting that menopause-related tau vulnerability may be independent of AD-related pathways.

Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography

“…We focused on temporal, parietal, and occipital brain regions that have shown sex differences on tau PET in female individuals compared with males. 3,28…”

The aging brain: risk factors and interventions for long term brain health in women

“…In addition, recovery in aspects of brain structure and metabolism postmenopause were linked to better postmenopause global cognition [28 ▪▪ ]. In a separate study, Buckley and colleagues showed in a sample of 328 cognitively normal individuals at midlife (mean age = 57), that postmenopausal, but not premenopausal women had greater levels of tau protein than men, as assessed by tau-Positron Emission Tomography [30 ▪▪ ].…”

“…As with work on menopause-related risks for cognitive decline, there are discrepancies among human clinical trials vs. observational studies of MHT on cognitive outcomes, as well as differences when comparing human and animal model literature, regarding what genetic and medical risks might define women who benefit most from MHT, what treatment should be given, and for how long [29,30 ▪▪ ,31]. Regarding who to treat, age, APOE ε4 status, and medical and lifestyle risks [29] are important to consider.…”

Menstrual cycle brain plasticity: Ultra-high field 7T MRI reveals changes in human medial temporal lobe volume in female adults

“…Area 35, corresponding to the transentorhinal region and medial perirhinal cortex 24,41 , has thus far received little attention in regards to endogenous ovarian hormone uctuations. This constitutes a critical knowledge gap given the relevance of this subregion to dementia progression and that changes in hormone status have been proposed to underlie sex differences in Alzheimer's disease pathology [42][43][44] .…”