Menopause moderates sex differences in tau PET signal: Findings from the Framingham Study

Abstract

AbstractBackgroundCognitively‐normal (CN) older women exhibit elevated tau‐PET signal in medial temporal and neocortical regions compared with men. The effect of menopause on tau deposition remains unclear. We explored menopausal status as a moderator of sex differences in tau deposition in middle‐aged adults.Method273 CN (Age=55yrs(±8), Female(n)=134, Post‐menopausal(n)=70) from the Framingham Study 3rd generation cohort underwent 18F‐Flortaucipir (FTP)‐PET and/or 11C‐Pittsburgh Compound‐B (PiB)‐PET scans. We examined FTP‐PET signal in four a priori regions that demonstrate large sex differences in CN older adults (entorhinal, rostral middle frontal, inferior parietal and lateral occipital). FTP‐PET and global PiB‐PET signal were referenced to cerebellar grey. Linear regression examined sex differences in each ROI, adjusting for age and PET camera. Separate models examined menopausal status (post‐menopause/pre‐menopause females), menopausal age (≤|>50 years), and interactions with APOEε4. Sensitivity analyses included age‐matched males (‘pseudo‐premenopausal’/‘pseudo‐menopausal’) against the menopause groups to account for confounds with chronological age.ResultMiddle‐aged females exhibited higher FTP‐PET signal in the inferior parietal, rostral middle frontal and lateral occipital regions than males by ∼0.04SUVr (p<0.009; Fig. 1). No sex or menopause differences were evident in PiB‐PET. Post‐menopausal females exhibited higher FTP‐PET signal in the lateral occipital lobe than pre‐menopausal (p=0.05; Fig. 2). Menopause age≤50 years corresponded with higher lateral occipital and rostral middle frontal FTP‐PET signal than >50years (p<0.05; Fig. 2). Post‐menopausal females maintained higher signal in lateral occipital, inferior parietal and rostral middle frontal regions compared with even age‐matched ‘pseudo‐menopausal’ males (Table 1). Finally, a significant menopause*APOEε4 interaction suggested that the menopause effect was only evident in APOEε4 non‐carriers, localized to the parietal lobe (p∼0.03; Fig. 3).ConclusionSex differences in tauopathy are apparent in CN individuals approximately 20 years earlier than previously demonstrated. Our findings suggest that sex differences are exacerbated by menopause, particularly when the age‐at‐menopause is below 50 years. Chronological age did not appear to confound the results, as age‐matched males exhibited significantly lower tau signal. Finally, the effect of APOEε4 carriership may ameliorate menopause effects; only pre‐menopausal APOEε4 non‐carriers appeared to exhibit protective effects of circulating estradiol relative to post‐menopausal non‐carriers. Future work will need to identify direct hormonal contributions, the impact of surgery and hormone‐therapy.