Sex-related differences in tau Positron Emission Tomography (PET) and the effects of Hormone Therapy (HT)

Importance: Female sex is a major risk factor for late-onset Alzheimer disease (AD), and sex hormones have been implicated as a possible protective factor. Neuroimaging studies that evaluated the effects of sex hormones on brain integrity have primarily emphasized neurodegenerative measures rather than amyloid and tau burden. Objective: We compared cortical amyloid and regional tau positron emission tomography (PET) deposition between cognitively normal males and females. We also compared preclinical AD pathology between females who have and have not used hormone therapy (HT). Finally, we compared the effects of amyloid and tau pathology on cognition, testing for both sex and HT effects. Design, Setting, and Participants: We analyzed amyloid, tau, and cognition in a cognitively normal cross-sectional cohort of older individuals (n = 148) followed at the Knight Alzheimer Disease Research Center. Amyloid and tau PET, medication history, and neuropsychological testing were obtained for each participant. Results: Within cognitively normal individuals, there was no difference in amyloid burden by sex. Whether or not we controlled for amyloid burden, female participants had significantly higher tau PET levels than males in multiple regions, including the rostral middle frontal and superior and middle temporal regions. HT accounted for a small reduction in tau PET; however, males still had substantially lower tau PET compared with females. Amyloid PET and tau PET burden were negatively associated with cognitive performance, although increasing amyloid PET did not have a deleterious effect on cognitive performance for women with a history of HT. Conclusions and Relevance: Regional sex-related differences in tau PET burden may contribute to the disparities in AD prevalence between males and females. The observed decreases tau PET burden in HT users has important implications for clinical practice and trials and deserves future consideration in longitudinal studies.