Sex-related Differences in Tau Positron Emission Tomography (PET) and the Effects of Hormone Therapy (HT)

Abstract

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.

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

“…38 We found sex differences in regional tau deposition in individuals approximately 20 years younger than those included in prior studies reporting sex differences. 11,12,16 Our findings replicate recent work in a diverse sample of later middle-aged individuals who also reported sex differences in cortical tau deposition independent of Aβ burden. 39 We extend these findings by reporting Aβ-independent sex differences in regional tau-PET deposition in areas not typically found to have early AD-related tau deposition.…”

“…We found sex differences in regional tau deposition in individuals approximately 20 years younger than those included in prior studies reporting sex differences 11,12,16 . Our findings replicate recent work in a diverse sample of later middle‐aged individuals who also reported sex differences in cortical tau deposition independent of Aβ burden 39 .…”

“…Further illustrating the potential importance of this hormonal transitional period, surgically induced menopause at an earlier age has been associated with cognitive decline and increased AD neuropathology at post‐mortem 23,24 . A recent observational study also reported that prior history of hormone therapy was protective against abnormal levels of tau‐PET in women 12 . Taken together, these findings support a nexus of AD‐related pathological risk associated with the menopausal transition.…”

“…A reduction in circulating endogenous 17β‐estradiol is associated with a proliferation of AD pathology in animal models 20 . In humans, the later stages of menopause have been associated with increased levels of Aβ, loss of white matter integrity and glucose hypometabolism 12,21,22 . Further illustrating the potential importance of this hormonal transitional period, surgically induced menopause at an earlier age has been associated with cognitive decline and increased AD neuropathology at post‐mortem 23,24 .…”

“…W omen demonstrate an elevated risk for progression to dementia compared to men, 1,2 particularly among those at greater genetic risk of sporadic Alzheimer's disease (AD) dementia. [3][4][5] Women also have a higher risk of elevated AD-related pathology, 6,7 specifically tau, 1,[8][9][10][11][12] and faster rates of brain atrophy compared to men. [13][14][15] In vivo studies of clinically normal older women have consistently shown higher tau positron emission tomography (PET) signal relative to men, 8,11,12,16 and elevated levels of cerebrospinal fluid (CSF) total tau in apolipoprotein ε4 (APOEε4) carriers relative to men.…”