Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline

Rachel F. Buckley, Matthew R. Scott, Heidi I. L. Jacobs, Aaron P. Schultz, Michael J. Properzi, Rebecca E. Amariglio, Timothy J. Hohman, Danielle V. Mayblyum, Zoe B. Rubinstein, Lyssa Manning, Bernard J. Hanseeuw, Elizabeth C. Mormino, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Objective The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. Methods Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined(18)F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*A beta-PET positive / negative (+ / -) and sex*apolipoprotein epsilon 4 (APOE epsilon 4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. Results Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p<0.007). beta-amyloid (A beta)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p<0.007); A beta + women exhibited greater FTP-signal than other groups. APOE epsilon 4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p= 0.04). Interpretation Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and A beta were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020

Original languageEnglish
Pages (from-to)921-932
Number of pages12
JournalAnnals of Neurology
Issue number5
Early online date31 Aug 2020
Publication statusPublished - Nov 2020


  • PET
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