A. Li, Hannah M Klinger, Mabel Seto, Colin Birkenbihl, Michael J. Properzi, Michelle Farrell, Emma G. Thibault, Aaron P. Schultz, Diana L. Townsend, Madison Cuppels, Jane A. Brown, Kathryn V. Papp, Rebecca Amariglio, Hyun‐Sik Yang, Michael C. Donohue, Robert A. Rissman, Tobey J. Betthauser, Rebecca E. Langhough, Erin M. Jonaitis, Karly Alex Cody, Sterling C. Johnson, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Rachel F. Buckley, Gillian Coughlan, the A4 Study Team
INTRODUCTION: Women show higher levels of Alzheimer's disease (AD) pathology than men, but the implications for cognitive decline remain unclear. Determining the extent to which tau burden differentially accelerates cognitive decline in men and women will provide critical insights into sex-specific pathways of disease progression. METHODS: We leveraged tau positron emission tomography (PET), amyloid beta (Aβ) PET, apolipoprotein E (APOE) ε4 genotyping, and longitudinal cognitive data over approximately 8.6 (standard deviation [SD] = 3.8) years from 1007 cognitively unimpaired adults across three cohorts. Cognitive trajectories were modeled with linear mixed-effects regression including sex × tau × time interactions, and results were synthesized using random-effects meta-analysis. RESULTS: Higher tau burden in medial and lateral temporal regions was associated with faster cognitive decline in women than in men. DISCUSSION: High tau burden carries a disproportionately greater cognitive cost for women, underscoring the need for sex-specific approaches to early detection and therapeutic intervention in AD. HIGHLIGHTS: A meta-analysis across three independent cohorts shows that female cognitive advantage at low tau shifts to vulnerability at higher tau. Sex differences in tau-related cognitive decline were consistent after accounting for amyloid burden. Sex-specific rates of cognitive decline should be considered in clinical trial design.