Abstract INTRODUCTION Although the link between the presence of amyloid and tau pathologies, neurodegeneration, and cognitive decline in aging individuals is established, it is less clear whether there are sex differences in vulnerability to these pathologies. METHODS A total of 1464 participants (7168 longitudinal assessments, 4.77 ± 3.78 years of follow‐up) were included from the National Alzheimer's Coordinating Center (NACC) database. Longitudinal mixed effects and mediation models examined the sex differences across cognitive decline trajectories of amyloid (A), tau (T), and neurodegeneration (N) groups. RESULTS A + T − males showed faster cognitive decline compared to A + T − females ( p < 0.005), whereas A + T + females showed steeper cognitive decline compared to A + T + males ( p < 0.0001). In addition, sex marginally moderated the mediating effect of tau on the relationship between amyloid and cognitive decline ( p = 0.046). DISCUSSION Sex differences in vulnerability to tau pathology in the presence of amyloid can shape cognitive decline trajectories. Highlights A + T − males showed faster cognitive decline compared to A + T − females. A + T + females showed faster cognitive decline compared to A + T + males. Tau status significantly mediated the relationship between amyloid status and cognitive decline. Sex marginally moderated the mediating relationship between amyloid, tau, and cognitive decline. The findings point to sex differences in the impact of tau pathology on cognition.
Zeighami et al. (Wed,) studied this question.
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