Davis EJ, Solsberg CW, White CC, et al. - In this cohort study of 508 people (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had a clinical diagnosis of Alzheimer disease {AD} at death; 293 [58.2%] had a pathological diagnosis of AD at death), the X chromosome was linked to cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is significant because specific X chromosome factors in women, men, or both may increase risk or resilience to biological pathways of aging and AD.

• Individuals in the Religious Orders Study and Rush Memory and Aging Project joint cohorts provided samples for RNA sequencing of the dorsolateral prefrontal cortex, which were followed up on annually for a mean (SD) of 6.3 (3.9) years.

• Women, but not men, had a significant association with cognitive change at the genome-wide level when X chromosome gene expression (29 genes) was adjusted for age at death, education, and AD pathology.

• Increased expression of the majority of discovered X genes (19 genes) was linked to slower cognitive decline in women.

• X chromosome gene expression (3 genes), which was adjusted for age at death and education, was connected with neuropathological tau burden at the genome-wide level in males but not in women, in contrast to cognition.