Background: Antipsychotic (AP) use in patients with Alzheimer’s disease (AD) is associated with increased mortality. However, potential sex differences among AP users with AD remain underexplored.

Methods: We conducted a retrospective cohort study using TriNetX, a global real-world health research network. Patients diagnosed with AD and prescribed antipsychotics were stratified by sex. Mortality risk, odds ratios (OR), risk ratios (RR), and hazard ratios (HR) were calculated. Kaplan–Meier survival curves and log-rank tests were used to assess survival probability over time.

Results: The female AP user cohort (n=112,566) showed lower mortality (25.2%) than male users (n=74,251; 27.6%). The risk difference was -0.024 (95% CI: -0.028 to -0.020, p<0.001), with a RR of 0.913 and OR of 0.883. Median survival was longer in females (3,018 days) than in males (2,372 days). Survival probabilities at the end of follow-up were 19.1% for women and 26.3% for men. The HR for female mortality was 0.823 (95% CI: 0.809-0.838, p<0.001). In an analysis including patients with longer follow-up, mortality remained significantly lower in females (17.2%) compared to males (27.2%), with a risk difference of -0.10 and HR of 0.544 (95% CI: 0.533-0.554, p<0.001). Median survival was 6,770 days for females versus 3,383 days for males.

Conclusions: Among Alzheimer’s patients using antipsychotics, females demonstrated lower mortality and longer survival than males. These findings underscore the importance of considering sex as a biological variable in treatment decisions and mortality risk assessments for AP use in AD.