Sex Differences in the Relationship of Biomarker Change to Memory Decline in Early Alzheimer’s Disease: an Observational Cohort Study

Background Alzheimer’s disease (AD) exhibits sex differences in pathology and cognitive trajectories. Understanding how these differences manifest across the Alzheimer’s continuum can improve early detection, diagnostics, and interventions. We examined sex differences in how cerebrospinal fluid pTau181/Aβ42 ratio changes relate to verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD. Methods In this retrospective, longitudinal, observational study, data were extracted from 404 participants (age range: 55-87.8, 98% non-Hispanic White) of the Alzheimer’s Disease Neuroimaging Initiative cohort study who were classified as either preclinical AD (69 females, 68 males) or MCI (113 females, 151 males) at baseline and had CSF pTau181/Aβ42 ratio and cognitive assessment data at at-least two timepoints. Using regression models, we examined the relationship between changes in CSF pTau181/Aβ42 and verbal memory and the moderating role of sex and AD stage over a mean follow-up period of 4 years. Verbal memory was represented by a composite z-score averaging Immediate and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype. Results A significant sex x diagnostic group x biomarker change interaction (ꞵ=-17.47, 95%CI = 27.60 to -7.33, p  = .001) indicated that sex differences in the relationship between changes in CSF pTau181/Aβ42 ratio and verbal memory differed by disease stage. While males in the preclinical AD stage showed steeper memory decline than females with increasing pTau181/Aβ42 ratios, this difference was not statistically significant. In contrast, in the mild cognitive impairment stage, a significant sex X biomarker change interaction (ꞵ=10.17, 95% CI = 4.94 to 15.40, p < .001) in the MCI stage indicated that females exhibited significantly steeper memory decline associated with increasing pTau181/Aβ42 ratios compared to males. Conclusion Sex differences in the relationship between AD biomarker levels and cognitive decline vary by disease stage. Although not statistically significant, females demonstrated resilience to memory decline in the preclinical stage, whereas, in the MCI stage, they experienced significantly steeper memory loss compared to males. Results suggest that accounting for sex in biomarker-based methods of disease detection and tracking can improve early detection and intervention in both sexes.