The Associations of Cerebrospinal Fluid ApoE and Biomarkers of Alzheimer’s Disease: Exploring Interactions With Sex

BACKGROUND: Sex-related difference in Alzheimer’s disease (AD) has been proposed, and apolipoprotein E (ApoE) isoforms have been suggested to be involved in the pathogenesis of AD. OBJECTIVE: We aimed to explore whether cerebrospinal fluid (CSF) ApoE is associated with AD biomarkers and whether the associations are different (between sexes). METHODS: Data of 309 participants [92 with normal cognition, 148 with mild cognitive impairment (MCI), and 69 with AD dementia] from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were cross-sectionally evaluated with the multiple linear regression model and longitudinally with the multivariate linear mixed-effects model for the associations of CSF ApoE with AD biomarkers. Sex–ApoE interaction was used to estimate whether sex moderates the associations of CSF ApoE and AD biomarkers. RESULTS: Significant interactions between CSF ApoE and sex on AD biomarkers were observed [amyloid-β (Aβ): p = 0.0169 and phosphorylated-tau (p-tau): p = 0.0453]. In women, baseline CSF ApoE levels were significantly associated with baseline Aβ (p = 0.0135) and total-tau (t-tau) (p < 0.0001) as well as longitudinal changes of the biomarkers (Aβ: p = 0.0104; t-tau: p = 0.0110). In men, baseline CSF ApoE levels were only correlated with baseline p-tau (p < 0.0001) and t-tau (p < 0.0001) and did not aggravate AD biomarkers longitudinally. CONCLUSION: The associations between CSF ApoE and AD biomarkers were sex-specific. Elevated CSF ApoE was associated with longitudinal changes of AD biomarkers in women, which indicates that CSF ApoE might be involved in the pathogenesis of AD pathology in a sex-specific way.