Sex Modifies the Associations of APOE ɛ4 with Neuropsychiatric Symptom Burden in Both At-Risk and Clinical Cohorts of Alzheimer’s Disease

Abstract

Background: Recent work suggests that APOE ɛ4/4 females with Alzheimer’s disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective: To examine the interaction of sex and APOE ɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261). Methods: Regression models examined the interactive effects of sex and APOE ɛ4 on the number of NPS experienced and NPS Severity. APOE ɛ3/4 and APOE ɛ4/4 were pooled in the at-risk cohort due to the sample size. Results: In the at-risk cohort, there was a significant sex*APOE ɛ4 interaction (p = 0.007) such that the association of APOE ɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOE ɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOE ɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOE ɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males. Conclusion: Our study suggests that sex modifies the association of APOE ɛ4 on NPS burden. APOE ɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.