Sex Modifies the Associations of APOE ε4 with Neuropsychiatric Symptom Burden in Both At-Risk and Clinical Cohorts of Alzheimer's Disease

Background: Recent work suggests that APOE epsilon 4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective: To examine the interaction of sex and APOE epsilon 4 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 epsilon 4 on the number of NPS experienced and NPS Severity. APOE epsilon 3/4 and APOE epsilon 4/4 were pooled in the at-risk cohort due to the sample size. Results: In the at-risk cohort, there was a significant sex*APOE epsilon 4 interaction (p = 0.007) such that the association of APOE epsilon 4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOE epsilon 4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOE epsilon 4/4 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 epsilon 3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males. Conclusion: Our study suggests that sex modifies the association of APOE epsilon 4 on NPS burden. APOE epsilon 4/4 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.

Automated summary

This study suggests that the gene APOE ε4 may be more strongly associated with neuropsychiatric symptom burden in females with Alzheimer's disease, especially in APOE ε4/4 females. This finding provides insights for further investigation into the underlying mechanisms of this association.