APOE epsilon 4 is associated with earlier symptom onset in LOAD but later symptom onset in EOAD

Background: We studied the effect of apolipoprotein E (APOE) epsilon 4 status and sex on age of symptom onset (AO) in early- (EO) and late- (LO) onset Alzheimer's disease (AD).Method: A total of 998 EOAD and 2562 LOAD participants from the National Alzheimer's Coordinating Center (NACC) were included. We used analysis of variance to examine AO differences between sexes and APOE genotypes and the effect of APOE epsilon 4, sex, and their interaction on AO in EOAD and LOAD, separately.Results: APOE epsilon 4 carriers in LOAD had younger AO and in EOAD had older AO. Female EOAD APOE epsilon 4 carriers had older AO compared to non-carriers (P < 0.0001). There was no difference for males. Both male and female LOAD APOE epsilon 4 carriers had younger AO relative to non-carriers (P < 0.0001).Conclusion: The observed earlier AO in EOAD APOE epsilon 4 non-carriers relative to carriers, particularly in females, suggests the presence of additional AD risk variants.