Abstract Background APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer’s pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer’s disease pathology (ADP) and Lewy-related pathology (LRP). Methods A retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer’s Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups. Results One thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7–2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47–0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02–110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance. Conclusions The odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.