OBJECTIVE: To investigate the association between APOE genotype and β-amyloid (Aβ) burden, as measured by PET in patients with subcortical vascular cognitive impairment (SVCI) and those with Alzheimer disease-related cognitive impairment (ADCI). METHODS: This was a cross-sectional study of 310 patients with SVCI and 999 with ADCI. To evaluate the effects of APOE genotype or diagnostic group on Aβ positivity, we performed multivariate logistic regression analyses. Further distinctive underlying features of latent subgroups were examined by employing a latent class cluster analysis approach. RESULTS: In comparison with ε3 homozygotes, in the ADCI group, ε2 carriers showed a lower frequency of Aβ positivity (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.23-0.79), while in the SVCI group, ε2 carriers showed a higher frequency of Aβ positivity (OR 2.26, 95% CI 1.02-5.01). In particular, we observed an interaction effect of ε2 carrier status and diagnostic group on Aβ positivity (OR 5.12, 95% CI 1.93-13.56), in that relative to ε3 homozygotes, there were more Aβ-positive ε2 carriers in the SVCI group than in the ADCI group. We also identified latent subgroups of Aβ-positive APOE ε2 carriers with SVCI and Aβ-positive APOE ε4 carriers with ADCI. CONCLUSIONS: Our findings suggest that APOE ε2 is distinctly associated with Aβ deposition in patients with SVCI and those with ADCI. Our findings further suggest that there is a distinctive subgroup of Aβ-positive APOE ε2 carriers with SVCI among patients with cognitive impairment.