In the current report, we show that homozygosity of APOE-ε1 can present with splenomegaly, where the human phenotype shows considerable overlap with lysosomal storage disorders, including the elevation of biomarkers (e.g., chitotriosidase activity, elevated in Gaucher and Niemann–Pick disease type B, and oxysterols, elevated in Niemann–Pick disease type B and C). Here, APOE is linked to Niemann-Pick disease type B.