Many cancer survivors experience cancer-related cognitive impairment (CRCI), which is characterized by problems of attention, working memory, and executive function following chemotherapy and/or hormonal treatment. APOE4, the strongest genetic risk factor for Alzheimer's Disease (AD), is also a risk factor for CRCI, especially among survivors exposed to chemotherapy. We explored whether the effects of APOE genotype to chemotherapy were associated with an increase in AD pathological processes, using a mouse model of amyloid (5XFAD) along with the E3 or E4 alleles of human APOE (E3FAD and E4FAD). Six-month-old female E3FAD mice (control n = 5, treated n = 5) and E4FAD (control n = 6, treated n = 6) were treated with two doses of doxorubicin (total 10 mg/kg) or DMSO vehicle. After six weeks, mice were euthanized and brains were analyzed by immunohistochemistry and biochemical assays. Doxorubicin-treated mice had the same level of Aβ in the brain as control mice, as measured by 6E10 immunohistochemistry, Aβ40 and Aβ42 ELISAs, and plaque morphologies. Doxorubicin significantly increased the level of the astrocytic response to Aβ deposits, which was independent of APOE genotype; no effects of doxorubicin were observed on the microglial responses. These data are consistent with a model in which the effects of doxorubicin on risk of CRCI is unrelated amyloid accumulation, but possibly related to glial responses to damage.