Influence of ApoE genotype on doxorubicin-induced cognitive impairment in juvenile rats

Many pediatric cancer survivors experience chemotherapy-induced cognitive impairment (CICI), which negatively impacts their quality of life. However, while some patients develop CICI, others do not, suggesting that genetic variants may contribute to the development of CICI. The Apolipoprotein E (ApoE) E4 allele has been identified as a risk variant for CICI among pediatric cancer survivors. However, the mechanisms by which ApoE4 contributes to the development of CICI remain unknown. Using a commonly used chemotherapeutic agent known to induce CICI, doxorubicin, we treated five-week-old rats homozygous for either the human ApoE3 or ApoE4 allele with doxorubicin (2 mg/kg/week for 4 weeks) or saline. Behavioral assessments revealed that ApoE4 rats were more susceptible to doxorubicin-induced impairments in visual and spatial memory compared to ApoE3 rats. Pathophysiological analyses showed a significant reduction in hippocampal neurogenesis of ApoE4 doxorubicin-treated rats relative to the other groups. Serum levels of GFAP were significantly increased in ApoE4 doxorubicin-treated rats. These findings suggest that the ApoE genotype influences vulnerability to CICI and highlight a potential mechanistic link through impaired neurogenesis, laying the groundwork for genotype-specific therapeutic strategies.