The apolipoprotein E (APOE) e4 allele is the most prevalent genetic risk factor for Alzheimer's disease (AD). APOE e4 carriers suffer greater morbidity from head trauma, stroke, and carbon monoxide poisoning, yet possible interactions between APOE genotype and cancer therapy on cognition are unclear. Neuropathological and biomarker studies of young asymptomatic APOE e4 carriers that show elevated neocortical amyloid and medial temporal neurofibrillary tangles and longitudinal neuropsychological studies that show accelerated memory decline beginning around age 55–60 years define preclinical AD and have set the stage for assessing the potential adverse cognitive effects of cancer therapy in APOE e4 carriers. Pediatr Blood Cancer 2014; 61:1739–1742. © 2013 Wiley Periodicals, Inc.