Protective Effects of APOE ϵ2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living with Cancer Study

Abstract

Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene e4 polymorphisms. APOE e4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas e2 polymorphisms protect against AD. However, the effects of e2 polymorphisms on CRCD have not been evaluated. Methods: We evaluated nonmetastatic breast cancer survivors (n 427) and matched noncancer controls (n 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an e2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with e2/e4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any e4 positivity. Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta 0.32, 95% confidence interval 0.00 to 0.65); the chemotherapy group with an e2 allele had higher scores at baseline and maintained higher scores over time compared with those without an e2 allele, and this protective effect was not seen for other groups. There was no effect of e2 on learning and memory domain scores. Conclusions: APOE e2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.