APOE Genotype–specific Cognitive Response to Aerobic Exercise in Postmenopausal Women with Breast Cancer

Cognitive symptoms are common in postmenopausal women treated for breast cancer (BC). In general and in BC, the Apolipoprotein E 4 allele ( APOE4) is linked to lower cognition and accelerated cognitive decline, but exercise generally benefits cognition. The purpose of this study was to examine whether the effect of aerobic exercise on cognitive function differs by APOE4 carriage in postmenopausal women with breast cancer. Longitudinal analysis of a 6-month randomized clinical trial of aerobic exercise in postmenopausal women with BC (2016–2022) was done. Subsample with APOE genotype and cognitive function data (before randomization and at intervention completion) were analyzed. Variables included group assignment (Control/Exercise), APOE4 carriage (No/Yes), and composite scores for 7 cognitive domains (Higher = better). Robust regression was used, adjusting for age, education, baseline cognitive score, and days on endocrine therapy, with group × APOE4 carrier interaction term. In this sample (n = 116, x̅ = 62 years old, 21% APOE4 carriage), APOE4 carriage moderated the effect of aerobic exercise on learning and memory (b = −0.544, p = 0.023). Non-carriers’ scores improved and APOE4 carriers’ scores declined. There were no other significant findings for attention, executive function, mental flexibility, processing speed, verbal memory, or working memory. In this hypothesis-generating study, aerobic exercise was associated with modest cognitive performance improvements in non-carriers, while APOE4 carriers did not demonstrate similar improvements. These exploratory findings suggest that a differing response for effects of exercise on cognition in post-menopausal women with BC may exist and be partially explained by APOE4 carriage.