Associations of BDNF methylation and rs6265 genotype with cognitive response to a six-month aerobic exercise intervention in women with early-stage breast cancer: results from the EPICC Trial.

Women with breast cancer often experience cognitive decline, an accelerated aging phenotype. While aerobic exercise may mitigate this decline, effects are inconsistent by domains, and the molecular mechanisms remain unknown. Given the brain-derived neurotrophic factor (BDNF)'s responsiveness to exercise and role in cognition, we investigated BDNF methylation and rs6265, its functional SNP, with cognitive responses to aerobic exercise. Leveraging data from a randomized clinical trial which found cognitive function improved with a six-month aerobic exercise than control group in women with breast cancer, we included sub-samples with either pre-randomization or post-intervention M-values. CpG-site level M-values (higher positive value = greater methylation) of BDNF, rs6265 genotype (CC/CT/TT), composite scores for each cognitive domain (higher scores = better performance), and linear mixed-effect modeling were used. Women (N = 117, 75% of trial participants) were on average 62.6 ± 7.84 years old. The majority were White (89.7%). Intervention effects were observed at four CpG sites: cg05189570, cg08382738, cg12067298, cg20340655. Methylation increases at cg05818894 (b = 0.138; p = 0.049) and cg06025631 (b = 0.373; p = 0.031) were correlated with attention and mental flexibility improvements, respectively. Working memory improvement in the exercise group was greater with less methylation increases at cg12296752 and cg15462887, but with greater methylation increases at cg06025631, cg04481212, and cg16257091. Processing speed improvement in the exercise group was greater with greater methylation increase at cg06260077. At pre-randomization, the additive T allele effect of rs6265 on methylation of cg10635145 and cg07238832 was detected. Findings suggest aerobic exercise may exert cognitive benefits through epigenetically regulated mechanisms, highlighting CpG-specific methylation as potential targets for managing cognitive decline in women with breast cancer.