Apolipoprotein E DNA Methylation Linked to Cognitive Decline in Postmenopausal Women With Breast Cancer.

BACKGROUND: Cognitive decline is common among individuals with breast cancer (BC), and carriage of the apolipoprotein E (APOE) ε4 allele increases risk. APOE DNA methylation (DNAm) may influence cognition through regulation of neuroinflammatory and amyloid-related pathways. Exercise is a potential factor affecting DNAm and cognition. This study examined associations between APOE DNAm and cognition in postmenopausal women with BC and evaluated moderation by APOE4 carriage status and exercise. METHODS: Data were drawn from a 6-month randomized trial of moderate-intensity exercise versus usual care. Cognition was assessed at baseline and 6 months, and change scores were calculated. APOE4 status (carrier, non-carrier) and baseline DNAm (M-value) were determined from peripheral blood. Regression models tested cross-sectional and longitudinal associations, adjusting for age and education. Moderation by APOE4 status and intervention group was also tested. RESULTS: Among 102 participants, APOE DNAm was consistently suggestively associated with cognition. Higher DNAm at promoter-region CpGs (cg04406254, cg14123992, cg20051876) was linked to poorer cognition, with direction and magnitude differing by APOE4 status and group. APOE4 carriers with higher DNAm showed better cognitive performance, and exercisers with higher DNAm showed improved outcomes, suggesting exercise may buffer epigenetic effects. CONCLUSIONS: Findings may implicate APOE DNAm as a biomarker of cognition and highlight exercise supporting cognitive health in women with BC, although replication is needed.