APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging

INTRODUCTION Whether APOE ε4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown. METHODS In Framingham Heart Study Offspring participants, we related antecedent echocardiographic remodeling (Examinations 4–6) to repeated brain MRI, and cardiac magnetic resonance phenotypes to regional cortical morphometry, testing cardiac × APOE ε4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen. RESULTS APOE ε4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion (β=−0.00858, P=1.45×10⁻⁴, q=0.0023; N=1,305; 3,787 MRI observations), the only FDR-significant result of 16 longitudinal tests, including with participant-specific MRI-time slopes (q=0.034); it weakened when intracranial volume × MRI time was modeled. Four regional ventricular cardiac × APOE ε4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE ε4-dependent association with left middle-occipital cortical-thickness variability (whole-brain q=0.017; permutation P=0.041) that persisted after ventricular adjustment. Cardiac phenotypes and trajectories showed no FDR-significant APOE ε4-dependent associations with plasma Aβ42/40, p-tau181, GFAP, or NfL, and adjustment for these biomarkers changed the regional interactions by at most 3.2%. Allen Human Brain Atlas data showed cholesterol-biosynthesis enrichment in the right superior frontal cortex, implicated by the LV end-systolic volume interaction, but without convergent pathway evidence. DISCUSSION APOE ε4 modified atrial–brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed. Highlights APOE ε4 modified how left atrial remodeling related to later brain ventricle growth. It was the only FDR-significant result of 16 tests and persisted with random slopes. In ε4 carriers, larger LA volume tracked lower occipital thickness variability. This atrial–cortical association was independent of LV mass and ejection fraction. Exploratory: HbA1c related to LV end-diastolic volume differently by APOE ε4 status.