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PreprintCC BY-NDmedRxiv

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

  • A. Badea1
  • J. Xu
  • D. T. Laskowitz
  • C. T. Badea1
  1. 1Duke Univ Medical Center
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Abstract

INTRODUCTIONWhether APOE {varepsilon}4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown.

METHODSIn 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 x APOE {varepsilon}4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen.

RESULTSAPOE {varepsilon}4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion ({beta}=-0.00858, P=1.45x10-, 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 x MRI time was modeled. Four regional ventricular cardiac x APOE {varepsilon}4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE {varepsilon}4-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 {varepsilon}4-dependent associations with plasma A{beta}42/40, 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.

DISCUSSIONAPOE {varepsilon}4 modified atrial-brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed.

HighlightsO_LIAPOE {varepsilon}4 modified how left atrial remodeling related to later brain ventricle growth. C_LIO_LIIt was the only FDR-significant result of 16 tests and persisted with random slopes. C_LIO_LIIn {varepsilon}4 carriers, larger LA volume tracked lower occipital thickness variability. C_LIO_LIThis atrial-cortical association was independent of LV mass and ejection fraction. C_LIO_LIExploratory: HbA1c related to LV end-diastolic volume differently by APOE {varepsilon}4 status. C_LI

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Cite

BibTeXRIS
BibTeX
@misc{badea2026apoe,
  title = {{APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging}},
  author = {A. Badea and J. Xu and D. T. Laskowitz and C. T. Badea},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.14.26365550},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.14.26365550v1},
  note = {CC BY-ND},
}
RIS
TY  - UNPB
TI  - APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging
AU  - A. Badea
AU  - J. Xu
AU  - D. T. Laskowitz
AU  - C. T. Badea
PY  - 2026
DA  - 2026/10/14
PB  - medRxiv
DO  - 10.64898/2026.10.14.26365550
UR  - https://www.medrxiv.org/content/10.64898/2026.10.14.26365550v1
AB  - INTRODUCTIONWhether APOE {varepsilon}4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown.  METHODSIn 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 x APOE {varepsilon}4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen.  RESULTSAPOE {varepsilon}4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion ({beta}=-0.00858, P=1.45x10-, 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 x MRI time was modeled. Four regional ventricular cardiac x APOE {varepsilon}4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE {varepsilon}4-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 {varepsilon}4-dependent associations with plasma A{beta}42/40, 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.  DISCUSSIONAPOE {varepsilon}4 modified atrial-brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed.  HighlightsO_LIAPOE {varepsilon}4 modified how left atrial remodeling related to later brain ventricle growth. C_LIO_LIIt was the only FDR-significant result of 16 tests and persisted with random slopes. C_LIO_LIIn {varepsilon}4 carriers, larger LA volume tracked lower occipital thickness variability. C_LIO_LIThis atrial-cortical association was independent of LV mass and ejection fraction. C_LIO_LIExploratory: HbA1c related to LV end-diastolic volume differently by APOE {varepsilon}4 status. C_LI
ER  -