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. 2025 Apr 6;17(2):e70099.
doi: 10.1002/dad2.70099. eCollection 2025 Apr-Jun.

Associations between APOE-TOMM40 '523 haplotypes and limbic system white matter microstructure

Katelyn E Mooney  1   2 , Derek B Archer  3   4   5 , Aditi Sathe  3 , Timothy J Hohman  3   5   6 , Ose Kadiri  2 , Melissa Lamar  7   8 , Konstantinos Arfanakis  7   9   10 , Lei Yu  7 , Lisa L Barnes  7   11 , Kacie D Deters  2
Affiliations

Associations between APOE-TOMM40 '523 haplotypes and limbic system white matter microstructure

Katelyn E Mooney et al. Alzheimers Dement (Amst). .

Abstract

Introduction: We assessed associations between apolipoprotein E Translocase of Outer Mitochondrial Membrane 40 (APOE-TOMM40)-'523 haplotypes and white matter microstructure (WMM) across limbic tracts important for memory and cognition in non-Hispanic Black and White individuals.

Methods: Linear regression models, stratified by APOE and racialized groups, assessed associations between TOMM40-'523-S and limbic tract WMM free-water (FW) and free-water-corrected fractional anisotropy (FAFWcorr).

Results: Black-ε4+-one-'523-S carriers had lower FW in the cingulum and inferior longitudinal fasciculus compared to Black-ε4+-no-'523-S carriers. Additionally, Black-ε4+-one-'523-S carriers had lower FW in the cingulum, uncinate, and fornix, and higher FAFWcorr in the uncinate compared to Black-ε4+-'523-S/S carriers. White-ε3/ε3-'523-S/S carriers had lower FAFWcorr in the cingulum and inferior temporal gyrus compared to White-ε3/ε3-no-'523-S carriers, and lower FAFWcorr in the cingulum compared to White-ε3/ε3-one-'523-S carriers.

Discussion: This supports prior work that '523-S is associated with abnormal aging in White-ε3/ε3 carriers, but is potentially risk-mitigating in Black-ε4+ carriers, while suggesting a differential effect by racialized background of APOE on WMM.

Highlights: White matter microstructure (WMM) across limbic tracts important for cognition was measured by diffusion MRI.Black apolipoprotein E (APOE) ε4+ carriers with one copy of TOMM40-'523-S had normal aging WMM metrics across several tracts, including the cingulum bundle, uncinate fasciculus, fornix, and inferior longitudinal fasciculus.White APOE ε3/ε3 carriers with two copies of TOMM40-'523-S had abnormal aging WMM metrics in the cingulum bundle and inferior temporal gyrus.APOE associations with aging may differ in racialized groups due to TOMM40-'523-S copy number.

Keywords: APOE; Alzheimer's disease (AD); Minority Aging Research Study; Rush Memory and Aging Project; TOMM40; aging; diffusion magnetic resonance imaging (dMRI); free water corrected metrics; genetic risk factors; limbic system tracts; white matter microstructure (WMM).

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Conflict of interest statement

Dr. Lisa Barnes (co‐author) serves as the Deputy Editor of “Alzheimer's & Dementia.” Dr. Timothy Hohman (co‐author) serves as the Deputy Editor for “Alzheimer's & Dementia: Translational Research and Clinical Intervention,” Senior Associate Editor for “Alzheimer's & Dementia,” and served on the Scientific Advisory Board for “Vivid Genomics.” No other competing interests were declared by the authors. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Residualized beta estimates of ‘523‐S copy number and WMM metrics across limbic system tracts in non‐Hispanic Black ε4+ participants, adjusted by age, sex, education, and clinical diagnosis. p−values < 0.05 are shown with *, p−values < 0.01 are shown with **. WMM, white matter microstructure.
FIGURE 2
FIGURE 2
Residualized beta estimates of ‘523‐S copy number and WMM metrics across limbic system tracts in non‐Hispanic White ε3/ε3 participants, adjusted by age, sex, education, and clinical diagnosis. p−values < 0.05 are shown with *, p−values < 0.01 are shown with **. WMM, white matter microstructure.
See this image and copyright information in PMC

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