HAI Book 2025 - Flipbook - Page 330
Mooney, Katelyn
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Associations between APOE-TOMM40 8523 haplotype variants and
limbic system white matter microstructure in Black and White individuals
Katelyn Mooney1,2, Derek Archer3,4,5, Aditi Sathe3, Timothy Hohman3,4,6, Ose Kadiri2, Melissa
Lamar7,8, Konstantinos Arfanakis7,9,10, Lei Yu7, Lisa Barnes7,11, Kacie Deters2
1
University of California Los Angeles, Neuroscience Interdepartmental Program (NSIDP), David Geffen School of
Medicine, Los Angeles, CA, USA., Los Angeles, CA, US
2
University of California Los Angeles, Department of Integrative Biology and Physiology, Los Angeles, CA, USA., Los
Angeles, CA, US
3
Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA., Nashville, TN,
US
4
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA., Nashville, TN, US
5
Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA., Nashville, TN, US
6
Vanderbilt Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA., Nashville, TN, US
7
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, USA., Chicago, IL, US
8
Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, USA, Chicago, IL, US
9
Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL, USA, Chicago, IL, US
10
Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, IL, USA,
Chicago, IL, US
11
Departments of Neurological Sciences, and Psychiatry and Behavioral Sciences, Rush University Medical Center,
Chicago, USA, Chicago, IL, US
Background: APOE-TOMM40-8523 haplotype variants influence cognitive decline, where Black APOE-ε3-8523-S
carriers experience faster decline, but Black APOE-ε4-8523-S carriers show slower decline. Little is known about
how APOE-TOMM40-8523 haplotypes are associated with brain microstructure, which is particularly important as
such changes may precede cognitive impairment. This study examines associations between APOE-TOMM40-8523
haplotypes and white matter microstructure (WMM) in limbic tracts involved in memory and cognition in nonHispanic Black and White individuals.
Methods: Non-Hispanic-White (N=500) and non-Hispanic-Black (N=144) participants from the Rush Memory and
Aging Project and Minority Aging Research Study were included. WMM was measured via diffusion MRI (dMRI),
preprocessed with PreQual, and analyzed using DTIFIT and MATLAB. Data was harmonized using Longitudinal
ComBat. Free-water (FW) and FW-corrected fractional anisotropy (FAFWcorr) were assessed in five limbic tracts,
including the cingulum bundle, uncinate fasciculus, fornix, inferior longitudinal fasciculus, and inferior temporal
gyrus transcallosal tract. TOMM40-8523-S copy-number associations with FW and FAFWcorr were analyzed via linear
regression models, stratified by APOE and racialized group, adjusting for age, sex/gender, education, and clinical
diagnosis.
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. They also had lower FW in the cingulum, uncinate, and fornix, and
higher FAFWcorr in the uncinate compared to Black-ε4+-8523-S/S carriers. White-ε3/ε3-8523-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-8523-S carriers.
Conclusion: This is the first study examining APOE-TOMM40-8523 on WMM in Black participants, and the first to
use FW-corrected metrics. Results support that 8523-S is deleterious in White-ε3/ε3 carriers but protective in
Black-ε4+ carriers, indicating a differential effect of APOE on brain integrity by racialized background.
HAI2025 - 330
