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[Preprint]. 2024 Jun 12:2024.06.10.598357.

doi: 10.1101/2024.06.10.598357.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

Amalia Peterson^{1

2}, Aditi Sathe¹, Dimitrios Zaras¹, Yisu Yang¹, Alaina Durant¹, Kacie D Deters³, Niranjana Shashikumar¹, Kimberly R Pechman¹, Michael E Kim⁴, Chenyu Gao⁵, Nazirah Mohd Khairi⁵, Zhiyuan Li⁵, Tianyuan Yao⁴, Yuankai Huo^{4

5}, Logan Dumitrescu^{1

2

6

7}, Katherine A Gifford^{1

2}, Jo Ellen Wilson^{1

8

9}, Francis Cambronero¹, Shannon L Risacher^{10

11}, Lori L Beason-Held¹², Yang An¹², Konstantinos Arfanakis^{13

14

15}, Guray Erus¹⁶, Christos Davatzikos¹⁶, Duygu Tosun¹⁷, Arthur W Toga¹⁸, Paul M Thompson¹⁹, Elizabeth C Mormino²⁰, Panpan Zhang^{1

21}, Kurt Schilling^{22

23}; Alzheimer’s Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer’s Disease Sequencing Project (ADSP); Marilyn Albert²⁴, Walter Kukull²⁵, Sarah A Biber²⁵, Bennett A Landman^{2

4

5

7

22

23

26}, Sterling C Johnson^{27

28}, Julie Schneider¹⁴, Lisa L Barnes¹⁴, David A Bennett¹⁴, Angela L Jefferson^{1

2

4}, Susan M Resnick¹², Andrew J Saykin^{10

11}, Timothy J Hohman^{1

2

6

7}, Derek B Archer^{1

2

6

7}

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN.
² Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.
³ Department of Integrative Biology and Physiology, University of California, Los Angeles.
⁴ Department of Computer Science, Vanderbilt University, Nashville, TN.
⁵ Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN.
⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN.
⁷ Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN.
⁸ Center for Cognitive Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN.
⁹ Veteran's Affairs, Geriatric Research, Education and Clinical Center, Tennessee Valley Healthcare System.
¹⁰ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN.
¹¹ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN.
¹² Laboratory for Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD.
¹³ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL.
¹⁴ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
¹⁵ Department of Diagnostic Radiology, Rush University Medical Center, Chicago, IL.
¹⁶ Department of Radiology, University of Pennsylvania, Philadelphia, PA.
¹⁷ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA.
¹⁸ Laboratory of Neuroimaging, USC Stevens Institute of Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, CA.
²⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA.
²¹ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.
²² Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN2.
²³ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN.
²⁴ Department of Neurology, Johns Hopkins School of Medicine Baltimore, MD.
²⁵ National Alzheimer's Coordinating Center, University of Washington, Seattle, WA.
²⁶ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN.
²⁷ Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI.
²⁸ Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI.

PMID: 38915636
PMCID: PMC11195046
DOI: 10.1101/2024.06.10.598357

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

Amalia Peterson et al. bioRxiv. 2024.

[Preprint]. 2024 Jun 12:2024.06.10.598357.

doi: 10.1101/2024.06.10.598357.

Authors

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, TN.
² Department of Neurology, Vanderbilt University Medical Center, Nashville, TN.
³ Department of Integrative Biology and Physiology, University of California, Los Angeles.
⁴ Department of Computer Science, Vanderbilt University, Nashville, TN.
⁵ Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN.
⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN.
⁷ Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN.
⁸ Center for Cognitive Medicine, Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN.
⁹ Veteran's Affairs, Geriatric Research, Education and Clinical Center, Tennessee Valley Healthcare System.
¹⁰ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN.
¹¹ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, IN.
¹² Laboratory for Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD.
¹³ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, IL.
¹⁴ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL.
¹⁵ Department of Diagnostic Radiology, Rush University Medical Center, Chicago, IL.
¹⁶ Department of Radiology, University of Pennsylvania, Philadelphia, PA.
¹⁷ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA.
¹⁸ Laboratory of Neuroimaging, USC Stevens Institute of Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, CA.
²⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA.
²¹ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN.
²² Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN2.
²³ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN.
²⁴ Department of Neurology, Johns Hopkins School of Medicine Baltimore, MD.
²⁵ National Alzheimer's Coordinating Center, University of Washington, Seattle, WA.
²⁶ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN.
²⁷ Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI.
²⁸ Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin, Madison, WI.

PMID: 38915636
PMCID: PMC11195046
DOI: 10.1101/2024.06.10.598357

Update in

Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.
Peterson A, Sathe A, Zaras D, Yang Y, Durant A, Deters KD, Shashikumar N, Pechman KR, Kim ME, Gao C, Mohd Khairi N, Li Z, Yao T, Huo Y, Dumitrescu L, Gifford KA, Wilson JE, Cambronero FE, Risacher SL, Beason-Held LL, An Y, Arfanakis K, Erus G, Davatzikos C, Tosun D, Toga AW, Thompson PM, Mormino EC, Habes M, Wang D, Zhang P, Schilling K; Alzheimer's Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer's Disease Sequencing Project (ADSP); Albert M, Kukull W, Biber SA, Landman BA, Johnson SC, Schneider J, Barnes LL, Bennett DA, Jefferson AL, Resnick SM, Saykin AJ, Hohman TJ, Archer DB. Peterson A, et al. Alzheimers Dement. 2025 Jan;21(1):e14343. doi: 10.1002/alz.14343. Epub 2024 Dec 22. Alzheimers Dement. 2025. PMID: 39711105 Free PMC article.

Abstract

Introduction: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized.

Methods: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FA_FWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status.

Results: Sex differences in FA_FWcorr in association and projection tracts, racial differences in FA_FWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced.

Discussion: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

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Conflict of interest statement

SCJ has served on advisory boards for Enigma Biomedical and ALZPath in the past two years. AJS receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177, U19 AG074879, and U24 AG074855). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and participated in Scientific Advisory Boards (Bayer Oncology, Eisai, Novo Nordisk, and Siemens Medical Solutions USA, Inc) and an Observational Study Monitoring Board (MESA, NIH NHLBI), as well as External Advisory Committees for multiple NIA grants. He also serves as Editor-in-Chief of Brain Imaging and Behavior, a Springer-Nature Journal.

Figures

**Figure 1.**
Forty-eight white matter tractography templates were used in the present study, and can be grouped into transcallosal (A), association (B), projection (C), and limbic tracts (D).

**Figure 2.**
The main effects of sex, race, and *APOE*-ε4 on change in white matter microstructure. Linear mixed effects regression was conducted to determine the association of sex, race, and *APOE*-ε4 positivity on change in FA_FWcorr (A) and change in FW (B). For both measures, heatmaps are grouped by tract-type and illustrate the test statistic (i.e., z-value) for each independent regression analysis. The top race, sex, and *APOE*-ε4 associations for both measures are illustrated with spaghetti plots.

See this image and copyright information in PMC

References

1. 2023 Alzheimer’s disease facts and figures. Alzheimers Dement 2023;19:1598–695. - PubMed
1. Nebel RA, Aggarwal NT, Barnes LL, et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimers Dement 2018;14:1171–83. - PMC - PubMed
1. Inano S, Takao H, Hayashi N, Abe O, Ohtomo K. Effects of age and gender on white matter integrity. AJNR Am J Neuroradiol 2011;32:2103–9. - PMC - PubMed
1. Cox SR, Ritchie SJ, Tucker-Drob EM, et al. Ageing and brain white matter structure in 3,513 UK Biobank participants. Nat Commun 2016;7:13629. - PMC - PubMed
1. Isaac Tseng WY, Hsu YC, Chen CL, et al. Microstructural differences in white matter tracts across middle to late adulthood: a diffusion MRI study on 7167 UK Biobank participants. Neurobiol Aging 2021;98:160–72. - PubMed

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This is a preprint.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

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Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

Authors

Affiliations

Update in

Abstract

Conflict of interest statement

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References

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