. 2025 Jan;21(1):e14343.

doi: 10.1002/alz.14343. Epub 2024 Dec 22.

Sex 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 E 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, Mohamad Habes²¹, Di Wang²¹, Panpan Zhang^{1

22}, Kurt Schilling^{23

24}; Alzheimer's Disease Neuroimaging Initiative (ADNI); BIOCARD Study Team; Alzheimer's Disease Sequencing Project (ADSP); Marilyn Albert²⁵, Walter Kukull²⁶, Sarah A Biber²⁶, Bennett A Landman^{2

4

5

7

23

24

27}, Sterling C Johnson^{28

29}, 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, Tennessee, USA.
² Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Department of Integrative Biology and Physiology, University of California, Los Angeles, California, USA.
⁴ Department of Computer Science, Vanderbilt University, Nashville, Tennessee, USA.
⁵ Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee, USA.
⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁷ Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Center for Cognitive Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁹ Veteran's Affairs, Geriatric Research, Education and Clinical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
¹⁰ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹¹ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹² Laboratory for Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
¹³ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.
¹⁴ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁵ Department of Diagnostic Radiology, Rush University Medical Center, Chicago, Illinois, USA.
¹⁶ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁷ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.
¹⁸ Laboratory of Neuroimaging, USC Stevens Institute of Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
²⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
²¹ Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
²² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²³ Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁴ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁵ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
²⁶ National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.
²⁷ Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
²⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
²⁹ Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

PMID: 39711105
PMCID: PMC11781133
DOI: 10.1002/alz.14343

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

Amalia Peterson et al. Alzheimers Dement. 2025 Jan.

. 2025 Jan;21(1):e14343.

doi: 10.1002/alz.14343. Epub 2024 Dec 22.

Authors

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
² Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Department of Integrative Biology and Physiology, University of California, Los Angeles, California, USA.
⁴ Department of Computer Science, Vanderbilt University, Nashville, Tennessee, USA.
⁵ Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee, USA.
⁶ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁷ Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁸ Department of Psychiatry and Behavioral Sciences, Center for Cognitive Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁹ Veteran's Affairs, Geriatric Research, Education and Clinical Center, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
¹⁰ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹¹ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹² Laboratory for Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
¹³ Department of Biomedical Engineering, Illinois Institute of Technology, Chicago, Illinois, USA.
¹⁴ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁵ Department of Diagnostic Radiology, Rush University Medical Center, Chicago, Illinois, USA.
¹⁶ Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁷ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.
¹⁸ Laboratory of Neuroimaging, USC Stevens Institute of Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
¹⁹ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
²⁰ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
²¹ Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
²² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²³ Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁴ Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁵ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
²⁶ National Alzheimer's Coordinating Center, University of Washington, Seattle, Washington, USA.
²⁷ Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.
²⁸ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
²⁹ Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

PMID: 39711105
PMCID: PMC11781133
DOI: 10.1002/alz.14343

Abstract

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

Methods: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FA_FWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status.

Results: Sex 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 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.

Highlights: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.

Keywords: Alzheimer's disease; aging; sex differences; white matter disease.

PubMed Disclaimer

Conflict of interest statement

S.C.J. has served on advisory boards for Enigma Biomedical and ALZPath in the past 2 years. A.J.S. 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. B.A.L. serves as editor in chief of SPIE Journal of Medical Imaging. L.L.B. serves as deputy editor of Alzheimer's & Dementia. A.L.J. serves on the NINDS DIVERSE VCID and NINDS RECOVERY observational study monitoring boards. She serves on the scientific advisory committee for the Paul B. Beeson Emerging Leaders Career Development Program, American Federation for Aging Research. She serves on the Clin‐STAR Coordinating Center External Advisory Committee, the external advisory board for the Kansas Alzheimer's Disease Core Center, and the Alzheimer's Disease and Related Dementia Advisory Council. A.W.T. serves on the RHU‐SHIVA data safety monitoring board and the ADNI Steering Committee and Executive Committee and is a member of the World Dementia Council and the Alzheimer's Disease Initiative Global Technical Advisory Committee. T.J.H. serves on the scientific advisory board for Vivid Genomics. He serves as Alzheimer's & Dementia: TRCI deputy editor and the Alzheimer's & Dementia senior associate editor. J.E.W. received financial support from IONIS pharmaceuticals. A.P., A.S., D.Z., Y.Y., A.D., K.D.D., N.S., K.R.P., M.E.K., C.G., N.M.K., Z.L., T.Y., Y.K., L.D., K.A.G., F.E.C., S.L.R., L.L.B.H., Y.A., K.A., G.E., C.D., D.T., P.M.T., E.C.M., M.H., D.W., P.Z., K.S., M.A., W.K., S.A.B., J.S., D.A.B., S.M.R., D.B.A., ADNI, BIOCARD, and ADSP have no conflicts to disclose. The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

**FIGURE 1**
Forty‐eight white matter tractography templates were used in the present study, and can be grouped into TC (A), association (B), projection (C), and limbic tracts (D). IFG, inferior frontal gyrus; IFOF, inferior fronto‐occipital fasciculus; ILF, inferior longitudinal fasciculus; IPL, inferior parietal lobe; M1, primary motor cortex; PMd, dorsal premotor; PMv, ventral premotor; S1, primary somatosensory cortex; SLF, superior longitudinal fasciculus; SLF‐TP, temporoparietal superior longitudinal fasciculus; SMA, supplementary motor area; SPL, superior parietal lobe; TC, transcallosal; UF, uncinate fasciculus.

**FIGURE 2**
The main effects of sex and *APOE* ε4 on change in white matter microstructure. Linear mixed effects regression was conducted to determine the association of sex 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 sex and *APOE* ε4 associations for both measures are illustrated with spaghetti plots. *Tracts surviving correction for multiple comparisons. *APOE*, apolipoprotein E; CC, corpus callosum; FA_FWcorr, free water‐corrected fractional anisotropy; FW, free water; IFG, inferior frontal gyrus; IFOF, inferior fronto‐occipital fasciculus; ILF, inferior longitudinal fasciculus; IPL, inferior parietal lobe; M1, primary motor cortex; PMd, dorsal premotor; PMv, ventral premotor; S1, primary somatosensory cortex; SLF, superior longitudinal fasciculus; SLF‐TP, temporoparietal superior longitudinal fasciculus; SMA, supplementary motor area; SPL, superior parietal lobe; TC, transcallosal; UF, uncinate fasciculus.

**FIGURE 3**
Aggregated tract‐type associations with changes in white matter microstructure. z values of individual tracts were grouped into the following tract types: association, limbic, projection, prefrontal TC, motor TC, parietal TC, and occipital TC for FA_FWcorr (A) and FW (B). The left, middle, and right columns display the sex main effect (red), *APOE* ε4 main effect (blue), and sex × *APOE* ε4 interaction (orange), respectively. *APOE*, apolipoprotein E; FA_FWcorr, free water–corrected fractional anisotropy; FW, free water; TC, transcallosal.

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Update of

Sex, racial, 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, Khairi NM, Li Z, Yao T, Huo Y, Dumitrescu L, Gifford KA, Wilson JE, Cambronero F, Risacher SL, Beason-Held LL, An Y, Arfanakis K, Erus G, Davatzikos C, Tosun D, Toga AW, Thompson PM, Mormino EC, 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. bioRxiv [Preprint]. 2024 Jun 12:2024.06.10.598357. doi: 10.1101/2024.06.10.598357. bioRxiv. 2024. Update in: Alzheimers Dement. 2025 Jan;21(1):e14343. doi: 10.1002/alz.14343. PMID: 38915636 Free PMC article. Updated. Preprint.

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References

1. Sachdev PS, Zhuang L, Braidy N, Wen W. Is Alzheimer's a disease of the white matter?. Curr Opin Psychiatry. 2013;26:244‐251. - PubMed
1. Ihara M, Polvikoski TM, Hall R, et al. Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with lewy bodies. Acta Neuropathol. 2010;119:579‐589. - PMC - PubMed
1. Simpson JE, Ince PG, Higham CE, et al. Microglial activation in white matter lesions and nonlesional white matter of ageing brains. Neuropathol Appl Neurobiol. 2007;33:670‐683. - PubMed
1. Lee S, Viqar F, Zimmerman ME, et al. White matter hyperintensities are a core feature of Alzheimer's disease: evidence from the dominantly inherited Alzheimer network. Ann Neurol. 2016;79:929‐939. - PMC - PubMed
1. Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795‐804. - PMC - PubMed

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

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

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