Structured 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 (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status.
RESULTS Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr 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.
Highlights
Sex, race, and APOE-ε4 carrier status relate to white matter microstructural integrity
Females generally have lower FAFWcorr compared to males
Non-Hispanic Black adults generally have lower FAFWcorr than non-Hispanic White adults
APOE-ε4 carriers tended to have higher FW than non-carriers
Systematic Review The authors used PubMed and Google Scholar to review literature that used conventional and free-water (FW)-corrected microstructural metrics to evaluate sex, race, and APOE-ε4 differences in white matter microstructure. While studies have previously explored differences by sex and APOE-ε4 status, less is known about racial differences and no large-scale FW-corrected analysis has been performed.
Interpretation Sex and race were more associated with FAFWcorr while APOE-ε4 status was associated with FW metrics. Association, projection, limbic, and occipital transcallosal tracts showed the greatest differences.
Future Direction Future studies to determine the biological and social pathways that lead to sex, racial, and APOE-ε4 differences are warranted.
Consent Statement All participants provided informed consent in their respective cohort studies.
Competing 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.
Footnotes
Conflicts of Interest and Disclosure 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.
Funding Acknowledgements: This study was supported by several funding sources, including K01-EB032898 (KGS), R01-EB017230 (BAL) K01-AG073584 (DBA), U24-AG074855 (TJH), 75N95D22P00141 (TJH), R01-AG059716 (TJH), UL1-TR000445 and UL1-TR002243 (Vanderbilt Clinical Translational Science Award), S10-OD023680 (Vanderbilt’s High-Performance Computer Cluster for Biomedical Research). The research was support in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Study data were obtained from the Vanderbilt Memory and Aging Project (VMAP). VMAP data were collected by Vanderbilt Memory and Alzheimer’s Center Investigators at Vanderbilt University Medical Center. This work was supported by NIA grants R01-AG034962 (PI: Jefferson), R01-AG056534 (PI: Jefferson), R01-AG062826 (PI: Gifford), U19-AG03655 (PI:Albert) and Alzheimer’s Association IIRG-08-88733 (PI: Jefferson). The data contributed from the Wisconsin Registry for Alzheimer’s Prevention was supported by NIA AG021155, AG0271761, AG037639, and AG054047. The BLSA is supported by the Intramural Research Program of the National Institutes of Health, National Institute on AgingThis research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Data collection and sharing for this project was funded (in part) by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Additional acknowledgments include the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS, U24AG041689) at the University of Pennsylvania, funded by NIA. Data contributed from MAP/ROS/MARS was supported by NIA R01AG017917, P30AG10161, P30AG072975, R01AG022018, R01AG056405, UH2NS100599, UH3NS100599, R01AG064233, R01AG15819 and R01AG067482, and the Illinois Department of Public Health (Alzheimer’s Disease Research Fund). Data can be accessed at www.radc.rush.edu. The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADCs : P50 AG005131 (PI James Brewer, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P50 AG005138 (PI Mary Sano, PhD), P50 AG005142 (PI Helena Chui, MD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005681 (PI John Morris, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG008051 (PI Thomas Wisniewski, MD), P50 AG008702 (PI Scott Small, MD), P30 AG010124 (PI John Trojanowski, MD, PhD), P30 AG010129 (PI Charles DeCarli, MD), P30 AG010133 (PI Andrew Saykin, PsyD), P30 AG010161 (PI David Bennett, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG013854 (PI Robert Vassar, PhD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P30 AG019610 (PI Eric Reiman, MD), P50 AG023501 (PI Bruce Miller, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 (PI Linda Van Eldik, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), P30 AG035982 (PI Russell Swerdlow, MD), P50 AG047266 (PI Todd Golde, MD, PhD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG049638 (PI Suzanne Craft, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P20 AG068024 (PI Erik Roberson, MD, PhD), P20 AG068053 (PI Marwan Sabbagh, MD), P20 AG068077 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD). NACC data can be accessed at naccdata.org.
