Sex, racial, andAPOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer’s disease
Authors: Peterson Amalia , Sathe Aditi , Zaras Dimitrios , Yang Yisu , Durant Alaina , Deters Kacie D. , Shashikumar Niranjana , Pechman Kimberly R. , Kim Michael E. , Gao Chenyu , Khairi Nazirah Mohd , Li Zhiyuan , Yao Tianyuan , Huo Yuankai , Dumitrescu Logan , Gifford Katherine A. , Wilson Jo Ellen , Cambronero Francis , Risacher Shannon L. , Beason-Held Lori L. , An Yang , Arfanakis Konstantinos , Erus Guray , Davatzikos Christos , Tosun Duygu , Toga Arthur W. , Thompson Paul M. , Mormino Elizabeth C. , Zhang Panpan , Schilling Kurt ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI),   The BIOCARD Study Team,   The Alzheimer’s Disease Sequencing Project (ADSP), Albert Marilyn , Kukull Walter , Biber Sarah A. , Landman Bennett A. , Johnson Sterling C. , Schneider Julie , Barnes Lisa L. , Bennett David A. , Jefferson Angela L. , Resnick Susan M. , Saykin Andrew J. , Hohman Timothy J. , Archer Derek B. 
Published: June 2024

Structured AbstractINTRODUCTIONThe effects of sex, race, and Apolipoprotein E (APOE) – Alzheimer’s disease (AD) risk factors – on white matter integrity are not well characterized.METHODSDiffusion 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, andAPOE-ε4 carrier status.RESULTSSex differences in FAFWcorrin association and projection tracts, racial differences in FAFWcorrin projection tracts, andAPOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced.DISCUSSIONThere are prominent differences in white matter microstructure by sex, race, andAPOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.HighlightsSex, race, andAPOE-ε4 carrier status relate to white matter microstructural integrityFemales generally have lower FAFWcorrcompared to malesNon-Hispanic Black adults generally have lower FAFWcorrthan non-Hispanic White adultsAPOE-ε4 carriers tended to have higher FW than non-carriersResearch in ContextSystematic ReviewThe authors used PubMed and Google Scholar to review literature that used conventional and free-water (FW)-corrected microstructural metrics to evaluate sex, race, andAPOE-ε4 differences in white matter microstructure. While studies have previously explored differences by sex andAPOE-ε4 status, less is known about racial differences and no large-scale FW-corrected analysis has been performed.InterpretationSex and race were more associated with FAFWcorrwhileAPOE-ε4 status was associated with FW metrics. Association, projection, limbic, and occipital transcallosal tracts showed the greatest differences.Future DirectionFuture studies to determine the biological and social pathways that lead to sex, racial, andAPOE-ε4 differences are warranted.Consent StatementAll participants provided informed consent in their respective cohort studies.