White Matter Abnormalities and Cognition in Aging and Alzheimer Disease
Christopher Peter, Aditi Sathe, Niranjana Shashikumar, Kimberly R. Pechman, Abigail W. Workmeister, T. Bryan Jackson, Yuankai Huo, Shubhabrata Mukherjee, Jesse Mez, Logan Dumitrescu, Katherine A. Gifford, Corey J. Bolton, Leslie S. Gaynor, Shannon L. Risacher, Lori L. Beason‐Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Duygu Tosun, Mohamad Habes, Di Wang, Arthur W. Toga, Paul M. Thompson, Panpan Zhang, Kurt G. Schilling, Marilyn Albert, Walter A. Kukull, Sarah Biber, Bennett A. Landman, Barbara B. Bendlin, Sterling C. Johnson, Julie A. Schneider, Lisa L. Barnes, David A. Bennett, Angela L. Jefferson, Susan M. Resnick, Andrew J. Saykin, Paul K. Crane, Michael L. Cuccaro, Timothy J. Hohman, Derek B. Archer, Olusegun Adegoke, Paul Aisen, Liana G. Apostolova, Miriam T. Ashford, Lisa Barnes, Laurel Beckett, Marie Bernard, Haley Bernhardt, Bret Borowski, Yuliana Cabrera, N. J. Cairns, Marı́a C. Carrillo, Kewei Chen, Mark Choe, Taylor Clanton, Godfrey Coker, Cat Conti, Karen Crawford, Sandhitsu R. Das, Charles DeCarli, Michael Donohue, Kelley Faber, Adam J. Fleisher, Derek Flenneiken, Evan Fletcher, Juliet Fockler, Arvin Forghanian-Arani, Tatiana M. Foroud, Nick C. Fox, Erin Franklin, Devon Gessert, Héctor Alfredo Baptista González, Robert C. Green, Jeffery Gunter, Danielle Harvey, Lindsey Hergesheimer, Carole Ho, Erin Householder, John K. Hsaio, Clifford R. Jack, Jonathan Jackson, William Jagust, Neda Jahanshad, Gustavo Jimenez‐Maggiora, Chengshu Jin, David Jones, Kejal Kantarci, Zaven S. Khachaturian, Alexander Knaack, Robert A. Koeppe, Adrienne Kormos, Susan Landau, Payam Mahboubi, Ian B. Malone, Eliezer Masliah, Donna Masterman, Chet Mathis, Garrett Miller
Abstract
Importance There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD). Objective To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment. Design, Setting, and Participants This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022. Participants were eligible if they had diffusion-weighted magnetic resonance imaging (dMRI) data, domain-specific cognitive composite z scores, demographic and clinical data, were aged 50 years or older, and passed neuroimaging quality control. Demographic and clinical covariates included age, sex, education, race and ethnicity, APOE haplotype status (ε2, ε3, ε4), and clinical status. The present study was conducted from June 2024 to February 2025. Exposures White matter microstructure and cognitive performance and decline. Main Outcomes and Measures Clinical diagnosis, imaging measures (dMRI, T1-weighted MRI, and amyloid and tau positron emission tomography), and cognitive tests. Results Of 4467 participants who underwent 9208 longitudinal cognitive sessions, 2698 (60.4%) were female, and the mean age (SD) was 74.3 (9.2) years; 3213 were cognitively unimpaired, 972 had mild cognitive impairment, and 282 had AD dementia. White matter free water (FW) showed the strongest associations with cross-sectional cognitive performance and longitudinal cognitive decline across all domains, particularly memory. FW in limbic tracts, such as the cingulum, presented the strongest associations with both memory performance (cingulum: β = −0.718; P < .001; fornix: β = −1.069; P < .001) and decline (cingulum: β = −0.115; P < .001; fornix: β = −0.153; P < .001). White matter FW measures interacted with baseline diagnosis, gray matter atrophy, APOE ε4 status, and amyloid positivity to predict poorer cognitive performance and accelerated cognitive decline. Noteworthy interactions include fornix FW and hippocampal volume (β = 10.598; P < .001), cingulum FW and SPARE-AD index (β = −0.532; P < .001), and inferior temporal gyrus transcallosal tract FW and baseline diagnosis (β = −0.537; P < .001), all predicting poorer memory performance. Conclusions and Relevance White matter microstructural changes, particularly FW, play a critical role in cognitive decline in aging and AD-related cognitive impairment. These findings highlight the importance of FW correction in dMRI studies and highlight the limbic system, especially the cingulum and fornix, as key regions associated with cognitive decline; the interaction models highlight that integrating FW-corrected metrics with other AD biomarkers may further elucidate the biological mechanisms of neurodegeneration in aging.