Peter, Christopher, Sathe, Aditi, Shashikumar, Niranjana, Pechman, Kimberly R., Workmeister, Abigail W., Jackson, T. Bryan, Huo, Yuankai, Mukherjee, Shubhabrata, Mez, Jesse, Dumitrescu, Logan C., Gifford, Katherine A., Bolton, Corey J., Gaynor, Leslie S., Risacher, Shannon L., Beason-Held, Lori L., An, Yang, Arfanakis, Konstantinos, Erus, Guray, Davatzikos, Christos, Tosun-Turgut, Duygu, Habes, Mohamad, Wang, Di, Toga, Arthur W., Thompson, Paul M., Zhang, Panpan, Schilling, Kurt G., Albert, Marilyn, Kukull, Walter, Biber, Sarah A., Landman, Bennett A., Bendlin, Barbara B., Johnson, Sterling C., Schneider, Julie, Barnes, Lisa L., Bennett, David A., Jefferson, Angela L., Resnick, Susan M., Saykin, Andrew J., Crane, Paul K., Cuccaro, Michael L., Hohman, Timothy J., Archer, Derek B., Zaras, Dimitrios, Yang, Yisu, Durant, Alaina, Kanakaraj, Praitayini, Kim, Michael E., Gao, Chenyu, Newlin, Nancy R., Ramadass, Karthik, Khairi, Nazirah Mohd, Li, Zhiyuan, Yao, Tianyuan, Choi, Seo-Eun, Klinedinst, Brandon, Lee, Michael L., Scollard, Phoebe, Trittschuh, Emily H., & Sanders, Elizabeth A. (2025). *JAMA Neurology.*
Understanding how the brain changes as we age鈥攅specially in conditions like Alzheimer鈥檚 disease鈥攊s an important area of research. One part of the brain that hasn鈥檛 been studied as much is the white matter, which acts like a network of 鈥渨ires鈥� connecting different brain areas. This large study looked at how the structure of white matter relates to thinking and memory skills in older adults, including those with Alzheimer鈥檚.
Researchers analyzed data from 9 separate studies, including nearly 4,500 adults aged 50 and older. Participants had brain scans using a technique called diffusion MRI (dMRI), along with memory and thinking tests over time. Most participants were cognitively healthy, while some had mild memory problems or Alzheimer鈥檚 dementia. The study focused on a specific feature of white matter called “free water” (FW), which can indicate damage or degeneration.
They found that higher levels of FW in white matter鈥攅specially in regions connected to memory like the cingulum and fornix鈥攚ere strongly linked to worse memory and faster cognitive decline. These changes were even more noticeable in people who had other signs of Alzheimer鈥檚, such as brain shrinkage, a genetic risk factor called APOE 蔚4, or positive tests for amyloid buildup (a hallmark of Alzheimer鈥檚).
Overall, the study shows that changes in white matter鈥攑articularly FW鈥攁re an important piece of the puzzle in understanding memory loss and aging. These findings suggest that future brain studies should pay close attention to FW and highlight the importance of brain regions like the cingulum and fornix in Alzheimer鈥檚-related decline.
Figure 1. 聽Cohort Characteristics and Data Harmonization
A, Participants were drawn from 9 well-established cohorts, including 3213 cognitively unimpaired (CU) individuals, 972 with mild cognitive impairment (MCI), and 282 with Alzheimer disease (AD) at baseline. B, The study also incorporated longitudinal data across 9208 cognitive sessions, spanning up to 13 years of follow-up. Longitudinal ComBat harmonization was applied to all imaging features to account for variability across imaging batches. C and D, Associations are shown between cingulum free-water (FW) and memory performance, using both raw (C) and harmonized (D) FW data, with points and lines color coded by imaging batch. Harmonized data were used across all analyses. ADNI indicates Alzheimer鈥檚 Disease Neuroimaging Initiative; BIOCARD, Biomarkers of Cognitive Decline Among Normal Adults; BLSA, Baltimore Longitudinal Study of Aging; MAP, Rush Memory and Aging Project; MARS, Minority Aging Research Study; NACC, National Alzheimer鈥檚 Coordinating Center; ROS, Religious Orders Study; VMAP, 91吃瓜网 Memory and Aging Project; WRAP, Wisconsin Registry for Alzheimer鈥檚 Prevention.
