Lorenz, Anna S.; Sathe, Aditi; Yang, Yisu; Durant, Alaina; Wu, Yiyang; Kim, Michael E.; Gao, Chenyu; Newlin, Nancy R.; Ramadass, Karthik; Kanakaraj, Praitayini; Khairi, Nazirah Mohd; Li, Zhiyuan; Yao, Tianyuan; Huo, Yuankai; Dumitrescu, Logan; Shashikumar, Niranjana; Pechman, Kimberly R.; Risacher, Shannon L.; Beason-Held, Lori L.; An, Yang; Arfanakis, Konstantinos; Erus, Guray; Davatzikos, Christos; Habes, Mohamad; Wang, Di; Tosun, Duygu; Toga, Arthur W.; Thompson, Paul M.; Mormino, Elizabeth C.; Zhang, Panpan; Schilling, Kurt; Albert, Marilyn; Kukull, Walter; Biber, Sarah A.; Landman, Bennett A.; Johnson, Sterling C.; Bendlin, Barbara; Schneider, Julie; Bennett, David A.; Jefferson, Angela L.; Resnick, Susan M.; Saykin, Andrew J.; Below, Jennifer E.; Hohman, Timothy J.; Archer, Derek B. (2026).听.听Alzheimer’s & Dementia, 22(7), e71630.听
Changes in the brain’s聽limbic white matter鈥攖he nerve fiber pathways involved in memory, learning, and emotion鈥攁re common in aging and聽Alzheimer’s disease (AD), but the genetic factors that influence these changes are not well understood. This study analyzed brain imaging and genetic data from 2,614 older adults across seven research cohorts, including many participants with cognitive impairment. The researchers found that differences in limbic white matter structure are strongly influenced by genetics and identified six regions of the genome associated with these brain changes. One of the strongest signals involved聽CDH19, a gene linked to聽oligodendrocytes, the cells responsible for producing myelin, the protective coating that surrounds nerve fibers. Several other genes, including聽RORA,听FAM107B, and聽KC6, were also associated with cognitive performance and the brain changes seen in Alzheimer’s disease. The findings further suggest that biological pathways related to insulin signaling, immune function, and cardiovascular health may contribute to white matter changes during aging. Overall, the study provides new evidence that the structure of limbic white matter is influenced by genetics and identifies several genes and biological pathways that may play a role in Alzheimer’s disease and age-related cognitive decline.
FIGURE 1
SNP heritability estimates for limbic white matter (WM) microstructure. SNP heritability of 35 FW-corrected dMRI metrics from seven WM tracts in the limbic system. Abbreviations: AxD, axial diffusivity; dMRI, diffusion magnetic resonance imaging; FA, fractional anisotropy; FWcorr, free-water corrected; MD, mean diffusivity; RD, radial diffusivity; WM, white matter.