White matter microstructure and macrostructure brain charts across the human lifespan

Abstract Normative reference charts are widely used in healthcare, especially for assessing the development of individuals by benchmarking anatomic and physiological features against population trajectories across the lifespan. Recent work has extended this concept to gray matter morphology in the brain, but no such reference framework currently exists for white matter (WM) even though WM constitutes the essential substrate for neuronal communication and large-scale network integration. Here, we present the first comprehensive WM brain charts, which describe how microstructural and macrostructural features of WM evolve across the lifespan, by leveraging over 35,120 diffusion MRI scans from 50 harmonized studies. Using generalized additive models for location, scale, and shape (GAMLSS), we estimate age- and sex-stratified trajectories for 72 individual white matter pathways, quantifying both tract-specific microstructural and morphometric features. We demonstrate that these WM brain charts enable four important applications: (1) defining normative trajectories of WM maturation and decline across distinct pathways, (2) identifying previously uncharacterized developmental milestones and spatial gradients of tract maturation, (3) detecting individualized deviations from normative patterns with clinical relevance across multiple neurological disorders, and (4) facilitating standardized, cross-study centile scoring of new datasets. By establishing a unified, interpretable reference framework for WM structure, these brain charts provide a foundational metric for research and clinical neuroscience. The accompanying open-access trajectories, centile scoring tools, and harmonization methods facilitate precise mapping of WM development, aging, and pathology across diverse populations. We release the brain charts and provide an out-of-sample alignment process as a Docker image: https://zenodo.org/records/17561821. Competing Interest Statement T.J.H: In addition to having grants from the NIH, serves on the scientific advisory board for Vivid Genomics. Serves as a consultant for Circular Genomics. Serves as Deputy Editor of Alzheimers & Dementia: Translational Research and Clinical Intervention. Serves as Senior Associate Editor for Alzheimers and Dementia. S.M.R: Is an employee of the Intramural Research Program of the NIA/NIH. As such, the BLSA studies and investigators are funded by the NIA. K.L.H: Participated in the Federation of Associations in Behavioral & Brain Sciences Hill Day in May 2025, meeting with congressional representatives to advocate for continued National Science Foundation (NSF) funding as part of the Coalition for National Science Funding efforts celebrating 75 years of NSF support. A.L.J: In addition to having grants from the NIH, serves as a member of the advisory board for Lantheus - Diagnostic and Therapeutic Innovations, Billerica, MA. Serves as Chair of the Observational Study Monitoring Board, Diverse-VCID: White Matter Lesion Etiology of Dementia in Diverse Populations (Diverse VCID) Study, Bethesda, MD. Member of the Observational Study Monitoring Board, Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery (DISCOVERY) Study, Bethesda, MD. Member of the External Advisory Board, Kansas Alzheimers Disease Core Center (P30), Kansas City, KS. Member of the Scientific Advisory Committee for Paul B. Beeson Emerging Leaders Career Development Program, John A. Hartford Foundation and American Federations for Aging Research, New York, NY. Member of the External Advisory Committee for the Clin-STAR Coordinating Center, American Federation for Aging Research, New York, NY. Member of the Alzheimers Disease and Related Dementia Advisory Council, State of Tennessee. All other authors declare no competing interests. Footnotes ↵A HABS-HD MPIs: Sid E O’Bryant, Kristine Yaffe, Arthur Toga, Robert Rissman, & Leigh Johnson; and the HABS-HD Investigators: Meredith Braskie, Kevin King, James R Hall, Melissa Petersen, Raymond Palmer, Robert Barber, Yonggang Shi, Fan Zhang, Rajesh Nandy, Roderick McColl, David Mason, Bradley Christian, Nicole Phillips, Stephanie Large, Joe Lee, Badri Vardarajan, Monica Rivera Mindt, Amrita Cheema, Lisa Barnes, Mark Mapstone, Annie Cohen, Amy Kind, Ozioma Okonkwo, Raul Vintimilla, Zhengyang Zhou, Michael Donohue, Rema Raman, Matthew Borzage, Michelle Mielke, Beau Ances, Ganesh Babulal, Jorge Llibre-Guerra, Carl Hill and Rocky Vig. ↵B Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf ↵C Data used in preparation of this article were derived from BIOCARD study, supported by grant U19 – AG033655 from the National Institute on Aging. The BIOCARD study team did not participate in the analysis or writing of this report, however, they contributed to the design and implementation of the study. A listing of BIOCARD investigators can be found on the BIOCARD website (on the ‘BIOCARD Data Access Procedures’ page, ‘Acknowledgement Agreement’ document). Additional analyses (both in main text and supplemental); inclusion of more data. All figures are updated and revised. Additional authors added who contributed to the revised manuscript.