Lesion-Level Subtypes of White Matter Hyperintensity Evolution Beyond Spatial Location

BACKGROUND AND OBJECTIVES: White matter hyperintensities (WMHs) are common neuroimaging markers of cerebrovascular pathology in aging and neurodegeneration. Despite their clinical relevance, WMH are typically quantified using global burden measures that assume a relatively homogeneous pathologic process. However, growing evidence suggests substantial biological heterogeneity across lesions. We aimed to identify lesion-level WMH subtypes beyond anatomic location and evaluate their associations with neurodegeneration and vascular risk. METHODS: We conducted a longitudinal observational study analyzing 3224 MRI scans from 403 participants spanning cognitively normal aging, mild cognitive impairment, Alzheimer, and Parkinson disease. Imaging at baseline and 2-year follow-up included structural, diffusion, and resting-state MRI. A total of 2107 WMH lesions were identified, and lesion-wise longitudinal changes were used to derive subtypes using unsupervised clustering. Associations with neurodegeneration and vascular risk factors were assessed using multivariable models with false discovery rate correction. RESULTS: lesion burden. Clustering robustness was supported by sensitivity analyses excluding anatomical location and by external validation in an independent cohort reproducing the main atrophy-related findings. DISCUSSION: WMH are not a homogeneous entity but comprise biologically distinct lesion subtypes with differential neurobiological and clinical significance. Lesion composition may therefore offer a more informative framework than global WMH burden for understanding cerebrovascular contributions to aging and neurodegeneration, with potential implications for risk stratification, clinical interpretation, and targeted interventions.