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 – Three lesion subtypes (L₁–L₃) were identified, frequently coexisting within the same individual. L₁ lesions were the most prevalent (48.1%), predominated in cognitively normal individuals, and exhibited relatively stable trajectories without association with brain atrophy. L₂ lesions represented a less frequent (11.3%) unstable subtype associated with weight gain (odds ratio [OR] 1.33, 95% CI 1.22–1.45; p_FDR ≤ 0.001), suggesting metabolic vulnerability. L₃ lesions (40.6%) represented an unstable subtype associated with brain atrophy (β = −0.11, 95% CI −0.16 to −0.05; p_FDR < 0.001), older age (OR 1.15, 95% CI 1.07–1.23; p_FDR < 0.001), and vascular risk reflected by pulse pressure changes (OR 1.09, 95% CI 1.03–1.15; p_FDR = 0.006). Global WMH burden was no longer associated with brain atrophy after accounting for L₃ 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.