This study revealed the spatial heterogeneity and differential pathological mechanisms of WMH through imaging subtype analysis: Although both PWMH and DWMH are driven by baseline factors such as age and hypertension, their risk profiles exhibit significant differences—PWMH is more prominently associated with coronary heart disease and renal dysfunction, while DWMH is independently driven by metabolic-microvascular interactive factors including smoking, diabetes mellitus, and abnormal β2-microglobulin. Here, HLA-G is linked to diabetes mellitus.