Objectives: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH). Methods: MRI scans of 1836 participants (median age 52.2±13.16) encompassing a wide age range (22–84 years) from the cross-sectional Study of Health in Pomerania (SHIP, Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8±10.2, with 747 observations) from the Baltimore Longitudinal Study of Aging (BLSA, USA) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer’s disease (AD) genetics and cognition were then investigated using linear regression. Results: WMH were found to occur non-uniformly, with higher frequency within spatially heterogeneous patterns encoded by four components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the 5th decade of life, whereas the other components appeared later in life during the 6th decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in elderly. Cognitive decline was associated with the dorsal component. Conclusions: These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiological mechanisms, and possibly with a differential link to vascular and neurodegenerative changes.