Abstract

Abstract INTRODUCTION White matter hyperintensities (WMHs) are a robust marker of brain aging and dementia risk, typically attributed to vascular pathology. However, impaired astrocytic support may also contribute. The locus coeruleus (LC), which degenerates early in aging and Alzheimer's disease, provides widespread noradrenergic projections that regulate astrocytic metabolism via β2‐adrenergic signaling. METHODS In a healthy aging cohort (N = 106), we quantified LC volume, WMHs, and voxel‐wise (q‐WMHs). Associations were tested, controlling for age, cardiovascular risk, and other subcortical nuclei. Spatial partial least squares regression related q‐WMH patterns to LC volume, age, and cortical adrenergic receptor expression. RESULTS LC volume was independently associated with WMH burden and mediated age‐related WMH increases. A latent q‐WMH pattern aligned with cortical β2‐adrenergic receptor expression and mediated its association with WMH burden. DISCUSSION LC degeneration may contribute to regional WMH vulnerability through noradrenergic mechanisms consistent with astrocytic β2‐adrenergic signaling, highlighting a potential nonvascular pathway influencing white matter integrity. Highlights Locus coeruleus (LC) atrophy predicts white matter hyperintensity (WMH) burden in aging. LC atrophy partially mediates the association between age and WMH burden. WMH spatial patterns align with cortical β2‐adrenergic receptor (ADRB2) expression gradients. LC atrophy increases coupling between WMH distribution and ADRB2 expression maps. Findings support a spatial vulnerability gradient linked to noradrenergic regulation of white matter.