White matter hyperintensities are associated with locus coeruleus atrophy and astrocytic β 2 -adrenergic receptor expression.

Abstract

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 β 2 -adrenergic signaling. 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. LC volume was independently associated with WMH burden and mediated age-related WMH increases. A latent q-WMH pattern aligned with cortical β 2 -adrenergic receptor expression and mediated its association with WMH burden. LC degeneration may contribute to regional WMH vulnerability through noradrenergic mechanisms consistent with astrocytic β 2 -adrenergic signaling, highlighting a potential nonvascular pathway influencing white matter integrity.