Purpose <p>White matter hyperintensities (WMHs) are commonly observed in aging and neurodegenerative diseases, but their impact on the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) system remains unclear. This study investigates the relationship between WMHs and gray matter nicotinic signaling, aiming to elucidate potential pathways contributing to neurodegeneration.</p> Methods <p>Multimodal imaging data using PET and MR imaging from 39 participants, including 19 healthy controls and 20 patients with Alzheimer’s disease dementia (AD), were analyzed. WMHs were identified on T1-weighted MPRAGE and T2-weighted TSE MR images using advanced segmentation algorithms. Probabilistic fiber tracking was applied to determine WMH-connected gray matter. PET-based total distribution volume (<i>V</i>_T) values of the α4β2-nAChR tracer (-)-[¹⁸F]Flubatine were compared between WMH-affected and unaffected gray matter regions.</p> Results <p>WMH volumes were significantly correlated with age, Fazekas and MMSE scores, but no differences in absolute or relative WMH volumes were observed between healthy controls and patients with AD. PET-based <i>V</i>_T values in WMH-connected gray matter showed no significant difference from contralateral unaffected regions, regardless of disease status or WMH burden. However, intra-individual differences in <i>V</i>_T values correlated with Fazekas scores, presumably driven by patients with AD. Pathway-based analyses revealed decreased <i>V</i>_T values in the medial cholinergic pathway of patients with AD but no significant differences in lateral pathways.</p> Conclusion <p>This study shows that WMHs do not significantly alter gray matter nicotinic signaling in directly connected regions. However, the results suggest subtle associations between WMH severity and specific cholinergic pathways, particularly in AD.</p>