White Matter Hyperintensities Moderates the Association between Diabetes and Non-AD Brain Atrophy

<p dir="ltr">OBJECTIVE: White matter hyperintensities (WMHs) moderates the association between diabetes and cognition, but the underlying mechanisms remain unknown. This study investigated the interaction between diabetes and WMHs on brain atrophy, the resulting atrophy patterns, and whether brain atrophy mediates the effect of diabetes on cognition.</p><p dir="ltr">RESEARCH DESIGN AND METHODS: This study included individuals without dementia from two independent memory clinic-based cohorts, Harmonization (Primary analysis, n=112 diabetes, n=284 controls) and Alzheimer's Disease Neuroimaging Initiative (ADNI; secondary analysis, n=64 diabetes, n=600 controls). Participants underwent longitudinal brain magnetic resonance imaging (MRI) and cognitive assessments, along with plasma pTau181 measurement as a marker of Alzheimer’s Disease (AD). WMHs and brain atrophy were quantified, with Schwarz signature, McEvoy signature, and hippocampal volume used as AD-specific atrophy measures.</p><p dir="ltr">RESULTS: Diabetes was not associated with brain atrophy cross-sectionally or longitudinally. Instead, an interactive effect between diabetes and WMHs on brain atrophy was observed. In Harmonization, this interaction was significant in cross-sectional analyses, affecting cortical gray matter and the frontal lobe. No interactive effect was found for AD-specific atrophy, and the observed interactive effect remained significant after adjusting for plasma pTau181. Cortical gray matter mediated the effect of diabetes on cognition at higher WMHs burden. These results were replicated in ADNI, where diabetes and WMHs interacted to accelerate brain atrophy over time.</p><p dir="ltr">CONCLUSIONS: Our study demonstrated diabetes and WMHs synergistically contribute to brain atrophy independent of AD, suggesting diabetes-associated cognitive impairment is primarily driven by cerebrovascular disease rather than Alzheimer pathology.</p><p><br></p>