White Matter Hyperintensities Moderate the Association Between Diabetes and Non-AD Brain Atrophy

White matter hyperintensities (WMHs) moderate the association between diabetes and cognition, but the underlying mechanisms remain unknown. This study investigated the interaction effect between diabetes and WMHs on brain atrophy, the resulting atrophy patterns, and whether brain atrophy mediates the effect of diabetes on cognition.

This study included individuals without dementia from two independent memory clinic-based cohorts: Harmonization (primary analysis, n = 112 case subjects with diabetes, n = 284 control subjects) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (secondary analysis, n = 64 case subjects with diabetes, n = 600 control subjects). Participants underwent longitudinal brain MRI and cognitive assessments, along with plasma pTau181 measurement as a marker of Alzheimer disease (AD). WMHs and brain atrophy were quantified, with Schwarz signature, McEvoy signature, and hippocampal volume used as AD-specific atrophy measures.

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.

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.