White matter hyperintensities and TDP-43 pathology in Alzheimer's disease.

Introduction: Greater white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) are seen with transactive response DNA-binding protein 43 (TDP-43) pathology in frontotemporal lobar degeneration (FTLD-TDP). WMH associations with TDP-43 pathology in Alzheimer's disease (AD-TDP) remain unclear.

Methods: A total of 157 participants from Mayo Clinic Rochester with autopsy-confirmed AD, known TDP-43 status, and antemortem fluid-attenuated inversion recovery (FLAIR) MRI were included. Vascular risk factors were assessed. A semi-automated WMH segmentation-quantification process produced total and regional WMH volumes. Penalized linear regression models adjusting for age at MRI analyzed TDP-43 associations (status and typing) with WMHs.

Results: TDP-43-positive status was not associated with WMH burden overall because opposite effects were seen based on AD-TDP typing. Despite similar antemortem vascular risk factors and postmortem vascular pathologies, AD-TDP type-α showed greater total and regional WMH burden (particularly in subcortical frontotemporal and basal ganglia regions) than TDP-43 negatives and AD-TDP type-β.

Discussion: AD-TDP types may have different WMH pathomechanisms, with type-α having associations more like FTLD-TDP than AD.

Highlights: In transactive response DNA-binding protein 43 (TDP-43) pathology in Alzheimer's disease (AD-TDP), TDP-43 status alone is not associated with total or regional WMH burden AD-TDP type-α shows greater total, frontotemporal subcortical, and basal ganglia white matter hyperintensities (WMHs) AD-TDP type-β shows less total and subcortical occipital WMHs AD-TDP type-α effect on WMH burden closely mimics the effects of frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) rather than AD Different relationships of AD-TDP types with WMHs suggest different pathomechanisms.