Enrichment of patients with concomitant limbic-predominant age-related TDP-43 encephalopathy (LATE) on the Alzheimer's disease continuum using hippocampal volume.

INTRODUCTION

Clinical overlap between Alzheimer's disease (AD) and limbic-predominant age-related transactive response DNA binding protein 43 (TDP-43) encephalopathy (LATE), combined with the absence of validated in vivo biomarkers, complicates identification of mixed AD/LATE pathology. We labeled individuals along the AD continuum with suspected concomitant LATE using the lower quartile hippocampal volume (HV) cut-off and examined associated atrophy and cognitive profiles.

METHODS

We studied cognitively impaired (CI) Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with T1-magnetic resonance imaging (MRI) and amyloid- and tau-positron emission tomography (PET). Participants were classified into suspected (s) AD+sLATE-, AD-sLATE+, or AD+sLATE+ based on amyloid status and HV quartiles. Medial temporal lobe (MTL) and whole-brain atrophy patterns and cognitive profiles were compared cross-sectionally and longitudinally. Classification was validated in an autopsy cohort.

RESULTS

AD+sLATE+ showed greater anterior hippocampal (AH) and amygdala atrophy than AD+sLATE-. AD-sLATE+ and AD+sLATE+ showed greater anterior MTL atrophy and worse memory and language performance. AD+sLATE+ also exhibited faster cognitive decline.

DISCUSSION: A simple HV quartile cut-off may help identify mixed AD/LATE pathology and support clinical trial enrichment.

HIGHLIGHTS: Quartiles of HVs stratify CI individuals. Approach distinguishes suspected AD+sLATE-, AD-sLATE+, and AD+sLATE+ subgroups. The method is simple, scalable, and requires no complex modeling or biomarker panels. It enables practical identification of mixed pathology in clinical settings. It supports trial enrichment by excluding or targeting mixed pathology cases.