Enrichment of patients with concomitant LATE on the Alzheimer’s disease continuum using hippocampal volume

Introduction Clinical overlap between Alzheimer’s disease (AD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), combined with 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 ADNI participants with T1-MRI and amyloid- and tau-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 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.